WO2015028409A1 - 6,7-dihydro-5h-benzo[7]annulene derivatives, method for the preparation thereof, pharmaceutical preparations comprising them, and the use thereof for producing medicaments - Google Patents
6,7-dihydro-5h-benzo[7]annulene derivatives, method for the preparation thereof, pharmaceutical preparations comprising them, and the use thereof for producing medicaments Download PDFInfo
- 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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- WO
- WIPO (PCT)
- Prior art keywords
- sulfonyl
- benzo
- dihydro
- annulen
- pyrrolidin
- Prior art date
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- GUWFOESQKSFAFF-UHFFFAOYSA-N n-ethylethanamine;hexane Chemical compound CCNCC.CCCCCC GUWFOESQKSFAFF-UHFFFAOYSA-N 0.000 description 1
- 125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005459 perfluorocyclohexyl group Chemical group 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229940075065 polyvinyl acetate Drugs 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- 229940075993 receptor modulator Drugs 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- UOWWJBXBBNQQIR-UHFFFAOYSA-N s-(3,3-dimethylbutyl) ethanethioate Chemical compound CC(=O)SCCC(C)(C)C UOWWJBXBBNQQIR-UHFFFAOYSA-N 0.000 description 1
- ROIXDKWBGOOXTL-UHFFFAOYSA-N s-(5,5,5-trifluoropentyl) ethanethioate Chemical compound CC(=O)SCCCCC(F)(F)F ROIXDKWBGOOXTL-UHFFFAOYSA-N 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- JZSNIRHFBXQBTF-SNVBAGLBSA-N tert-butyl (2r)-2-(3-hydroxypropyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@@H]1CCCO JZSNIRHFBXQBTF-SNVBAGLBSA-N 0.000 description 1
- UFFWDIWYUYSEES-HZPDHXFCSA-N tert-butyl (2r,4r)-4-[tert-butyl(dimethyl)silyl]oxy-2-(3-ethoxy-3-oxopropyl)pyrrolidine-1-carboxylate Chemical compound CCOC(=O)CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C UFFWDIWYUYSEES-HZPDHXFCSA-N 0.000 description 1
- JZSNIRHFBXQBTF-JTQLQIEISA-N tert-butyl (2s)-2-(3-hydroxypropyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1CCCO JZSNIRHFBXQBTF-JTQLQIEISA-N 0.000 description 1
- GVCDXIVKYBPYQE-JTQLQIEISA-N tert-butyl (2s)-2-(3-methoxy-3-oxopropyl)pyrrolidine-1-carboxylate Chemical compound COC(=O)CC[C@@H]1CCCN1C(=O)OC(C)(C)C GVCDXIVKYBPYQE-JTQLQIEISA-N 0.000 description 1
- AOVSULZRHILJIN-ZETCQYMHSA-N tert-butyl (2s)-4,4-difluoro-2-formylpyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C=O AOVSULZRHILJIN-ZETCQYMHSA-N 0.000 description 1
- FUDKXBTUIHSMIL-QWHCGFSZSA-N tert-butyl (2s,4r)-4-[tert-butyl(dimethyl)silyl]oxy-2-formylpyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O FUDKXBTUIHSMIL-QWHCGFSZSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000007944 thiolates Chemical class 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000001946 ultra-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical group COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
Abstract
The invention relates to selective estrogen receptor modulators (SERMs) and to methods for the preparation thereof, to the use thereof for the treatment and/or prophylaxis of disorders, and to the use thereof for producing medicaments for the treatment and/or prophylaxis of disorders, more particularly of bleeding disorders, osteoporosis, endometriosis, myomas, hormone-dependent tumors, for hormone replacement therapy and for contraception.
Description
6,7-Dihvdro-5H-benzo[71annulen-Derivate, Verfahren zu ihrer Herstellung, pharmazeutische Präparate die diese enthalten, sowie deren Verwendung zur Herstellung von Arzneimitteln 6,7-Dihydro-5H-benzo [71annulene derivatives, processes for their preparation, pharmaceutical preparations containing them and their use for the preparation of medicaments
Die Erfindung betrifft„Selective Estrogen Receptor Modulators" (SERM) und Verfahren zu ihrer Herstellung, ihre Verwendung zur Behandlung und/oder Prophylaxe von Krankheiten sowie ihre Verwendung zur Herstellung von Arzneimitteln zur Behandlung und/oder Prophylaxe von Krankheiten, insbesondere von Blutungsbeschwerden, Osteoporose, Endometriose, Myomen, hormonabhängigen Tumoren, zur Hormonersatztherapie und zur Kontrazeption. 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.
Der Östrogen Rezeptor (estrogen receptor - ER; bzw. seine beiden Subtypen der ERa und der ERß) gehören zur Familie der nukleären Hormonrezeptoren. Der ER ist für die Vermittlung einer Vielzahl der weiblichen Geschlechts- bzw. Feritilitätsfunktionen verantwortlich (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, Möller C, Schwede W, Wintermantel T.). Die Beeinflussung der Funktion des ER durch synthetische Liganden, sei es Agonisten wie Ethinylestradiol, SERMs wie Raloxifen oder destabilisierende, reine Antagonisten wie z.B. Fulvestrant, kann zur Linderung der Symptome bzw. des Verlaufs diverser Erkrankungen führen (insbesondere von Blutungsbeschwerden, Osteoporose, Endometriose, Myomen, hormonabhängigen Tumoren, zur Hormonersatztherapie und zur Kontrazeption) (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, Möller C, Schwede W, Wintermantel T.). The estrogen receptor (ER) or its two subtypes of ERa and ERβ 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, whether agonists such as ethinylestradiol, SERMs such as raloxifene or destabilizing, pure antagonists such as e.g. Fulvestrant, 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.).
Endometriose ist eine Östrogen-abhängige Erkrankung (Serdar E. Bulun, N Engl J Med 2009;360:268-79.). Verbindungen, die die Wirkung des Hormons Östrogen an seinen Rezeptoren inhibieren und die darüber hinaus den Östrogen-Rezeptor destabilisieren sind daher geeignet zur Behandlung dieser Erkrankung, da dieser zentrale Wirkmechanismus blockiert wird. Es ist dabei wichtig, dass der Abbau des Rezeptors nicht vollständig erfolgt, da solche Verbindungen verstärkt zu hypoÖstrogenen Nebenwirkungen führen könnten (Aman U Buzdar; John FR Robertson, Ann Pharmacother 2006;40: 1572-83.). SERM sind Verbindungen, die gewebeselektiv entweder eine antiÖstrogene/ Östrogen-inhibierende bzw. eine Östrogene oder partiell Östrogene Wirkung haben, beispielsweise am Uterus die Wirkung des Östrogens inhibieren, am Knochen aber eine neutrale oder dem Östrogen ähnliche Wirkung haben. Als Beispiele für solche Verbindungen werden Tamoxifen, Raloxifen und Bazedoxifen angeführt. Zu unterscheiden sind SERM von reinen AntiÖstrogenen, die in
allen Geweben eine rein antagonistische, die Wirkung von Östrogenen inhibierende Wirkung haben und keine Östrogene oder partiell Östrogene Wirkung in einem Gewebe zeigen. 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 bazedoxifene. 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) gehören zu den AntiÖstrogenen und fuhren auf Proteinebene zu einem vollständigen Abbau des Östrogenrezeptors in den Zielzellen. Als Beispiel für ein reines Antiöstrogen bzw. SERD sei die Verbindung Fulvestrant genannt. SERD (Selective Estrogen Receptor Downregulators) belong to the antiestrogens and lead at the protein level to a complete degradation of the estrogen receptor in the target cells. As an example of a pure antiestrogen or SERD, the compound fulvestrant is called.
Neben der Inhibition der transkriptionellen Aktivität des Östrogenrezeptors (ERs) beeinflussen Antiöströgene das Expressionsniveau des ER in den Zielgeweben über eine Stimulation des proteolytischen Abbaus des ERs (siehe oben, Definition SERD). Im Vergleich mit einem ER-E2 Komplex hat der ER gebunden im Komplex mit dem reinen Antiöstrogen Fulvestrant eine substantiell kürzere Halbwertszeit. Im Gegenteil dazu wird die ER-Stabilität durch das SERM Tamoxifen verstärkt, so dass es insgesamt zu einer ER-Stablisierung kommt. In der Summe ist davon auszugehen, dass die Fähigkeit reiner AntiÖstrogene und bestimmter SERMs die ER-Degradation zu induzieren signifikant zur Gesamtwirkung der Verbindungen beiträgt. Verbindungen, die eine destabilisierende Eigenschaft zeigen, aber gleichzeitig die gewünschten gewebespezifischen agonistischen Qualitäten wie z.B. Knochenprotektion zeigen, sollten insgesamt ein überlegenes pharmakologischen Profil vorweisen, da sie ein geringeres Nebenwirkungspotential wie z.B. die Stimulation des Endometriums haben. Solche Liganden können besonders für ihren Einsatz in bestimmten Indikationsfeldern, wie z.B. dem Tamoxifen-resistenten Brustkrebs (Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen-resistant breast Cancer: implications for treatment of advanced disease. 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), der Endometriose, der Linderung von Blutungsbeschwerden, der Osteoporose oder von Uterusmyomen geeignet sein. In addition to inhibiting the transcriptional activity of the estrogen receptor (ERs), 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). Compared with an ER-E2 complex, the ER bound in complex with the pure antiestrogen fulvestrant has a substantially shorter half-life. On the contrary, the ER stability is enhanced by the Tamoxifen SERM, resulting in overall ER stabilization. In sum, it is expected that 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. Show overall superior pharmacological profile, as they have a lower side effect potential, such as have the stimulation of the endometrium. Such 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.
Bereits in der Vergangenheit wurden 6,7-Dihydro-5H-benzo[7]annulen-DerivateAlready in the past, 6,7-dihydro-5H-benzo [7] annulene derivatives
(Benzocycloheptene) als SERMs beschrieben. (Benzocycloheptene) described as SERMs.
WO2012/084711 beschreibt eine neue Serie von N-substituierten Azetidinderivativen die als Selective Estrogen Receptor Modulator (SERM) geeignet sind. WO2012 / 084711 describes a new series of N-substituted azetidine derivatives which are suitable as selective estrogen receptor modulator (SERM).
In der WO 2009/047343 werden Benzocycloheptene als Östrogene und in der DE 19833786 Diphenylbenzocycloheptene mit antiÖstrogenen Eigenschaften beschrieben. In WO 2009/047343 benzocycloheptenes are described as estrogens and in DE 19833786 diphenylbenzocycloheptenes with antiestrogenic properties.
Über weitere selektive Estrogen Receptor Modulatoren basierend auf einer Benzocyclohepten- Struktur wird in der WO 2003/016270 berichtet.
Weitere Diphenylbenzocyclohepten-Derivate mit antiÖstrogenen Eigenschaften werden in McCague, Raymond; Leclercq, Guy; Jordan, V. Craig, Journal of Medicinal Chemistry (1988), 31(7), 1285-90 sowie in Murphy, Catherine S.; Parker, Christopher J.; McCague, Raymond; Jordan, V. Craig, Molecular Pharmacology (1991), 39(3), 421-8 beschrieben. Further selective estrogen receptor modulators based on a benzocycloheptene structure are reported in WO 2003/016270. Other diphenylbenzocycloheptene derivatives having anti-estrogenic properties are disclosed in McCague, Raymond; Leclercq, Guy; Jordan, V. Craig, Journal of Medicinal Chemistry (1988), 31 (7), 1285-90 and Murphy, Catherine S .; Parker, Christopher J .; McCague, Raymond; Jordan, V. Craig, Molecular Pharmacology (1991), 39 (3), 421-8.
In der WO 2011/161101 und in der WO 2013/083568 werden 6,7-Dihydro-5H- benzo[7]annulen-Derivate beschrieben, die an der 8-Position mit einem aromatischen Substituenten verknüpft sind und die an Position 9 eine aliphatische Kette aufweisen, die mit einer acyclischen Aminogruppe substituiert ist. Die in WO 2011/161101 und in WO 2013/083568 beschriebenen Verbindungen wirken alsWO 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. Ein Großteil der beanspruchten 6,7-Dihydro-5H-benzo[7]annulen-Derivate zeigt dabei - im Gegensatz zu bisher bekannten SERMs wie Tamoxifen, Raloxifene oder ähnlichen Verbindungen - zusätzlich eine destabilisierende Wirkung auf den ERa-Gehalt (verbleibender relativer ERa-Gehalt von kleiner oder gleich 30%). Über den gesamten Strukturbereich zeigen diese Verbindungen eine hohe antiÖstrogene Wirkung in vitro. 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%). Over the entire structural region, these compounds show high antiestrogenic activity in vitro.
Es wurden nun weitere 6,7-Dihydro-5H-benzo[7]annulen-Derivate gefunden, die im Vergleich zu den im oben beschriebenen Stand der Technik (WO 2011/161101 und WO 2013/083568) beschriebenen 6,7-Dihydro-5H-benzo[7]annulenen statt einer mit einer acyclischen Aminogruppe substituierten aliphatischen Alkylkette an Position 9 eine aliphatische Alkylkette aufweisen, die mit einem Stickstoffatom substituiert ist, das in eine Heterocycloalkyl-Gruppe eingebunden ist. Further 6,7-dihydro-5H-benzo [7] annulene derivatives have now been found which, in comparison with the 6,7-dihydro-5H-benzo [7] benzene derivatives described in the above-described prior art (WO 2011/161101 and WO 2013/083568). 5H-benzo [7] annulenes, instead of an acyclic-amino-substituted aliphatic alkyl chain at position 9, have an aliphatic alkyl chain substituted with a nitrogen atom incorporated into a heterocycloalkyl group.
Überraschenderweise sind die beanspruchten Verbindungen ebenfalls als SERM aktiv. Die beanspruchten Verbindungen weisen ebenso wie die in WO 2011/161101 und WO 2013/083568 beschriebenen 6,7-Dihydro-5H-benzo[7]annulen-Derivate eine destabilisierende Wirkung auf den ERa-Gehalt auf (verbleibender relativer ERa-Gehalt von kleiner oder gleich 30%) und zeigen eine hohe antiÖstrogene Wirkung in vitro (ICso-Werte kleiner als 0.6 micromolar für die Inhibition der Östradiol- induzierten Luciferaseaktivität). Surprisingly, 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 ERα content (remaining relative ERα 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).
Aufgabe der vorliegenden Erfindung ist es daher, weitere als SERM wirkende Verbindungen zur Verfügung zu stellen. Die neuen als SERM aktiven Verbindungen weisen im Vergleich zu den aus dem Stand der Technik bekannten Verbindungen eine vergleichbar gut destabilisierende Wirkung auf den ERa-Gehalt bei gleichzeitig hoher antiöstrogener Wirkung in vitro auf.
Gegenstand der vorliegenden Erfindung sind Verbindungen der Formel (I): It is therefore an object of the present invention to provide further compounds which act as SERM. Compared to the compounds known from the prior art, the new compounds active as SERM have a comparatively good destabilizing effect on the ERα content with simultaneously high anti-estrogenic activity in vitro. The present invention relates to compounds of the formula (I):
(i) (I)
worin wherein
R1, R2, R3 und R4 unabhängig voneinander für Wasserstoff, Ci-C6-Alkyl, Ci-C6-Alkoxy, Halogen- Ci-Cö-alkyl, Hydroxy-Ci-Cö-alkyl, Halogen-Ci-C6-alkoxy, Hydroxy-C2-C6- alkoxy, Halogen, Hydroxy, Nitril, Ci-C4-Alkyl-C(=0)- oder Ci-C4-Alkyl-S02- stehen; 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, halogeno-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkyl alkoxy, hydroxy-C 2 -C 6 -alkoxy, halogen, hydroxy, nitrile, C 1 -C 4 -alkyl-C (= O) - or C 1 -C 4 -alkyl-SO 2 -;
R5, R6und R7 unabhängig voneinander für Wasserstoff, Halogen, Ci-C i-Alkyl oder Nitril stehen; R 5, R 6 and R 7 independently represent hydrogen, halogen, Ci-Ci alkyl or nitrile;
R8, R9 für Wasserstoff, Hydroxy oder Fluor stehen, jedoch sind R8 und R9 nicht gleichzeitig Hydroxy oder nicht gleichzeitig Hydroxy und Fluor; 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 für -O-CH2-, -CH2- oder -CH2-CH2- steht; Xi is -O-CH2-, -CH2- or -CH2-CH2-;
X2 für Stickstoff oder -CH- steht; X 2 is nitrogen or -CH-;
Y für Ci-C/i-Alkyl, per- oder teilfluoriertes Ci-C/i-Alkyl oder per- oder teilfluoriertes Cs-Cs-Cycloalkyl steht; Y is Ci-C / i-alkyl, per- or partially fluorinated Ci-C / i-alkyl or per- or partially fluorinated Cs-Cs-cycloalkyl;
Q für -SO2-, -SO-, -S- oder -O- steht; Q is -SO 2 -, -SO-, -S- or -O-;
m für 4, 5, 6 oder 7 steht; m is 4, 5, 6 or 7;
q für 1 , 2, 3 oder 4 steht; q is 1, 2, 3 or 4;
t für 0, 1, 2, 3 oder 4 steht t is 0, 1, 2, 3 or 4
und ihre Salze, Solvate oder Solvate der Salze, einschließlich aller Kristallmodifikationen. and their salts, solvates or solvates of the salts, including all crystal modifications.
Erfindungsgemäße Verbindungen sind die Verbindungen der Formel (I) und deren Salze, Solvate und Solvate der Salze sowie die von Formel (I) umfassten, nachfolgend als Ausführungsbeispiele genannten Verbindungen und deren Salze, Solvate und Solvate der Salze,
soweit es sich bei den von Formel (I) umfassten, nachfolgend genannten Verbindungen nicht bereits um Salze, Solvate und Solvate der Salze handelt einschließlich aller Kristallmodifikationen. 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.
Die erfindungsgemäßen Verbindungen können in Abhängigkeit von ihrer Struktur in stereoisomeren Formen (Enantiomere, Diastereomere) existieren. Die Erfindung umfasst deshalb die En- antiomeren und/oder Diastereomeren und ihre jeweiligen Mischungen. Aus solchen Mischungen von Enantiomeren und/oder Diastereomeren lassen sich die stereoisomer einheitlichen Bestandteile in dem Fachmann bekannter Weise isolieren. Depending on their structure, 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.
Sofern die erfindungsgemäßen Verbindungen in tautomeren Formen vorkommen können, umfasst die vorliegenden Erfindung sämtliche tautomere Formen. Als Salze sind im Rahmen der vorliegenden Erfindung physiologisch unbedenkliche Salze der erfindungsgemäßen Verbindungen bevorzugt. Umfasst sind aber auch Salze, die für pharmazeutische Anwendungen selbst nicht geeignet sind aber beispielsweise für die Isolierung oder Reinigung der erfindungsgemäßen Verbindungen verwendet werden können. 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.
Physiologisch unbedenkliche Salze der erfindungsgemäßen Verbindungen umfassen Säure- additionssalze von Mineralsäuren, Carbonsäuren und Sulfonsäuren, z.B. Salze der Chlorwasserstoffsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Methansulfonsäure, Ethansulfonsäure, Toluolsulfonsäure, Benzolsulfonsäure, Essigsäure, Ameisensäure, Trifluoressigsäure, Propionsäure, Milchsäure, Weinsäure, Äpfelsäure, Zitronensäure, Fumarsäure, Maleinsäure und Benzoesäure. 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.
Physiologisch unbedenkliche Salze der erfindungsgemäßen Verbindungen umfassen auch Salze üblicher Basen, wie beispielhaft und vorzugsweise Alkalimetallsalze (z.B. Natrium- und Kaliumsalze), Erdalkalisalze (z.B. Calcium- und Magnesiumsalze) und Ammoniumsalze, abgeleitet von Ammoniak oder organischen Aminen mit 1 bis 16 C-Atomen, wie beispielhaft und vorzugsweise Ethylamin, Diethylamin, Triethylamin, Ethyldiisopropylamin, Monoethanolamin, Diethanolamin, Triethanolamin, Dicyclohexylamin, Dimethylaminoethanol, Prokain, Dibenzylamin, N-Methylmorpholin, Arginin, Lysin, Ethylendiamin und N-Methylpiperidin. 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.
Als Solvate werden im Rahmen der Erfindung solche Formen der erfindungsgemäßen Verbindungen bezeichnet, welche in festem oder flüssigem Zustand durch Koordination mit Lösungsmittelmolekülen einen Komplex bilden. Hydrate sind eine spezielle Form der Solvate, bei denen die Koordination mit Wasser erfolgt. Als Solvate sind im Rahmen der vorliegenden Erfindung Hydrate bevorzugt. 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.
Außerdem umfasst die vorliegende Erfindung auch Prodrugs der erfindungsgemäßen Verbindungen. Der Begriff „Prodrugs" umfaßt Verbindungen, welche selbst biologisch aktiv oder
inaktiv sein können, jedoch während ihrer Verweilzeit im Körper zu erfindungsgemäßen Verbindungen umgesetzt werden (beispielsweise metabolisch oder hydrolytisch). In addition, the present invention also includes prodrugs of the compounds of the invention. The term "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).
Im Rahmen der vorliegenden Erfindung haben die Substituenten, soweit nicht anders spezifiziert, die folgende Bedeutung: Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
Alkyl: alkyl:
Alkyl steht im Rahmen der Erfindung für einen linearen oder verzweigten Alkylrest mit der jeweils angegebenen Anzahl an Kohlenstoffatomen. Beispielhaft seien genannt: Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl, iso-Butyl, 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 und 2-Ethylbutyl. Bevorzugt sind: Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl, 2-Methylbutyl und Neopentyl. In the context of the invention, 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-Ci-C6-alkyl: Hydroxy-Ci-C6-alkyl:
Hydroxy-Ci-C6-alkyl steht im Rahmen der Erfindung für einen linearen oder verzweigten Alkylrest mit 1 bis 6 Kohlenstoffatomen, der in der Kette oder endständig eine Hydroxy-Gruppe als Substituenten trägt. Beispielhaft seien genannt: Hydroxymethyl, 1 -Hydroxyethyl, 2-Hydroxy ethyl, 1 -Hydroxy-l -methylethyl, l,l-Dimethyl-2-hydroxy ethyl, 1 -Hydroxypropyl, 2-Hydroxypropyl, 3-Hydroxypropyl, 1 -Hydroxy-2- methylpropyl, 2-Hydroxy- 1 -methylpropyl, 2-Hydroxy-2 -methylpropyl, 1 -Hydroxybutyl, 2-Hydroxybutyl, 3- Hydroxybutyl und 4-Hydroxybutyl. Bevorzugt sind: Hydroxymethyl, 2-Hydroxyethyl und 3-Hydroxypropyl. 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-Ci-C6-alkyl: Halogen-Ci-C6 alkyl:
Halogen-Ci-C6-alkyl steht im Rahmen der Erfindung für einen linearen oder verzweigten Alkylrest mit 1 bis 6 Kohlenstoffatomen, der in der Kette oder endständig ein oder mehrere Halogenatome als Substituenten trägt. Bevorzugt ist Fluor als Halogenatom. Beispielhaft seien genannt: -CF3, -CHF2, -CH2F, -CF2CF3, oder -CH2CF3. 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: alkoxy:
Alkoxy steht im Rahmen der Erfindung für einen linearen oder verzweigten Alkoxyrest mit 1 bis 6 Kohlenstoffatomen. Beispielhaft seien genannt: Methoxy, Ethoxy, n-Propoxy, Isopropoxy, 1-Methylpropoxy, n-Butoxy, iso-Butoxy, tert-Butoxy, n-Pentoxy, iso-Pentoxy, 1-Ethylpropoxy, 1-Methylbutoxy, 2-Methylbutoxy, 3-Methylbutoxy und n-Hexoxy. Bevorzugt ist ein linearer oder verzweigter Alkoxyrest mit 1 bis 4 Kohlenstoffatomen. Beispielhaft seien genannt: Methoxy, Ethoxy, n-Propoxy, 1-Methylpropoxy, n-Butoxy und iso-Butoxy. Bevorzugt ist Methoxy. 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:
Hydroxy-C2-C6-alkoxy steht im Rahmen der Erfindung für einen linearen oder verzweigten Alkoxyrest mit 2 bis 6 Kohlenstoffatomen, der in der Kette oder endständig eine Hydroxy-Gruppe als Substituenten trägt. Beispielhaft seien genannt: 2-Hydroxyethoxy und 2-Hydroxypropoxy. Bevorzugt ist 2-Hydroxy- ethoxy. Hydroxy-C2-C6-alkoxy: Hydroxy-C 2 -C 6 -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-Ci-C6-alkoxy: Halogen-Ci-C6-alkoxy:
Halogen-Ci-C6-alkoxy steht im Rahmen der Erfindung für einen linearen oder verzweigten Alkoxyrest mit 1 bis 6 Kohlenstoffatomen, der in der Kette oder endständig ein oder mehrere Halogenatome als Substituenten trägt. Bevorzugt ist Fluor als Halogenatom. Beispielhaft seien genannt: -OCF3, -OCHF2, -OCH2F, -OCF2CF3, oder -OCH2CF3 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: cycloalkyl:
Cycloalkyl steht für einen mono- oder bicychschen, gesättigten, monovalenten Kohlenwasserstoffrest mit in der Regel 3 bis 10, bevorzugt 3 bis 8, und besonders bevorzugt 3 bis 7 Kohlenstoffatomen. 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.
Beispielhaft für monocyclische Cycloalkylreste seien genannt: Examples of monocyclic cycloalkyl radicals are:
Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl und Cycloheptyl. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Besonders bevorzugt ist ein Cyclopropyl-, Cylopentyl- oder ein Cyclohexylrest. Particularly preferred is a cyclopropyl, cylopentyl or cyclohexyl radical.
Beispielhaft für bicyclische Cycloalkylreste seien genannt: Examples of bicyclic cycloalkyl radicals are:
Perhydropentalenyl, Decalinyl. Perhydropentalenyl, decalinyl.
Halogen: Halogen:
Halogen steht für Fluor, Chlor, Brom und Iod. Bevorzugt sind Fluor und Chlor. Besonders bevorzugt ist Fluor. Perfluoriertes Ci-C4-Alkyl: Halogen is fluorine, chlorine, bromine and iodine. Preference is given to fluorine and chlorine. Particularly preferred is fluorine. Perfluorinated C 1 -C 4 -alkyl:
Perfluoriertes Ci-C i-Alkyl steht für einen vollständig fluorierten geradkettigen oder verzweigten Alkylrest mit in der Regel 1 bis 4, bevorzugt 1 bis 3 Kohlenstoffatomen, beispielhaft und vorzugsweise für Trifluormethyl, Pentafluorethyl, Heptafluorpropyl und Heptafluorisopropyl. Teilfluoriertes Ci-C4-Alkyl: Perfluorinated 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 4 -alkyl:
Teilfluoriertes Ci-C/i-Alkyl steht für einen teilweise fluorierten geradkettigen oder verzweigten Alkylrest mit in der Regel 1 bis 4 Kohlenstoffatomen - ausgewählt, aber nicht beschränkt auf 1 ,2,2,2- Tetrafluorethyl, 1 , 1 ,2,2-Tetrafluorethyl, 2,2,2-Trifluor-l -(trifluormethyl)ethyl, 1 , 1 ,3,3,3- Pentafluorpropyl, 1 , 1 , 2,3,3, 3-Hexafluorpropyl, 1 ,1 ,2,2,3,3,4,4-Octafluorbutyl, 1 , 2,2,3,3, 3-Hexafluor- 1 -methylpropyl, 1 , 1 ,3,3, 3-Pentafluor-2-(trifluormethyl)propyl, 2,2,2-Trifluor-l -methyl-l - 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 -
(trifluormethyl)ethyl, 2-Fluor-l , l -bis(fluormethyl)ethyl. Bevorzugt sind 1 ,2,2,2-Tetrafluorethyl,
1,1,3,3,3-Pentafluorpropyl, 1, 1,2,3,3, 3-Hexafluorpropyl und 2,2,2-Trifluor-l-(trifluormethyl)ethyl. Besonders bevorzugt sind 2,2,2-Trifluor-l-(trifluormethyl)ethyl und 1,1,3,3,3-Pentafluorpropyl. (trifluoromethyl) ethyl, 2-fluoro-1, l-bis (fluoromethyl) ethyl. Preference is given to 1, 2,2,2-tetrafluoroethyl, 1,1,3,3,3-pentafluoropropyl, 1, 1,2,3,3, 3-hexafluoropropyl and 2,2,2-trifluoro-1- (trifluoromethyl) ethyl. Particularly preferred are 2,2,2-trifluoro-1- (trifluoromethyl) ethyl and 1,1,3,3,3-pentafluoropropyl.
Perfluoriertes C3-C8-Cycloalkyl: Perfluorinated C3-C8-cycloalkyl:
Perfluoriertes Cs-Cs-Cycloalkyl steht für eine vollständig fluorierte Cycloalkylgruppe mit in der Regel 3 - 8, bevorzugt 5 - 6 Kohlenstoffatomen, beispielhaft und vorzugsweise für Perfluorcyclopentyl und Perfluorcyclohexyl. 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.
Teilfluoriertes C3-C8-Cycloalkyl: Partially fluorinated C3-C8-cycloalkyl:
Teilfluoriertes C3-C8-Cycloalkyl steht für eine teilweise fluorierte Cycloalkylgruppe mit in der Regel 3 bis 8 Kohlenstoffatomen - ausgewählt, aber nicht beschränkt auf: 2,2-Difluorcycloheptyl,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,
2- Fluorcycloheptyl, 3,3-Difluorcycloheptyl, 3-Fluorcycloheptyl, 4,4-Difluorcycloheptyl, 4-Fluorcycloheptyl, 4,4-Difluorcyclohexyl, 4-Fluorcyclohexyl, 3,3-Difluorcyclohexyl,2-fluorocycloheptyl, 3,3-difluorocycloheptyl, 3-fluorocycloheptyl, 4,4-difluorocycloheptyl, 4-fluorocycloheptyl, 4,4-difluorocyclohexyl, 4-fluorocyclohexyl, 3,3-difluorocyclohexyl,
3- Fluorcyclohexyl, 2,2-Difluorcyclohexyl, 2-Difluorcyclohexyl, 3,3-Difluorcyclopentyl, 3-Fluorcyclopentyl, 2,2-Difluorcyclopentyl, 2-Fluorcyclopentyl, 3,3-Difluorcyclobutyl,3-fluorocyclohexyl, 2,2-difluorocyclohexyl, 2-difluorocyclohexyl, 3,3-difluorocyclopentyl, 3-fluorocyclopentyl, 2,2-difluorocyclopentyl, 2-fluorocyclopentyl, 3,3-difluorocyclobutyl,
3-Fluorcyclobutyl, 2,2-Difluorcyclobutyl, 2-Fluorcyclobutyl, 2,2-Difluorcyclopropyl, 2-Fluorcyclopropyl. Bevorzugt sind 4,4-Difluorcyclohexyl, 4-Fluorcyclohexyl, 3,3-Difluorcyclohexyl,3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 2-fluorocyclobutyl, 2,2-difluorocyclopropyl, 2-fluorocyclopropyl. Preference is given to 4,4-difluorocyclohexyl, 4-fluorocyclohexyl, 3,3-difluorocyclohexyl,
3.3- Difluorcyclopentyl, 3,3-Difluorcyclobutyl und 2,2-Difluorcyclopropyl. Besonders bevorzugt ist3.3- difluorocyclopentyl, 3,3-difluorocyclobutyl and 2,2-difluorocyclopropyl. Particularly preferred
4.4- Difluorcyclohexyl. 4.4- difluorocyclohexyl.
Heterocycloalkyl: heterocycloalkyl:
Heterocycloalkyl steht im Rahmen der Erfindung für einen gesättigten Heterocyclus mit insgesamt 5 oder 6 Ringatomen, der ein bis drei Ring-Heteroatome aus der Reihe N oder O enthält. Entsprechend der allgemeinen Formel (I) ist die Sequenz -X1-X2-N- in eine Ringstruktur eingefügt, die eine Heterocycloalkyl-Gruppe darstellt. Beispielhaft seien genannt: Pyrrolidin, Tetrahydro-lH-pyrazol, Morpholin, 1,3,4-Oxadiazinan, Piperidin und Hexahydropyridazin. Bevorzugt sind: Pyrrolidin, Piperidin und Morpholin. 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. According to general formula (I), 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.
Wenn Reste in den erfindungsgemäßen Verbindungen substituiert sind, können die Reste, soweit nicht anders spezifiziert, ein- oder mehrfach substituiert sein. Im Rahmen der vorliegenden Erfindung gilt, dass für alle Reste, die mehrfach auftreten, deren Bedeutung unabhängig voneinander ist. Eine Substitution mit ein, zwei oder drei gleichen oder verschiedenen Substituenten ist bevorzugt. Ganz besonders bevorzugt ist die Substitution mit einem Substituenten. If 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.
Im Sinne der vorliegenden Erfindung umfasst der Begriff "Behandlung" oder "behandeln" ein Hemmen, Verzögern, Aufhalten, Lindern, Abschwächen, Einschränken, Verringern, Unter- drücken, Zurückdrängen oder Heilen einer Krank-'heit, eines Leidens, einer Erkrankung, einer Verletzung oder einer gesund-'heit-'lichen Störung, der Entfaltung, des Verlaufs oder des Fortschreitens solcher
Zustände und/oder der Symptome solcher Zustände. Der Begriff "Therapie" wird hierbei als syno^nym mit dem Be^griff "Behandlung" verstanden. For the purposes of the present invention, the term "treatment" or "treating" 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. The term "therapy" is hereby understood to be synonymous with the term "treatment".
Die Begriffe "Prävention", "Prophylaxe" oder "Vorbeugung" werden im Rahmen der vorliegenden Erfin-'dung synonym verwendet und bezeichnen das Vermeiden oder Vermindern des Risikos, eine Krank-'heit, ein Leiden, eine Erkrankung, eine Verletzung oder eine gesundheitliche Störung, eine Entfaltung oder ein Fort-'schrei-'ten solcher Zustände und/oder die Symptome solcher Zustände zu bekom-men, zu erfahren, zu erleiden oder zu haben. The terms "prevention", "prophylaxis" or "prevention" are used interchangeably in the context of the present invention and denote 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.
Die Behandlung oder die Prävention einer Krankheit, eines Leidens, einer Erkrankung, einer Ver-'letzung oder einer gesundheitlichen Störung können teilweise oder vollständig erfolgen. Ein weiterer Gegenstand der Erfindung bezieht sich auf Verbindungen der Formel (I), worin The treatment or prevention of a disease, a disease, a disease, a displacement or a health disorder can be partial or complete. Another object of the invention relates to compounds of formula (I) wherein
R1, R2, R3 und R4 unabhängig voneinander für Wasserstoff, Ci-C6-Alkyl, Ci-C6-Alkoxy, Halogen-Ci-C6-alkyl, Hydroxy-Ci-C6-alkyl, Halogen-Ci-C6-alkoxy, Hydroxy-C2-C6-alkoxy, Halogen, Hydroxy, Nitril, Ci-C4-Alkyl-C(=0)- oder Ci-C4-Alkyl-S02- stehen. 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, halogeno-C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkyl alkoxy, hydroxy-C 2 -C 6 -alkoxy, halogen, hydroxyl, nitrile, C 1 -C 4 -alkyl-C (= O) - or C 1 -C 4 -alkyl-SO 2 -.
Ein weiterer Gegenstand der Erfindung bezieht sich auf Verbindungen der Formel (I), worin R5, R6 und R7 unabhängig voneinander für Wasserstoff, Halogen, Ci-C3-Alkyl oder Nitril stehen. 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.
Ein weiterer Gegenstand der Erfindung bezieht sich auf Verbindungen der Formel (I), worin X2 für -CH- steht. Another object of the invention relates to compounds of formula (I) wherein X 2 is -CH-.
Ein weiterer Gegenstand der Erfindung bezieht sich auf Verbindungen der Formel (I), worin Q für -SO2-, -SO- oder -S- steht. Another object of the invention relates to compounds of formula (I) wherein Q is -SO 2 -, -SO- or -S-.
Ein weiterer Gegenstand der Erfindung bezieht sich auf Verbindungen der Formel (I), worin m für 5 oder 6 steht. Another object of the invention relates to compounds of formula (I) wherein m is 5 or 6.
Ein weiterer Gegenstand der Erfindung bezieht sich auf Verbindungen der Formel (I), worin Another object of the invention relates to compounds of formula (I) wherein
R1, R2, R3 und R4 unabhängig voneinander für Wasserstoff, Ci-C i-Alkyl, Ci-C i-Alkoxy, Halogen, Hydroxy, Nitril oder Ci-C3-Alkyl-SC>2- stehen. 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-.
Ein weiterer Gegenstand der Erfindung bezieht sich auf Verbindungen der Formel (I), worin für -SO2- oder -S- steht.
Ein weiterer Gegenstand der Erfindung bezieht sich auf Verbindungen der Formel (I), worin t für 1 , 2, 3 oder 4 steht. 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.
Ein weiterer Gegenstand der Erfindung bezieht sich auf Verbindungen der Formel (I), worin R1, R2, R3 und R4 unabhängig voneinander für Wasserstoff, Halogen oder Hydroxy stehen. Ein weiterer Gegenstand der Erfindung bezieht sich auf Verbindungen der Formel (I), worin R5, R6 und R7 unabhängig voneinander für Wasserstoff oder Halogen stehen. Another object of the invention relates to compounds of formula (I) wherein R 1 , R 2 , R 3 and R 4 are independently hydrogen, halogen 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 halogen.
Ein weiterer Gegenstand der Erfindung bezieht sich auf Verbindungen der Formel (I), worin Xi für -O-CH2- oder -CH2- steht. Another object of the invention relates to compounds of formula (I) wherein Xi is -O-CH 2 - or -CH 2 -.
Ein weiterer Gegenstand der Erfindung bezieht sich auf Verbindungen der Formel (I), worin Another object of the invention relates to compounds of formula (I) wherein
Y für -Ci-C i-Alkyl oder per- oder teilfluoriertes -Ci-C i-Alkyl steht. Y is -Ci-C i-alkyl or per- or partially fluorinated -Ci-C i-alkyl.
Ein weiterer Gegenstand der Erfindung bezieht sich auf Verbindungen der Formel (I), worin Q für -SO2- steht. Another object of the invention relates to compounds of formula (I) wherein Q is -SO 2 -.
Ein weiterer Gegenstand der Erfindung bezieht sich auf Verbindungen der Formel (I), worin q für 2, 3 oder 4 steht. Another object of the invention relates to compounds of formula (I) wherein q is 2, 3 or 4.
Ein weiterer Gegenstand der Erfindung bezieht sich auf Verbindungen der Formel (I), worin t für 2, 3 oder 4 steht. Another object of the invention relates to compounds of formula (I) wherein t is 2, 3 or 4.
Ein weiterer Gegenstand der Erfindung bezieht sich auf Verbindungen der Formel (I), worin R1, R2, R3 und R4 unabhängig voneinander für Wasserstoff, Fluor oder Hydroxy stehen. Ein weiterer Gegenstand der Erfindung bezieht sich auf Verbindungen der Formel (I), worin R5, R6 und R7 unabhängig voneinander für Wasserstoff oder Fluor stehen. 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.
Ein weiterer Gegenstand der Erfindung bezieht sich auf Verbindungen der Formel (I), worinAnother object of the invention relates to compounds of formula (I) wherein
Y für eine tert-Butylgruppe, CF3 oder C2F5 steht.
Die in den jeweiligen Kombinationen bzw. bevorzugten Kombinationen von Resten im einzelnen angegebenen Restedefinitionen werden unabhängig von den jeweiligen angegebenen Kombinationen der Reste beliebig auch durch Restedefinitionen anderer Kombination ersetzt. 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.
Ganz besonders bevorzugt sind Kombinationen von zwei oder mehreren der oben genannten Vorzugsbereiche. Very particular preference is given to combinations of two or more of the abovementioned preferred ranges.
Die oben aufgeführten allgemeinen oder in Vorzugsbereichen angegebenen Restedefinitionen gelten sowohl für die Endprodukte der Formel (I) als auch entsprechend für die jeweils zur Herstellung benötigten Ausgangsstoffe bzw. Zwischenprodukte. The abovementioned general or preferred radical definitions apply both to the end products of the formula (I) and correspondingly to the starting materials or intermediates required in each case for the preparation.
Bevorzugt sind Verbindungen der Formel (I), worin R1, R2, R3 und R4 unabhängig voneinander für Wasserstoff, Ci-Cö-Alkyl, Ci-C6-Alkoxy, Halogen-Preference is given to compounds of the formula (I) in which 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
Ci-C6-alkyl, Hydroxy-Ci-Cö-alkyl, Halogen-Ci-C6-alkoxy, Hydroxy-C2-C6- alkoxy, Halogen, Hydroxy, Nitril, Ci-C4-Alkyl-C(=0)- oder Ci-C4-Alkyl-S02- stehen; C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, halogeno-C 1 -C 6 -alkoxy, hydroxy-C 2 -C 6 -alkoxy, halogen, hydroxyl, nitrile, C 1 -C 4 -alkyl-C (= O) - or - Ci-C 4 -alkyl-S0 2 - stand;
R5, R6und R7 unabhängig voneinander für Wasserstoff, Halogen, Ci-C3-Alkyl oder Nitril stehen; R 5, R 6 and R 7 are independently hydrogen, halogen, Ci-C3-alkyl or nitrile;
R8, R9 für Wasserstoff, Hydroxy oder Fluor stehen, jedoch sind R8 und R9 nicht gleichzeitig Hydroxy oder nicht gleichzeitig Hydroxy und Fluor; 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 für -O-CH2-, -CH2- oder -CH2-CH2- steht; Xi is -O-CH2-, -CH2- or -CH2-CH2-;
X2 für -CH- steht; X 2 is -CH-;
Y für -Ci-C i-Alkyl, per- oder teilfluoriertes -Ci-C i-Alkyl oder per- oder teilfluoriertes C3-C8-Cycloalkyl steht; Y is -Ci-C i-alkyl, per- or partially fluorinated -Ci-C i-alkyl or per- or partially fluorinated C3-C8-cycloalkyl;
Q für -SO2-, -SO- oder -S- steht; Q is -SO 2 -, -SO- or -S-;
m für 5 oder 6 steht; m is 5 or 6;
q für 1 , 2, 3 oder 4 steht; q is 1, 2, 3 or 4;
t für 0, 1, 2, 3 oder 4 steht t is 0, 1, 2, 3 or 4
und ihre Salze, Solvate oder Solvate der Salze, einschließlich aller Kristallmodifikationen. and their salts, solvates or solvates of the salts, including all crystal modifications.
Ebenfalls bevorzugt sind Verbindungen der Formel (I), worin Also preferred are compounds of formula (I) wherein
R1, R2, R3 und R4 unabhängig voneinander für Wasserstoff, Ci-C/i-Alkyl, Ci-C i-Alkoxy, Halogen, R 1 , R 2 , R 3 and R 4 independently of one another represent hydrogen, C 1 -C -alkyl, C 1 -C -alkoxy, halogen,
Hydroxy, Nitril oder Ci-C3-Alkyl-SC>2- stehen; Hydroxy, nitrile or C 1 -C 3 alkyl SC> 2-;
R5, R6und R7 unabhängig voneinander für Wasserstoff, Halogen, Ci-C3-Alkyl oder Nitril stehen;
R8, R9 für Wasserstoff, Hydroxy oder Fluor stehen, jedoch sind R8 und R9 nicht gleichzeitig Hydroxy oder nicht gleichzeitig Hydroxy und Fluor; 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 für -O-CH2-, -CH2- oder -CH2-CH2- steht; Xi is -O-CH2-, -CH2- or -CH2-CH2-;
X2 für -CH- steht; X 2 is -CH-;
Y für -Ci-C i-Alkyl, per- oder teilfluoriertes -Ci-C i-Alkyl oder per- oder teilfluoriertes Cs-Cs-Cycloalkyl steht; Y is -Ci-C i-alkyl, per- or partially fluorinated -Ci-C i-alkyl or per- or partially fluorinated Cs-Cs-cycloalkyl;
Q für -SO2- oder -S- steht; Q is -SO 2 - or -S-;
m für 5 oder 6 steht; m is 5 or 6;
q für 1 , 2, 3 oder 4 steht; q is 1, 2, 3 or 4;
t für 1, 2, 3 oder 4 steht t stands for 1, 2, 3 or 4
und ihre Salze, Solvate oder Solvate der Salze, einschließlich aller Kristallmodifikationen. and their salts, solvates or solvates of the salts, including all crystal modifications.
Weiterhin bevorzugt sind Verbindungen der Formel (I), worin Preference is furthermore given to compounds of the formula (I) in which
R1, R2, R3 und R4 unabhängig voneinander für Wasserstoff, Halogen oder Hydroxy stehen; R 1 , R 2 , R 3 and R 4 independently represent hydrogen, halogen or hydroxy;
R5, R6und R7 unabhängig voneinander für Wasserstoff oder Halogen stehen; R 5 , R 6 and R 7 are independently hydrogen or halogen;
R8, R9 für Wasserstoff, Hydroxy oder Fluor stehen, jedoch sind R8 und R9 nicht gleichzeitig Hydroxy oder nicht gleichzeitig Hydroxy und Fluor; 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 für -O-CH2- oder -CH2- steht; Xi is -O-CH 2 - or -CH 2 -;
X2 für -CH- steht; X 2 is -CH-;
Y für -Ci-C/i-Alkyl oder per- oder teilfluoriertes -Ci-C/i-Alkyl steht; Y is -Ci-C / i-alkyl or perfluorinated or partially fluorinated -Ci-C / i-alkyl;
Q für -SO2- steht; Q is -SO 2 -;
m für 5 oder 6 steht; m is 5 or 6;
q für 2, 3 oder 4 steht; q is 2, 3 or 4;
t für 2, 3 oder 4 steht t stands for 2, 3 or 4
und ihre Salze, Solvate oder Solvate der Salze, einschließlich aller Kristallmodifikationen. and their salts, solvates or solvates of the salts, including all crystal modifications.
Besonders bevorzugt sind Verbindungen der Formel (I), worin Particular preference is given to compounds of the formula (I) in which
R1, R2, R3 und R4 unabhängig voneinander für Wasserstoff, Fluor oder Hydroxy stehen; R 1 , R 2 , R 3 and R 4 independently represent hydrogen, fluorine or hydroxy;
R5, R6und R7 unabhängig voneinander für Wasserstoff oder Fluor stehen; R 5 , R 6 and R 7 are independently hydrogen or fluorine;
R8, R9 für Wasserstoff, Hydroxy oder Fluor stehen, jedoch sind R8 und R9 nicht gleichzeitig Hydroxy oder nicht gleichzeitig Hydroxy und Fluor;
Xi für -O-CH2- oder -CH2- steht; x2 für -CH- steht; 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 für eine tert-Butylgruppe, CF3 oder C2F5 steht; Y is a tert-butyl group, CF 3 or C 2 F 5;
Q für -SO2- steht; Q is -SO 2 -;
m für 5 oder 6 steht; q für 2, 3 oder 4 steht; m is 5 or 6; q is 2, 3 or 4;
t für 2, 3 oder 4 steht t stands for 2, 3 or 4
und ihre Salze, Solvate oder Solvate der Salze, einschließlich aller Kristallmodifikationen. and their salts, solvates or solvates of the salts, including all crystal modifications.
Ganz besonders bevorzugt sind die nachfolgenden Verbindungen der Formel (I): Very particular preference is given to the following compounds of the formula (I):
2-Fluor-8-(4-fluor-3-hydroxyphenyl)-9- {6-[(2R)-2- {4-[(4,4,5,5,5-pentafluorpentyl)- sulfonyl]butyl}pyrrolidin-l -yl]hexyl} -6,7-dihydro-5H-benzo[7]annulen-3-ol 2-fluoro-8- (4-fluoro-3-hydroxyphenyl) -9- {6 - [(2R) -2- {4 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] butyl} pyrrolidin-1-yl] hexyl} -6,7-dihydro-5H-benzo [7] annulen-3-ol
8-(3-Fluo^henyl)-9- {6-[(2S)-2- {3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l -yl]hexyl} -6,7- dihydro-5H-benzo [7] annulen-3 -ol 8- (3-Fluorohexyl) -9- {6 - [(2S) -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -6, 7-dihydro-5H-benzo [7] annulen-3-ol
8-(4-Fluo^henyl)-9- {6-[(2R)-2- {2-[(4,4,5,5,5-pentafluo^entyl)sulfonyl]ethyl}pyrrolidin-l -yl]hexyl} 6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (4-Fluoro-1-ylene) -9- {6 - [(2R) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidin-1-yl ] hexyl} 6,7-dihydro-5H-benzo [7] annulen-3-ol
8-(4-Fluo^henyl)-9- {6-[(2R)-2- {2-[(3,3,3 rifluo^ropyl)sulfonyl]ethyl}pyrrolidin-l -yl]hexyl} -6,7- dihydro-5H-benzo [7] annulen-3 -ol 8- (4-Fluoro-henyl) -9- {6 - [(2R) -2- {2 - [(3,3,3-trifluoropropyl) sulfonyl] ethyl} pyrrolidin-1-yl] hexyl} -6 , 7-dihydro-5H-benzo [7] annulen-3-ol
8-(4-Fluorphenyl)-9- {6-[(2S)-2- {2-[(4,4,4-trifluorbutyl)sulfonyl]ethyl}pyrrolidin-l -yl]hexyl} -6,7- dihydro-5H-benzo [7] annulen-3 -ol 8- (4-fluorophenyl) -9- {6 - [(2S) -2- {2 - [(4,4,4-trifluorobutyl) sulfonyl] ethyl} pyrrolidin-1-yl] hexyl} -6,7- dihydro-5H-benzo [7] annulen-3-ol
8-(4-Fluo^henyl)-9- {6-[(2R)-2- {2-[(4,4,4-trifluorbutyl)sulfonyl]ethyl}pyrrolidin-l -yl]hexyl} -6,7- dihydro-5H-benzo [7] annulen-3 -ol 8- (4-Fluoro-1Hylene) -9- {6 - [(2R) -2- {2 - [(4,4,4-trifluorobutyl) sulfonyl] ethyl} pyrrolidin-1-yl] hexyl} -6, 7-dihydro-5H-benzo [7] annulen-3-ol
8-(4-Fluo^henyl)-9- {6-[(2R)-2- {2-[(3,3,3-trifluorpropyl)sulfonyl]ethyl}pyrrolidin-l -yl]hexyl} -6,7- dihydro-5H-benzo [7] annulen-3 -ol 8- (4-Fluoro-1-yl) -9- {6 - [(2R) -2- {2 - [(3,3,3-trifluoropropyl) sulfonyl] ethyl} pyrrolidin-1-yl] hexyl} -6, 7-dihydro-5H-benzo [7] annulen-3-ol
8-(4-Fluorphenyl)-9- {6-[(2S)-2- {2-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]ethyl}pyrrolidin-l -yl]hexyl} 6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (4-fluorophenyl) -9- {6 - [(2S) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidin-1-yl] hexyl} 6 , 7-dihydro-5H-benzo [7] annulene-3-ol
2-Fluor-8-(4-fluo^henyl)-9- {6-[(2S)-2- {2-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]ethyl}pyrrolidin-l - yl]hexyl} -6,7-dihydro-5H-benzo[7]annulen-3-ol 2-Fluoro-8- (4-fluoro-4-yl) -9- {6 - [(2S) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidine-1 - yl] hexyl} -6,7-dihydro-5H-benzo [7] annulen-3-ol
2-Fluor-8-(4-fluo^henyl)-9- {6-[(2R)-2- {2-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]ethyl}pyrrolidin-l - yl]hexyl} -6,7-dihydro-5H-benzo[7]annulen-3-ol 2-Fluoro-8- (4-fluorenyl) -9- {6 - [(2R) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidine-1 - yl] hexyl} -6,7-dihydro-5H-benzo [7] annulen-3-ol
2-Fluor-8-(4-fluo^henyl)-9- {6-[(2R)-2- {2-[(4,4,4-trifluorbutyl)sulfonyl]ethyl}pyrrolidin-l -yl]hexyl} 6,7-dihydro-5H-benzo[7]annulen-3-ol
2-Fluor-8-(4-fluo henyl)-9-ί6-[(2S)-2-{2-[(4,4,4 rifluorbutyl)sulfonyl]ethyl} yrrolidin -yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol 2-Fluoro-8- (4-fluoro-5-yl) -9- {6 - [(2R) -2- {2 - [(4,4,4-trifluorobutyl) sulfonyl] ethyl} pyrrolidin-1-yl] hexyl } 6,7-dihydro-5H-benzo [7] annulen-3-ol 2-Fluoro-8- (4-fluoroheyl) -9 -6- [(2S) -2- {2 - [(4,4,4-trifluorobutyl) sulfonyl] ethyl} yrrolidin-yl] hexyl} - 6,7 dihydro-5H-benzo [7] annulene-3-ol
2-Fluor-8-(4-fluo^henyl)-9-{6-[(2S)-2-{2-[(3,3,3-trifluo^ropyl)sulfonyl]ethyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 2-Fluoro-8- (4-fluoro-1-yl) -9- {6 - [(2S) -2- {2 - [(3,3,3-trifluoropropenyl) sulfonyl] ethyl} pyrrolidin-1-yl ] hexyl} -6,7-dihydro-5H-benzo [7] annulene-3-ol
2-Fluor-8-(4-fluo^henyl)-9-{6-[(2R)-2-{2-[(3,3,3-trifluo^ropyl)sulfonyl]ethyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 2-Fluoro-8- (4-fluorenyl) -9- {6 - [(2R) -2- {2 - [(3,3,3-trifluorophenyl) sulfonyl] ethyl} pyrrolidin-1-yl ] hexyl} -6,7-dihydro-5H-benzo [7] annulene-3-ol
4-Fluor-8-(4-fluo henyl)-9-ί6-[(2R)-2-{4-[(4,4,5,5,5 entafluo entyl)sulfonyl]butyl}pyIτolidin - yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 4-Fluoro-8- (4-fluorohexyl) -9---6 - [(2R) -2- {4 - [(4,4,5,5,5-entafluoro-ethyl) -sulfonyl] -butyl} -pyrolidinyl-1-yl] -hexyl } -6,7-dihydro-5H-benzo [7] annulene-3-ol
4-Fluor-8^4-fluo^henyl)-9-{6-[(2S)-2-{3-[(4,4,5,5,5-pentafluoipentyl)sulfonyl]propyl}pynOlidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 4-fluoro-8 ^ 4-fluo ^ henyl) -9- {6 - [(2S) -2- {3 - [(4,4,5,5,5-pentafluoipentyl) sulfonyl] propyl} pyrrolidine-l- yl] hexyl} -6,7-dihydro-5H-benzo [7] annulene-3-ol
4-Fluor-8-(4-fluo^henyl)-9-{6-[(2S)-2-{3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyirolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 4-Fluoro-8- (4-fluo ^ henyl) -9- {6 - [(2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyirolidin-l - yl] hexyl} -6,7-dihydro-5H-benzo [7] annulen-3-ol
8-(3,4-Difluorphenyl)-9-{6-[(2S)-2-{3-[(4,4,5,5,5-pentafluo entyl)sulfonyl]propyl}pyrτolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (3,4-Difluorophenyl) -9- {6 - [(2S) -2- {3 - [(4,4,5,5,5-pentafluorosyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(3,4-Difluo^henyl)-9-{6-[(2S)-2-{3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (3,4-Difluoroethylenyl) -9- {6 - [(2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl ] hexyl} -6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(3,4-Difluo henyl)-9-{6-[(2R)-2-{2-[(4,4,5,5,5 entafluoφentyl)sulfonyl]ethyl}pyrrolidm-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (3,4-difluorohexyl) -9- {6 - [(2R) -2- {2 - [(4,4,5,5,5-entafluoropentyl) sulfonyl] ethyl} pyrrolidm-1-yl] hexyl } -6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(3,4-Difluo henyl)-9-{6-[(2S)-2 3-[(3,3,3 rifluo ropyl)sulfonyl]propyl}pyrrolidm-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (3,4-difluorohexyl) -9- {6 - [(2S) -2,3 - [(3,3,3-trifluoropropyl) sulfonyl] -propyl} pyrrolidm-1-yl] hexyl} -6,7 dihydro-5H-benzo [7] annulene-3-ol
8-(3,5-Difluo henyl)-9-{6-[(2R)-2-{4-[(4,4,5,5,5 entafluoφentyl)sulfonyl]butyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (3,5-difluorohexyl) -9- {6 - [(2R) -2- {4 - [(4,4,5,5,5-entafluoropentyl) sulfonyl] butyl} pyrrolidin-1-yl] hexyl } -6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(3,5-Difluo henyl)-9-{6-[(2R)-2-{2-[(4,4,5,5,5 entafluoφentyl)sulfonyl]ethyl}pyrrolidm-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (3,5-difluorohexyl) -9- {6 - [(2R) -2- {2 - [(4,4,5,5,5-entafluoropentyl) sulfonyl] ethyl} pyrrolidm-1-yl] hexyl } -6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(2,4-Difluo henyl)-9-{6-[(2S)-2-{2-[(4,4,5,5,5-pentafluoφentyl)sulfonyl]ethyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (2,4-difluorohexyl) -9- {6 - [(2S) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidin-1-yl] hexyl} -6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(2,4-Difluo^henyl)-9-{6-[(2S)-2-{2-[(4,4,4-trifl™ 8- (2,4-Difluo ^ henyl) -9- {6 - [(2S) -2- {2 - [(4,4,4-trifl ™
dihydro-5H-benzo[7]annulen-3-ol dihydro-5H-benzo [7] annulene-3-ol
8-(2,4-Difluo henyl)-9-{6-[(2S)-2-{2-[(3,3,3 rifluoφropyl)sulfollyl]ethyl}pyrrolidm-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (2,4-difluorohexyl) -9- {6 - [(2S) -2- {2 - [(3,3,3-trifluoropropyl) sulfollyl] ethyl} pyrrolidm-1-yl] hexyl} - 6, 7-dihydro-5H-benzo [7] annulene-3-ol
8-(2,4-Difluo henyl)-9-{6-[(2S)-2 3-[(3,3,3 rifluo ropyl)sulfonyl]propyl}pyrrolidm-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol
8- (3,4-Difluorphenyl)-9- {6-[(2R)-2- {4-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]butyl}pyrrolidin-l - yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (2,4-difluorohexyl) -9- {6 - [(2S) -2,3 - [(3,3,3-trifluoropropyl) sulfonyl] -propyl} pyrrolidm-1-yl] hexyl} -6,7 dihydro-5H-benzo [7] annulene-3-ol 8- (3,4-Difluorophenyl) -9- {6 - [(2R) -2- {4 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] butyl} pyrrolidin-1-yl] hexyl } -6,7-dihydro-5H-benzo [7] annulene-3-ol
9- {6-[(3R)-3- {2-[(4,4,5,5,5-Pentafluo^entyl)sulfonyl]ethyl}mo^holin-4-yl]hexyl}-8-phenyl-6,7- dihydro-5H-benzo [7] annulen-3 -ol 9- {6 - [(3R) -3- {2 - [(4,4,5,5,5-pentafluorodentyl) sulfonyl] ethyl} mam-holin-4-yl] hexyl} -8-phenyl 6,7-dihydro-5H-benzo [7] annulen-3-ol
8-(4-Fluo^henyl)-9- {6-[(2R)-2- {4-[(4,4,5,5,5-pentafluo^entyl)sulfonyl]butyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (4-Fluoro-1-yl) -9- {6 - [(2R) -2- {4 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] -butyl} -pyrrolidin-1-yl ] hexyl} -6,7-dihydro-5H-benzo [7] annulene-3-ol
8- (4-Fluo^henyl)-9- {6-[(2R,4R)-4-fluor-2- {3-[(4,4,4 rifluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (4-Fluorohexyl) -9- {6 - [(2R, 4R) -4-fluoro-2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -6,7-dihydro-5H-benzo [7] annulene-3-ol
9- [6-(4,4-Difluor-2- {3-[(4,4,4-trifluorbutyl)sulfo^ 9- [6- (4,4-Difluoro-2- {3 - [(4,4,4-trifluorobutyl) sulfo]
6,7-dihydro-5H-benzo[7]annulen-3-ol 6,7-dihydro-5H-benzo [7] annulene-3-ol
(3R,5R)-l- {6-[8-(4-Fluorphenyl)-3-hydroxy-6,7-dihydro-5H-benzo[7]annulen-9-yl]hexyl}-5- {3- [(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-3-ol (3R, 5R) -l- {6- [8- (4-fluorophenyl) -3-hydroxy-6,7-dihydro-5H-benzo [7] annulen-9-yl] hexyl} -5- {3- [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin-3-ol
8-(3-Hydroxyphenyl)-9- {6-[(2S)-2- {3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (3-Hydroxyphenyl) -9- {6 - [(2S) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(4-Fluorphenyl)-9- {6-[(2S)-2- {3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol
8- (4-fluorophenyl) -9- {6 - [(2S) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6,7-dihydro-5H-benzo [7] annulene-3-ol
yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol yl] hexyl} -6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(3,5-Difluo^henyl)-9- {6-[(2S)-2- {3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (3,5-Difluoroethylenyl) -9- {6 - [(2S) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidin-1-yl ] hexyl} -6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(3-Hydroxyphenyl)-9- {6-[(2S)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (3-Hydroxyphenyl) -9- {6 - [(2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(4-Fluorphenyl)-9- {6-[(2S)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (4-fluorophenyl) -9- {6 - [(2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(3,5-Difluo^henyl)-9- {6-[(2S)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (3,5-Difluoroethylenyl) -9- {6 - [(2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl ] hexyl} -6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(2-Fluorphenyl)-9- {6-[(2S)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (2-fluorophenyl) -9- {6 - [(2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(2-Fluorphenyl)-9- {6-[(2R)-2- {3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (2-fluorophenyl) -9- {6 - [(2R) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(4-Fluorphenyl)-9- {6-[(2R)-2- {3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(3-Fluorphenyl)-9- {6-[(2R)-2- {3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (4-fluorophenyl) -9- {6 - [(2R) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6,7-dihydro-5H-benzo [7] annulene-3-ol 8- (3-fluorophenyl) -9- {6 - [(2R) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(3-Hydroxyphenyl)-9- {6-[(2R)-2- {3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (3-Hydroxyphenyl) -9- {6 - [(2R) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(4-Fluorphenyl)-9- {6-[(2R)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (4-fluorophenyl) -9- {6 - [(2R) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(3-Fluorphenyl)-9- {6-[(2R)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (3-fluorophenyl) -9- {6 - [(2R) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(3-Fluorphenyl)-9- {6-[(2S)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (3-fluorophenyl) -9- {6 - [(2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(4-Fluo^henyl)-9- {6-[(2R)-2- {3-[(4,4,4-trifluorbu1yl)sulfonyl]propyl}pyiTolidin -yl]hexyl}-6,7- dihydro-5H-benzo [7] annulen-3 -ol 8- (4-Fluorohexyl) -9- {6 - [(2R) -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyi-tolidine-yl] hexyl} -6,7- dihydro-5H-benzo [7] annulen-3-ol
8-(3-Fluo^henyl)-9- {6-[(2R)-2- {3-[(4,4,4-trifluorbu1yl)sulfonyl]propyl}pyiTolidin-l-yl]hexyl}-6,7- dihydro-5H-benzo [7] annulen-3 -ol 8- (3-fluorenyl) -9- {6 - [(2R) -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyi-tolidin-1-yl] hexyl} -6, 7-dihydro-5H-benzo [7] annulen-3-ol
8-(4-Fluo^henyl)-9- {6-[(2R)-2- {3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl} -6,7- dihydro-5H-benzo [7] annulen-3 -ol 8- (4-fluorenyl) -9- {6 - [(2R) -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -6, 7-dihydro-5H-benzo [7] annulen-3-ol
8-(3-Fluorphenyl)-9- {6-[(2R)-2- {3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl} -6,7- dihydro-5H-benzo [7] annulen-3 -ol 8- (3-fluorophenyl) -9- {6 - [(2R) -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -6,7- dihydro-5H-benzo [7] annulen-3-ol
8-(3,5-Difluorphenyl)-9- {6-[(2R)-2- {3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (3,5-difluorophenyl) -9- {6 - [(2R) -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6, 7-dihydro-5H-benzo [7] annulene-3-ol
8-(4-Fluorphenyl)-9- {6-[(2S)-2- {3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-6,7- dihydro-5H-benzo [7] annulen-3 -ol 8- (4-fluorophenyl) -9- {6 - [(2S) -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -6,7- dihydro-5H-benzo [7] annulen-3-ol
8- (4-Fluorphenyl)-9- {6-[(2S)-2- {3-[(5,5,5-trifluorpentyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-6,7- dihydro-5H-benzo [7] annulen-3 -ol 8- (4-fluorophenyl) -9- {6 - [(2S) -2- {3 - [(5,5,5-trifluoropentyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -6,7- dihydro-5H-benzo [7] annulen-3-ol
9- {6-[(2S)-2- {3-[(3,3-Dimethylbutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-8-(4-fluorphenyl)-6,7- dihydro-5H-benzo [7] annulen-3 -ol 9- {6 - [(2S) -2- {3 - [(3,3-dimethylbutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -8- (4-fluorophenyl) -6,7-dihydro- 5H-benzo [7] annulen-3-ol
8-(4-Fluorphenyl)-9- {6-[(2S)-2- {3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl} -6,7- dihydro-5H-benzo [7] annulen-3 -ol 8- (4-fluorophenyl) -9- {6 - [(2S) -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -6,7- dihydro-5H-benzo [7] annulen-3-ol
8- (3-Fluorphenyl)-9- {6-[(2S)-2- {3-[(5,5,5-trifluorpentyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-6,7- dihydro-5H-benzo [7] annulen-3 -ol 8- (3-fluorophenyl) -9- {6 - [(2S) -2- {3 - [(5,5,5-trifluoropentyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -6,7- dihydro-5H-benzo [7] annulen-3-ol
9- {6-[(2S)-2- {3-[(3,3-Dimethylbutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-8-(3-fluorphenyl)-6,7- dihydro-5H-benzo [7] annulen-3 -ol
8-(2,4-Difluo henyl)-9- {6-[(2S)-2- {3-[(4,4,5,5,5- entafluo entyl)sulfonyl] Γo yl} yΓrolidin-l - yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 9- {6 - [(2S) -2- {3 - [(3,3-dimethylbutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -8- (3-fluorophenyl) -6,7-dihydro- 5H-benzo [7] annulen-3-ol 8- (2,4-difluorohexyl) -9- {6 - [(2S) -2- {3 - [(4,4,5,5,5-entafluoro-enyl) -sulfonyl] -o-yl} -yrolidin-1 L - yl] hexyl} -6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(2,4-Difluo^henyl)-9- {6-[(2S)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyiTolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (2,4-Difluoroethylenyl) -9- {6 - [(2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyi-tolidine-1-yl ] hexyl} -6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(2,4-Difluo^henyl)-9- {6-[(2S)-2- {3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyirolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (2,4-Difluoroethylenyl) -9- {6 - [(2S) -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyirolidin-1-yl] hexyl} - 6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(2,4-Difluorphenyl)-9- {6-[(2S)-2- {3-[(5,5,5-trifluorpentyl)sulfonyl]propyl}pyrrolidin-l -yl]hexyl} - 6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (2,4-Difluorophenyl) -9- {6 - [(2S) -2- {3 - [(5,5,5-trifluoropentyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6, 7-dihydro-5H-benzo [7] annulene-3-ol
8-(3-Fluo^henyl)-9- {6-[(2S)-2- {3-[(4,4,4-trifluorbu1yl)sulfonyl]propyl}pyiTolidin-l-yl]hexyl}-6,7- dihydro-5H-benzo [7] annulen-3 -ol 8- (3-fluorenyl) -9- {6 - [(2S) -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyi-tolidin-1-yl] hexyl} -6, 7-dihydro-5H-benzo [7] annulen-3-ol
8-(2-Fluo^henyl)-9- {6-[(2S)-2- i3-[(3,3,3-trifluo^ropyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl} -6,7- dihydro-5H-benzo [7] annulen-3 -ol 8- (2-Fluoro-1henyl) -9- {6 - [(2S) -2-i3 - [(3,3,3-trifluoropropyl) sulfonyl] -propyl} pyrrolidin-1-yl] hexyl} -6 , 7-dihydro-5H-benzo [7] annulen-3-ol
8-(2,4-Difluorphenyl)-9- {6-[(2R)-2- {3-[(4,4,5,5,5-pentafluo entyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl} -6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (2,4-Difluorophenyl) -9- {6 - [(2R) -2- {3 - [(4,4,5,5,5-pentafluorosyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -6,7-dihydro-5H-benzo [7] annulen-3-ol
8-(2,4-Difluo henyl)-9- {6-[(2R)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (2,4-difluorohexyl) -9- {6 - [(2R) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(2,4-Difluo henyl)-9- {6-[(2R)-2- {3-[(3,3,3-trifluo ropyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (2,4-difluorohexyl) -9- {6 - [(2R) -2- {3 - [(3,3,3-trifluoroproyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(2,4-Difluo henyl)-9- {6-[(2S)-2- {3-[(3,3-dimethylbutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (2,4-difluorohexyl) -9- {6 - [(2S) -2- {3 - [(3,3-dimethylbutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -6,7 dihydro-5H-benzo [7] annulene-3-ol
8-(2,4-Difluo henyl)-9- {6-[(2R)-2- {3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl} - 6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (2,4-difluorohexyl) -9- {6 - [(2R) -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6 , 7-dihydro-5H-benzo [7] annulene-3-ol
8-(3-Hydroxyphenyl)-9- {6-[(3R)-3- {2-[(4,4,5,5,5-pentafluoφentyl)sulfonyl]ethyl}moφholin-4- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (3-Hydroxyphenyl) -9- {6 - [(3R) -3- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} -morpholinyl-4-yl] hexyl} - 6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(3-Fluoφhenyl)-9- {5-[(2S)-2- {3-[(4,4,5,5,5-pentfluoφentyl)sulfonyl]propyl}pyrrolidin-l- yl]pentyl} -6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (3-Fluoro-phenyl) -9- {5 - [(2S) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] -propyl} pyrrolidin-1-yl] -pentyl} - 6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(3-Fluc^henyl)-9- {5-[(2S)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l - yl]pentyl} -6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (3-Fluchenyl) -9- {5 - [(2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl] pentyl } -6,7-dihydro-5H-benzo [7] annulen-3-ol
8-(4-Fluoφhenyl)-9- {5-[(2S)-2- {3-[(4,4,5,5,5-pentafluoφentyl)sulfonyl]propyl}pyrrolidin-l- yl]pentyl} -6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (4-Fluoro-phenyl) -9- {5 - [(2S) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] -propyl} -pyrrolidin-1-yl] pentyl} - 6,7-dihydro-5H-benzo [7] annulene-3-ol
8-(4-Fluoφhenyl)-9- {5-[(2S)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl]pentyl} -6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(4-Fluo^henyl)-9- {5-[(2R)-2- {4-[(4Λ^ 8- (4-Fluoro-phenyl) -9- {5 - [(2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] -propyl} pyrrolidin-1-yl] -pentyl} - 6,7-dihydro-5H-benzo [7] annulene-3-ol 8- (4-fluorenyl) -9- {5 - [(2R) -2- {4 - [(4Λ ^
yl]pentyl} -6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(4-Fluorphenyl)-9- {5-[(2S)-2- {3-[(4,4,4- trifluorbutyl)sulfonyl]propyl}pyrrolidin-l-yl]pentyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol
yl] pentyl} -6,7-dihydro-5H-benzo [7] annulene-3-ol 8- (4-fluorophenyl) -9- {5 - [(2S) -2- {3 - [(4,4 , 4-trifluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl] pentyl} -6,7-dihydro-5H-benzo [7] annulen-3-ol
dihydro-5H-benzo [7] annulen-3 -ol dihydro-5H-benzo [7] annulen-3-ol
9- {5-[(2S)-2- {3-[(3,3-Dimethylbutyl)sulfonyl]pro^^ 9- {5 - [(2S) -2- {3 - [(3,3-dimethylbutyl) sulfonyl] -propyl)
dihydro-5H-benzo [7] annulen-3 -ol dihydro-5H-benzo [7] annulen-3-ol
Die erfindungsgemäßen Verbindungen sind potente SERMs, die eine destabilisierende Wirkung auf den ERa-Gehalt auf (verbleibender relativer ERa-Gehalt von kleiner oder gleich 30%) und zeigen eine hohe antiÖstrogene Wirkung in vitro (IC50-Werte kleiner als 0.6 micromolar für die Inhibition der Östradiol-induzierten Luciferaseaktivität). The compounds according to the invention are potent SERMs which have a destabilizing effect on the ERα content (remaining relative ERα 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).
Gegenstand der vorliegenden Erfindung sind Verbindungen der Formel (I) zur Behandlung und/oder Prophylaxe von Krankheiten. The present invention relates to compounds of the formula (I) for the treatment and / or prophylaxis of diseases.
Die erfindungsgemäßen Verbindungen zeigen unvorhersehbar ein wertvolles pharmakologisches und pharmakokinetisches Wirkspektrum. Sie eignen sich daher zur Verwendung als Arzneimittel zur Behandlung und/oder Prophylaxe von Krankheiten bei Menschen und Tieren. Der Begriff „Behandlung" im Rahmen der vorliegenden Erfindung schließt die Prophylaxe ein. Die pharmazeutische Wirksamkeit der erfindungsgemäßen Verbindungen lässt sich durch ihre Wirkung als SERM erklären. Wie die Tabellen 1-3 zeigen, sind die erfindungsgemäßen Verbindungen potente SERMs, wodurch sie in der Lage sind, die in vitro eine hohe antiÖstrogene Wirkung zeigen und gleichzeitig den ERa destabilisieren. Die erfindungsgemäßen Verbindungen sind daher besonders zur Behandlung und/oder Prophylaxe der Endometriose geeignet. 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. The term "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 ERα. The compounds according to the invention are therefore particularly suitable for the treatment and / or prophylaxis of endometriosis.
Desweiteren eignen sich die erfindungsgemäßen Verbindungen zur Inhibition der Ovulation, zur Hemmung der Spermienreifung, zur Linderung der Symptome der Andropause und Menopause, d. h. zur männlichen und weiblichen Hormonersatztherapie, zur Prävention bzw. Prophylaxe und zur Behandlung von mit der Dysmenorrhoe einhergehenden Beschwerden, von dysfunktionellen uterinen
Blutungen, der Akne, von kardiovaskulären Erkrankungen, der Hypercholesterinämie und der Hyperlipidämie, der Artherosclerose, der Proliferation arterieller Glattmuskelzellen, des Atemnotsyndroms bei Neugeborenen, des primären pulmonaren Bluthochdrucks, der Osteoporose, des Knochenverlusts bei postmenopausalen Frauen, bei hysterektomierten Frauen oder bei Frauen, die mit LHRH Agonisten oder Antagonisten behandelt wurden, der rheumatoiden Artritis, der Alzheimerschen Krankheit, der Endometriose, von Myomen, von hormonabhängigen Tumoren, wie zum Beispiel Mamma- oder Endometriumscarcinom, der Unfruchtbarkeit, von prostatischen Erkrankungen, von benignen Erkrankungen der Brust, wie z.B. Mastopathie, von Schlaganfall, von Alzheimer und von anderen Erkrankungen des zentralen Nervensystems, die mit dem Zelltod von Neuronen einhergehen. Furthermore, 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.
Weiterer Gegenstand der vorliegenden Erfindung ist die Verwendung der erfindungsgemäßen Verbindungen zur Herstellung eines Arzneimittels zur Behandlung und/oder Prophylaxe von Erkrankungen, insbesondere der zuvor genannten Erkrankungen. Weiterer Gegenstand der vorliegenden Erfindung ist ein Verfahren zur Behandlung und/oder Prophylaxe von Erkrankungen, insbesondere der zuvor genannten Erkrankungen, unter Verwendung einer wirksamen Menge der erfindungsgemäßen Verbindungen. 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.
Weiterer Gegenstand der vorliegenden Erfindung ist die Verwendung der erfindungsgemäßen Verbindungen zur Behandlung und/oder Prophylaxe von Erkrankungen, insbesondere der zuvor genannten Erkrankungen. 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.
Weiterer Gegenstand der vorliegenden Erfindung sind die erfindungsgemäßen Verbindungen zur Verwendung in einem Verfahren zur Behandlung und/oder Pro~phylaxe der zuvor genannten Erkrankungen. 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.
Weiterer Gegenstand der vorliegenden Erfindung sind Arzneimittel, enthaltend mindestens eine erfindungsgemäße Verbindung und mindestens einen oder mehrere weitere Wirkstoffe, insbesondere zur Behandlung und/oder Prophylaxe der zuvor genannten Erkrankungen. Als geeignete Kombinationswirkstoffe seien beispielhaft und vorzugsweise genannt: Aromataseinhibitoren, 17beta HSD1 Inhibitoren, Steroid Sulfatase (STS)-Inhibitoren, LHRH-Analoga, LHRH Antagonisten, GnRH- Agonisten und -Antagonisten, Kisspeptin Rezeptor (KISSR)-Antagonisten, selektiven Androgen Rezeptor Modulatoren (SARMs), Androgenen, selektiven Progesteron Rezeptor Modulatoren (SPRMs), Gestagenen, Progesteron-Rezeptor-Antagonisten, oralen Kontrazeptiva, Östrogenen, Inhibitoren der Mitogen Aktivierten Protein (MAP) Kinasen sowie Inhibitoren der MAP Kinasen, Kinasen (Mkk3/6, Mekl/2, Erkl/2) Inhibitoren der Proteinkinasen B (PKBa/ß/γ; Akt 1/2/3), Inhibitoren der Phosphoinositid-3 -Kinasen (PI3K), Inhibitoren der Cyclin-abhängigen Kinase
(CDKl/2), Inhibitoren des Hypoxie Induzierten Signalweges (HIFI alpha Inhibitoren, Aktivatoren der Prolylhydroxylasen), Histon Deacetylase (HDAC)-Inhibitoren, Prostaglandin F Rezeptor (FP) (PTGFR)-Antagonisten und Nicht-steroidale Enzündungshemmern (NSAIDs) 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. Examples of 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 kinases B (PKBa / ß / γ; Akt 1/2/3), inhibitors of phosphoinositide-3-kinases (PI3K), inhibitors of cyclin-dependent kinase (CDK1 / 2), Hypoxia Induced Signaling Inhibitors (HIFI alpha Inhibitors, Prolyl Hydroxylase Activators), Histone Deacetylase (HDAC) Inhibitors, Prostaglandin F Receptor (FP) (PTGFR) Antagonists, and Non-steroidal Anti-Inflammatory Drugs (NSAIDs)
Die Erfindung betrifft auch pharmazeutische Zusammensetzungen, die mindestens eine Verbindung der allgemeinen Formel I (oder physiologisch verträgliche Additionssalze mit organischen und anorganischen Säuren davon) enthalten und die Verwendung dieser Verbindungen zur Herstellung von Arzneimitteln, insbesondere für die zuvor genannten Indikationen. 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.
Diese pharmazeutischen Zusammensetzungen und Arzneimittel können vorzugsweise zur oralen, aber auch zur rektalen, vaginalen, subkutanen, perkutanen, intravenösen, bukkalen, transdermalen oder intramuskulären Applikation angewendet werden. Sie enthalten neben üblichen Träger- und/oder Verdünnungsmitteln mindestens eine Verbindung der allgemeinen Formel (I) bzw. deren Salze. These pharmaceutical compositions and pharmaceutical compositions may preferably be used for oral, but also for rectal, vaginal, subcutaneous, percutaneous, intravenous, buccal, transdermal or intramuscular administration. In addition to conventional carriers and / or diluents they contain at least one compound of the general formula (I) or salts thereof.
Die Arzneimittel der Erfindung werden mit den üblichen festen oder flüssigen Trägerstoffen oder Verdünnungs^mitteln und den üblicherweise verwendeten pharma-'zeutisch-technischen Hilfsstoffen entsprechend der gewünschten Applikationsart mit einer geeigneten Dosierung in bekannter Weise hergestellt. Die bevorzugten Zubereitungen bestehen in einer Darreichungs-form, die zur oralen Applikation geeignet ist. Solche Darreichungsformen sind beispielsweise Tabletten, Filmtabletten, Dragees, Kapseln, Pillen, Pulver, Lösun-'gen oder Suspensionen oder auch Depotformen. 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. Such dosage forms are, for example, tablets, film-coated tablets, dragees, capsules, pills, powders, solutions or suspensions or else depot forms.
Selbstverständlich kommen auch parenterale Zubereitungen wie Injektionslösungen in Betracht. Weiterhin seien als Zubereitungen beispielsweise auch Supposi~torien und Mittel zur vaginalen Anwendung genannt. Of course, parenteral preparations such as injection solutions come into consideration. Furthermore are tories as preparations for example, Supposi ~ and called agents for vaginal application.
Entsprechende Tabletten können beispielsweise durch Mischen des Wirkstoffs mit bekannten Hilfsstoffen, beispielsweise inerten Verdünnungsmitteln wie Dextrose, Zucker, Sorbit, Mannit, Polyvinylpyrrolidon, Sprengmit-teln wie Maisstärke oder Alginsäure, Bindemitteln wie Stärke oder Gelatine, Gleitmitteln wie Magnesium-'stearat oder Talk und/oder Mitteln zur Erzielung eines Depoteffektes wie Carboxylpolymethylen, Carboxylmethyicellulose, Celluloseacetatphthalat oder Polyvinylace^tat, erhalten werden. Die Tabletten können auch aus mehreren Schichten bestehen. 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.
Entsprechend können Dragees durch Überziehen von analog den Tabletten hergestellten Kernen mit üblicherweise in Drageeüberzügen verwendeten Mitteln, beispielsweise Poly-'vinyl-pyrrolidon oder Schellack, Gummiarabicum, Talk, Titanoxid oder Zucker, hergestellt werden. Dabei kann auch die Drageehülle aus mehreren Schichten bestehen, wobei die oben bei den Tabletten erwähnten Hilfsstoffe verwendet werden können. 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. In this case, the dragee wrapper can also consist of several layers, wherein the auxiliaries mentioned above in the case of the tablets can be used.
Lösungen oder Suspensionen mit den erfindungsgemäßen Verbindungen der allgemeinen Formel (I) können zusätzlich geschmacksverbessernde Mittel wie Saccharin, CyclaTnat oder Zucker sowie z.B.
Aromastoffe wie Vanillin oder Orangenextrakt enthalten. Sie können außerdem Suspen-'dierhilfsstoffe wie Natriumcar-'boxymethylcellulose oder Konservierungs-stoffe wie p-Hydroxybenzoate enthalten. 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.
Die Verbindungen der allgemeinen Formel (I) enthaltende Kapseln können beispielsweise hergestellt werden, indem man die Verbindung(en) der allgemeinen Formel (I) mit einem inerten Träger wie Milchzucker oder Sorbit mischt und in Gelatinekapseln einkapselt. 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.
Geeignete Suppositorien lassen sich beispielsweise durch Vermischen mit dafür vorgesehenen Trägermitteln wie Neutralfetten oder Polyethylenglykol bzw. deren Derivaten herstellen. Suitable suppositories can be prepared, for example, by mixing with suitable carriers such as neutral fats or polyethylene glycol or derivatives thereof.
Die erfindungsgemäßen Verbindungen sind partielle Östrogendestabilisatoren und besitzen antiÖstrogene Aktivität. erfindungsgemäßen Verbindungen sind besonders zur oralen Applikation geeignet.
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.
Herstellung der erfindungsgemäßen Verbindungen Preparation of the compounds of the invention
Die Herstellung der erfindungsgemäßen Verbindungen der Formel (I) wird durch die nachfolgenden Schemata verdeutlicht. The preparation of the compounds of the formula (I) according to the invention is illustrated by the following schemes.
Einige Intermediate, die zur Herstellung der erfindungsgemäßen Verbindungen verwendet wurden, werden in der WO 03/033461, in der WO 2011/161101 und in der WO 2013/083568 beschrieben und sind in den Schemata 1 bis 3 dargestellt. Weitere Intermediate können analog dazu synthetisiert werden oder sind nachfolgend beschrieben. Some intermediates used to prepare the compounds of this invention are described in WO 03/033461, in WO 2011/161101 and in WO 2013/083568, and are shown in Schemes 1 to 3. Other intermediates can be synthesized analogously or are described below.
Die Herstellung der Intermediate 12-16 kann nach Schema 4a bzw. 4b erfolgen, wobei Xi, X2, R8, R9, t und Y wie oben beschrieben definiert sind, PG für eine Schutzgruppe und X für eine Abgangsgruppe stehen.
Schema 4a The preparation of the intermediates can 12-16 according to Scheme 4a and 4b take place, wherein Xi, X2, R 8, R 9, t and Y are defined as described above, X is PG is a protecting group and a leaving group. Scheme 4a
Schema 4b Scheme 4b
Die Startmaterialien 11 können kommerziell erworben werden (z.B. CAS 73365-02-3; CAS 69610-41-9; CAS 192320-50-6) oder nach den dem Fachmann bekannten Bedingungen synthetisiert werden (US 2011/105520 AI ; WO 2011/53706 AI ; US 2007/191361 AI ; WO 2004/76407 A2; Tetrahedron 1991, 47, 5051). PG steht für eine Schutzgruppe und kann nach den dem Fachmann geeigneten Bedingungen für die Synthese ausgewählt werden, wie es für die Syntheseführung und die abschließende Abspaltung der Schutzgruppe PG geeignet ist (Theodora W. Greene and Peter G. M.
Wuts in„Protective Groups in Organic Synthesis" 3rd. Editition, (1999), John Wiley & Sons, Inc.; New York). Hier werden Carbamatschutzgruppen bevorzugt und ganz besonders die tert- Butyloxycarbonyl-Schutzgruppe. Auch Derivate von 12 wurden schon in der Literatur beschrieben und können so nach den dem Fachmann bekannten Methoden als Startmaterialien eingesetzt werden (Org. Lett. 2007, 9, 5283; WO 2011/111875 AI ; Tetrahedron Lett. 1997, 38, 3609; Org. Lett. 2012, 12, 2222; Bioorg. Med. Chem. 1997, 7, 1665; WO 2011/111875 AI). Intermediate 12 können nach den dem Fachmann bekannten Bedingungen durch Reduktion der Carbonsäure 11 mit zum Beispiel Lithiumaluminiumhydrid oder Boran zum Alkohol reduziert werden (J. Med. Chem. 1990, 33, 3190; Chem. Ber. 1990, 123, 555; Synthesis 1990, 925; Synth. Commun. 1991, 21, 1 ; Angew. Chem. 1989, 101, 220; J. Chem. Soc, Perkin Trans. 1, 1997, 2891 ; J. Org. Chem. 1993, 58, 3568; Synth. Commun. 1996, 26, 703). Hierbei ist die Methode mit Boran besonders bevorzugt, wobei der Einsatz von Boran Dimethylsulfid Komplex ganz besonders bevorzugt wird. Die Intermediate 13 (X steht für eine aktivierende Gruppe) können nach den dem Fachmann bekannten Methoden aktiviert werden (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), wobei die Überführung in das Mesylat bevorzugt wird. Die Intermediate 14 können nach den dem Fachmann bekannten Verfahren hergestellt werden (Tetrahedron Lett. 1987, 28, 535; Tetrahedron Lett. 1995, 36, 1223; J. Med. Chem. 2004, 47, 3275; Pharm. Chem. J. 1989, 23, 998), wobei die Synthese der hier verwendeten Thioacetate in WO 2011/161101 beschrieben wird. Hierbei wird die Freisetzung des Thiolats aus dem Thioacetat mit Natriummethanolat und die nachfolgende Umsetzung mit dem Mesylat bevorzugt. Die Intermediate 15 können nach den dem Fachmann bekannten Methoden hergestellt werden (J. Org. Chem. 1957, 22, 241 ; J. Org. Chem. 2004, 69, 3824; J. Am. Chem. Soc. 1941, 63, 2939; Org. Lett. 1999, 1, 189). Hierbei wird besonders die Oxidation mit Persäuren bevorzugt. Die Freisetzung der Intermediate 16 kann nach den dem Fachmann bekannten Bedingungen (Theodora W. Greene and Peter G. M. Wuts in„Protective Groups in Organic Synthesis" 3rd. Editition, (1999), John Wiley & Sons New York) erfolgen. Im Falle der tert-Butyloxycarbonyl-Schutzgruppe wird die saure Abspaltung bevorzug, wobei die Abspaltung mit Trifluoressigsäure besonders bevorzugt wird. 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. Greene and Peter GM Wuts in "Protective Groups in Organic Synthesis" 3rd Ed., (1999), John Wiley & Sons, Inc., New York), which prefer carbamate protecting groups, and especially the tert-butyloxycarbonyl protecting group literature and can thus be used as starting materials by the methods known to those skilled in the art (Org. Lett., 2007, 9, 5283, WO 2011/111875 A1, Tetrahedron Lett., 1997, 38, 3609; Org. Lett. 2012, 12, No. 2,922, Bioorg. Med. Chem. 1997, 7, 1665, WO 2011/111875 A1) Intermediates 12 can be reduced to the alcohol by reducing the carboxylic acid 11 with, for example, lithium aluminum hydride or borane to the alcohol (J. Med. Chem. 1990, 33, 3190; Chem. Ber. 1990, 123, 555; Synthesis 1990, 925; Synth. Commun. 1991, 21, 1; Angew. Chem. 1989, 101, 220; J. Chem. Soc, Perkin Trans. 1, 1997, 2891; J. Org. Chem. 1993, 58, 3568; Synth. Commun., 1996, 26, 703), in which case the method with borane is special He preferred, wherein the use of borane dimethyl sulfide complex is very particularly preferred. The intermediates 13 (X stands for an activating group) 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. 1941, 63, 2939 Org. Lett. 1999, 1, 189). In this case, 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.
Die Herstellung der Intermediate 17-20 kann nach Schema 5a und 5b erfolgen, wobei Xi, X2, R8, R9, t und Y wie oben beschrieben definiert sind und PG für eine Schutzgruppe steht.
The preparation of intermediates 17-20 can be carried out according to Schemes 5a and 5b, wherein Xi, X2, R 8 , R 9 , t and Y are defined as described above and PG is a protective group.
Die Startmaterialien ST 17 können nach den dem Fachmann bekannten Methoden hergestellt werden (WO 2011/161101 AI ; WO 2005/77968 A2). Die Intermediate 17 können nach den dem
Fachmann bekannten Bedingungen hergestellt werden (J. Org. Chem. 1975, 40, 284; Tetrahedron 2010, 66, 2642). Hierbei ist die Methode mit Acetonitril besonders bevorzugt. Die Intermediate 18 können nach den dem Fachmann bekannten Methoden mit dem Wittig-Reagenz 17 hergestellt werden (J. Org. Chem. 1975, 40, 284; Tetrahedron 2010, 66, 2642; Bioorg. Med. Chem. 2002, 10, 1399; Tetrahedron 1994, 50, 7093), wobei die Umsetzung mit Kalium-tert-butanolat bei anfangs -30 bis -40 °C durchgeführt wird. Die Intermediate 19 können nach den dem Fachmann bekannten Verfahren hergestellt werden (Houben Weyl,„Methoden der organischen Chemie", Bd. 4/lc Teil 1, S. 14 ff. (1980), Georg Thieme Verlag Stuttgart, New York), dabei wird die Umsetzung mit Palladium auf Aktivkohle unter einer Wasserstoffatmosphäre bevorzugt. Die Freisetzung der Intermediate 20 kann nach den dem Fachmann bekannten Bedingungen, wie für die Intermediate 16 beschrieben, erfolgen. Besonders bevorzugt ist auch hier die Spaltung mit Trifluoressigsäure. 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.
Die Herstellung der Intermediate 21-27 kann nach Schema 6a bzw. 6b erfolgen, wobei Xi, X2, R8, R9, t und Y wie oben beschrieben definiert sind und PG für eine Schutzgruppe und X für eine Abgangsgruppe stehen. Schema 6a The preparation of intermediates 21-27 can be carried out according to Scheme 6a or 6b, wherein Xi, X2, R 8 , R 9 , t and Y are defined as described above and PG is a protective group and X is a leaving group. Scheme 6a
22a 23a 22a 23a
26a
Schema 6b 26a Scheme 6b
26b 26b
Die Intermediate 21 können nach den dem Fachmann bekannten Bedingungen hergestellt werden (J. Med. Chem. 1991, 34, 2547; Org. Lett. 2000, 2, 3765; Synth. Commun. 2006, 36, 3001; Org. Lett. 2007, 9, 2477; Angew. Chem. Int. Ed. 2002, 41, 3284). Hierbei ist die Methode mit organischen Basen bevorzugt, und ganz besonders bevorzugt mit Trialkylaminen. Die Intermediate 22 können nach den dem Fachmann bekannten Methoden (Houben Weyl,„Methoden der organischen Chemie", Bd. 4/lc Teil 1, S. 14 ff. (1980), Georg Thieme Verlag Stuttgart, New York) hergestellt werden, wobei die Hydrierung mit Palladium auf Aktivkohle bevorzugt wird. Als Wasserstoffquelle kann sowohl Wasserstoffgas als auch Cyclohexadien eingesetzt werden. Die Reduktion zum Intermediat 23 kann nach den dem Fachmann bekannten Methoden erfolgen (Org. Lett. 2007, 9, 2477; Science of Synthesis: Houben- Weyl Methods of Molecular Transformation, Version 3.10 September 2010). So können zum Beispiel Natriumborhydrid, Lithiumborhydrid oder Aluminiumhydride eingesetzt werden. Hierbei wird die Reduktion mit Diisobutylaluminiumhydrid (DIBAL-H) bevorzugt. Die Intermediate 24 (X steht für eine aktivierende Gruppe) können nach den dem Fachmann bekannten Methoden aktiviert werden, wie es für die Verbindungen 13 beschrieben wurde, wobei die
Überführung in das Tosylat bevorzugt wird. Die Intermediate 25 können nach den dem Fachmann bekannten Verfahren hergestellt werden, analog der Synthese der Intermediate 14. Die Intermediate 26 können nach den dem Fachmann bekannten Verfahren hergestellt werden, analog der Synthese der Intermediate 15, wobei Persäuren bevorzugt werden. Die Abspaltung der Aminoschutzgruppe zum Intermediat 27 erfolgt wie bei Intermediat 16 beschrieben, dabei ist Trifluoressigsäure oder Salzsäure für die Abspaltung der tert-Butoxycarbonylgruppe bevorzugt. 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). Here, 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. (1980), Georg Thieme Verlag Stuttgart, New York), wherein Both hydrogen gas and cyclohexadiene can be used as the hydrogen source, and the reduction to intermediate 23 can be carried out by methods known to the person skilled in the art (Org. Lett., 2007, 9, 2477, Science of Synthesis: Houben-Chemie, Vol. For example, sodium borohydride, lithium borohydride, or aluminum hydrides may be used, with reduction preference given to diisobutylaluminum hydride (DIBAL-H) intermediates 24 (X is an activating group) the methods known in the art are activated, as described for the compounds 13, wherein the Transfer to the tosylate is preferred. 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.
Im Falle der Intermediate 27 mit R8 oder R9 = Hydroxy kann die Schutzgruppe auf den Stufen der Intermediate 25, 26 oder 27 abgespalten werden, wie es dem Fachmann bekannt ist (Theodora W. Greene and Peter G. M. Wuts in„Protective Groups in Organic Synthesis" 3rd. Editition, (1999), John Wiley & Sons, Inc.; New York). Als Schutzgruppe für die Hydroxygruppe können unterschiedliche Gruppen eingesetzt werden. Es werden Ether-Schutzgruppen bevorzugt, ganz besonders bevorzugt werden Silylether-Gruppen, speziell die tert-Butyldimethylsilylgruppe. Die Silylschutzgruppen können sauer oder mit Tetrabutylammoniumfluorid abgespalten werden, wobei letztere Methode bevorzugt wird. Die Abspaltung der Schutzgruppe wird nach der Oxidation zum Intermediat 26 bevorzugt. In the case of intermediates 27 with R 8 or R 9 = hydroxy, 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.
Abkürzungsverzeichnis Chemie List of abbreviations Chemistry
Abkürzungen und Akronyme: Abbreviations and acronyms:
CI Chemische Ionisation (bei MS) CI Chemical Ionization (in MS)
DC Dünnschichtchromatographie TLC thin layer chromatography
DMF Dimethylformamid DMF dimethylformamide
DMAP N,N-Dimethylpyridin-4-amin DMAP N, N-dimethylpyridine-4-amine
DMSO Dimethylsulfoxid DMSO dimethyl sulfoxide
d. Th. der Theorie (bei Ausbeute) d. Th. Of theory (at yield)
ESI Elektrospray-Ionisation (bei MS) ESI electrospray ionization (in MS)
GC-MS Gaschromatographie-gekoppelte Massenspektroskopie GC-MS gas chromatography-coupled mass spectroscopy
H Stunde(n) H hour (s)
HPLC Hochdruck-, Hochleistungsflüssigkeitschromatographie HPLC high pressure, high performance liquid chromatography
LC-MS Flüssigkeitschromatographie-gekoppelte Massenspektroskopie LC-MS liquid chromatography-coupled mass spectroscopy
Mass found Gefundene Masse im Massensprektrum Mass found Found mass in the mass spectrum
Min Minute(n) Min minute (s)
ml Milliliter ml of milliliters
MS Massenspektroskopie MS mass spectroscopy
NMR Kernresonanzspektroskopie NMR nuclear magnetic resonance spectroscopy
Rf Retentionsindex (bei DC)
Rt Retentionszeit (bei HPLC) Rf Retention Index (at DC) R t retention time (by HPLC)
RT Raumtem eratur RT room temperature
TFA Trifluoressigsäure TFA trifluoroacetic acid
THF Tetrahydrofuran THF tetrahydrofuran
Reinigung der erfindungsgemäßen Verbindungen Purification of the compounds of the invention
In einigen Fällen konnten die erfindungsgemäßen Verbindungen durch präparative HPLC zum Beispiel durch ein Autopurifier-Gerät der Firma Waters (Detektion der Verbindungen durch UV- Detektion sowie Elektrospray-Ionisation) in Kombination mit kommerziell erhältlichen, vorgepackten HPLC Säulen (zum Beispiel Säule XBridge (Firma Waters), C18, 5μηι, 30 x 100mm) gereinigt werden. Als Lösemittelsystem wurde Acetonitril/Wasser mit Zusätzen von Ammoniak, Ammoniumacetat, Trifluoressigsäure oder Ameisensäure verwendet. Statt Acetonitril konnte beispielsweise auch Methanol verwendet werden. In some cases, 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, 5μηι, 30 x 100mm) are cleaned. The solvent system used was acetonitrile / water with additions of ammonia, ammonium acetate, trifluoroacetic acid or formic acid. Instead of acetonitrile, for example, methanol could also be used.
Der Fluss bei der Reinigung betrug 50 ml/min. The flow in the purification was 50 ml / min.
Zum Entfernen des HPLC-Lösemittelgemisches wurde eine Gefriertrocknung oder eine Vakuumzentrifugation verwendet. Die so erhaltenen Verbindungen konnten als TFA-Salze bzw. Formiatsalze vorliegen und konnten in die freien Basen durch die dem Fachmann bekannten Standardprozeduren überführt werden. 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 free bases by the standard procedures known to the person skilled in the art.
In einigen Fällen konnten die erfindungsgemäßen Verbindungen durch Chromatographie an Kieselgel gereinigt werden. Hierbei wurden zum Beispiel vorgepackte Silica Gel Cartridges (zum Beispiel von der Firma Separtis, Isolute® Flash silica gel) in Kombination mit dem Flashmaster II Chromatograhiegerät (Argonaut/Biotage) und Lösungsmittel bzw. Lösungsmittelgemische wie zum Beispiel Hexan, Hexan/Ethylacetat oder Dichlormethan, Dichlormethan/Methanol verwendet, wobei auch wässrige Ammoniaklösung zugegeben werden konnte. Strukturanalytik der erfindungsgemäßen Verbindungen In some cases, the compounds of the invention could be purified by chromatography on 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. Structural analysis of the compounds of the invention
In einigen Fällen wurde für die Aufnahme eines Massenspektrums ein Waters ZQ4000 Gerät oder ein Single Quadrupol API (Atomic Pressure Ionization) Massendetektor {Waters) verwendet. Bei den NMR-Daten der erfindungsgemäßen Verbindungen gelten folgende Bedeutungen: In some cases, a Waters ZQ4000 device or a single quadrupole API (Atomic Pressure Ionization) mass detector {Waters) was used to acquire a mass spectrum. In the NMR data of the compounds according to the invention, the following meanings apply:
s Singulett s singlet
D Dublett D doublet
T Triplett
Q Quartett T triplet Q Quartet
Quin Quintett Quin Quintet
M Multiplett M multiplet
Br breit Br wide
Mc Zentriertes Multiplett Mc Centered Multiplett
Drehwerte wurden wie folgt bestimmt: Instrument: JASCO P2000 Polarimeter; Wellenlänge 589 nm; Temperatur: 20 °C; Integrationszeit 10 s; Schichtdicke 100 mm. Rotational values were determined as follows: Instrument: JASCO P2000 Polarimeter; Wavelength 589 nm; Temperature: 20 ° C; Integration time 10 s; Layer thickness 100 mm.
Chemische Namen wurden mit Hilfe von ACD/Name Batch Version 12.01 erstellt. Chemical names were created using ACD / Name Batch version 12.01.
Die Intermediate 1-6 sind bekannt und können wie in den Schemata 1-3 beschrieben hergestellt werden. Intermediates 1-6 are known and can be prepared as described in Schemes 1-3.
Intermediat 7 Intermediate 7
5-[8-(4-Fluorphenyl)-3-methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl]pent-4-in-l-ol 5- [8- (4-fluorophenyl) -3-methoxy-6,7-dihydro-5H-benzo [7] annulene-9-yl] pent-4-yn-l-ol
35.4 g (62.5 mmol) 8-(4-Fluorphenyl)-3-methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl 1,1,2,2,3,3,4,4,4-nonafluor-butan-l-sulfonat (beschrieben in WO 2011/161101) wurden in 200 ml wasserfreiem DMF gelöst. Hierzu wurden 7.89 g (93.7 mmol) Pent-4-in-l-ol, 35.7 ml (256.2 mmol) Triethylamin, 2.167 g (1.875 mmol) Tetrakis-(triphenylphosphin)-palladium-(0) und 476.1 mg (2.5 mmol) Kupfer-(I)-iodid gegeben. Anschließend wurde 3 h bei 85°C unter Schutzgas gerührt. Die flüchtigen Bestandteile wurden im Vacuum abgezogen. Es wurde Essigsäureethylester und Wasser zugegeben, die Phasen wurden separiert und die wäßrige Phase wurde nach Zugabe von etwas gesättigter Natriumchloridlösung zweimal mit Essigsäureethylester extrahiert. Die vereinigten organischen Phasen wurden zweimal mit Wasser und einmal mit gesättigter Natriumchloridlösung gewaschen, über Natriumsulfat getrocknet und eingeengt. Der Rückstand wurde über Kieselgel (Gradient Hexan/Essigsäureethylester) gereinigt. Es wurden 10.2 g (46% d.Th.) Produkt isoliert und ohne weitere Reinigung direkt in der nächsten Stufe umgesetzt. 35.4 g (62.5 mmol) of 8- (4-fluorophenyl) -3-methoxy-6,7-dihydro-5H-benzo [7] annulen-9-yl 1,1,2,2,3,3,4,4 4-nonafluoro-butane-1-sulfonate (described in WO 2011/161101) were dissolved in 200 ml of anhydrous DMF. To this was added 7.89 g (93.7 mmol) of pent-4-yn-1-ol, 35.7 ml (256.2 mmol) of triethylamine, 2.167 g (1.875 mmol) of tetrakis (triphenylphosphine) palladium (0) and 476.1 mg (2.5 mmol). Given copper (I) iodide. The mixture was then stirred at 85 ° C under inert gas for 3 h. The volatiles were removed in vacuo. Ethyl acetate and water were added, the phases were separated and the aqueous phase was extracted twice with ethyl acetate after addition of a little saturated sodium chloride solution. The combined organic phases were washed twice with water and once with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified over silica gel (gradient hexane / ethyl acetate). 10.2 g (46% of theory) of product were isolated and reacted directly in the next stage without further purification.
Intermediat 8:
5-[8-(4-Fluorphenyl)-3-methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl]penti Intermediate 8: 5- [8- (4-fluorophenyl) -3-methoxy-6,7-dihydro-5H-benzo [7] annulene-9-yl] penti
10.2 g (29.1 mmol) 5-[8-(4-Fluorphenyl)-3-methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl]pent-4-in- l-ol und 1.02 g 10Gew.% Palladium auf Aktivkohle wurden in 120 ml Methanol und 1.87 g Kaliumhydroxid bei RT und Normaldruck 20 min hydriert. Anschließend wurden nochmals 1.02 g 10Gew.% Palladium auf Aktivkohle hinzugefügt und weiter bei RT und Normaldruck hydriert, bis 2 Moläquivalente Wasserstoffgas aufgenommen worden waren. Es wurde über Celite abgesaugt, mit Methanol nachgewaschen und bis zur Trockene eingeengt. Der Rückstand wurde in Dichlormethan/Wasser aufgenommen, die Phasen wurden getrennt und die organische Phase wurde zweimal mit Wasser und einmal mit gesättigter Natriumchloridlösung gewaschen. Es wurde über Natriumsulfat getrocknet und eingeengt. Es fielen 10.5 g (102% d. Th.) Produkt an. 10.2 g (29.1 mmol) of 5- [8- (4-fluorophenyl) -3-methoxy-6,7-dihydro-5H-benzo [7] annulen-9-yl] pent-4-indol and 1.02 g 10% by weight of palladium on activated carbon were hydrogenated in 120 ml of methanol and 1.87 g of potassium hydroxide at RT and normal pressure for 20 min. Subsequently, another 1.02 g of 10% by weight of palladium on activated charcoal was added and further hydrogenated at RT and normal pressure until 2 molar equivalents of hydrogen gas had been taken up. It was filtered off with suction through Celite, washed with methanol and concentrated to dryness. The residue was taken up in dichloromethane / water, the phases were separated and the organic phase was washed twice with water and once with saturated sodium chloride solution. It was dried over sodium sulfate and concentrated. It produced 10.5 g (102% of theory) of product.
'H-NMR (300 MHz, DMSO-de): δ = 1.05 - 1.25 (m, 6H), 1.93 - 2.11 (m, 4H), 2.29 - 2.36 (m, 2H), 2.62 (t, 2H), 3.18 - 3.27 (m, 2H), 3.77 (s, 3H), 4.23 (t, 1H), 6.80 - 6.86 (m, 2H), 7.15 - 7.31 (m, 5H). 'H-NMR (300 MHz, DMSO-de): δ = 1.05-1.25 (m, 6H), 1.93-2.11 (m, 4H), 2.29-2.26 (m, 2H), 2.62 (t, 2H), 3.18 - 3.27 (m, 2H), 3.77 (s, 3H), 4.23 (t, 1H), 6.80 - 6.86 (m, 2H), 7.15 - 7.31 (m, 5H).
Intermediat 9: Intermediate 9:
8-(4-Fluorphenyl)-9-(5-hydroxypentyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol 8- (4-fluorophenyl) -9- (5-hydroxypentyl) -6,7-dihydro-5H-benzo [7] annulene-3-ol
Zu 100 ml wasserfreiem Dichlormethan wurden 103.7 ml (103.7 mmol) Bortribromidlösung, 1.0M in Dichlormethan, gegeben. Im Eisbad wurden bei maximal 5°C 11.11 g (103.7 mmol) 2,6- Dimethylpyridin in 50 ml wasserfreiem Dichlormethan zugetropft. 10.5 g (29.6 mmol) 5-[8-(4- Fluorphenyl)-3-methoxy-6,7-dihydro-5H-benzo[7]annulen-9-yl]pentan-l-ol in 50 ml wasserfreiem Dichlormethan wurden bei maximal 5°C zugetropft. Die Eisbadkühlung wurde über Nacht auf RT kommen gelassen. Die Reaktionslösung wurde in Eiswasser gegossen. Der ausgefallene Niederschlag wurde durch Zugabe von etwas Aceton gelöst. Die Phasen wurden separiert und die wäßrige Phase wurde zweimal mit Dichlormethan extrahiert. Die vereinigten organischen Phasen wurden einmal mit gesättigter Natriumchloridlösung gewaschen, über Natriumsulfat getrocknet und eingeengt. Der
Rückstand wurde über Kiselgel (Gradient Hexan/Essigsäureethylester) gereinigt. Es wurden 8.2 g (81% d. Th.) Produkt isoliert. To 100 ml of anhydrous dichloromethane was added 103.7 ml (103.7 mmol) of boron tribromide solution, 1.0 M in dichloromethane. In an ice bath, 11.11 g (103.7 mmol) of 2,6-dimethylpyridine in 50 ml of anhydrous dichloromethane were added dropwise at a maximum of 5 ° C. 10.5 g (29.6 mmol) of 5- [8- (4-fluorophenyl) -3-methoxy-6,7-dihydro-5H-benzo [7] annulen-9-yl] -pentan-1-ol in 50 ml of anhydrous dichloromethane at a maximum of 5 ° C added dropwise. The ice bath cooling was allowed to come to RT overnight. The reaction solution was poured into ice-water. The precipitate was dissolved by adding a little acetone. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with saturated sodium chloride solution, dried over sodium sulfate and concentrated. Of the Residue was purified over silica gel (gradient hexane / ethyl acetate). 8.2 g (81% of theory) of product were isolated.
'H-NMR (400MHZ, DMSO-d6): δ [ppm] = 1.01 - 1.27 (m, 6H), 1.93 - 2.09 (m, 4H), 2.30 (t, 2H), 2.53 (d, 2H), 3.16 - 3.27 (m, 2H), 4.24 (t, 1H), 6.62 - 6.71 (m, 2H), 7.08 - 7.31 (m, 5H), 9.31 (s, 1H). 'H-NMR (400MHz, DMSO-d 6): δ [ppm] = 1:01 to 1:27 (m, 6H), 1.93 - 2:09 (m, 4H), 2.30 (t, 2H), 2:53 (d, 2H), 3.16-3.27 (m, 2H), 4.24 (t, 1H), 6.62-6.71 (m, 2H), 7.08-7.31 (m, 5H), 9.31 (s, 1H).
Intermediat 10: Intermediate 10:
9-(5-Brompentyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol 9- (5-bromopentyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulene-3-ol
8.2 g (24.1 mmol) 8-(4-Fluorphenyl)-9-(5-hydroxypentyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol in 150 ml wasserfreiem THF wurden bei 0-5°C mit 12.64 g (48.2 mmol) Triphenylphosphin versetzt. Bei 0-5°C wurden 15.98 g (48.2 mmol) Tetrabromkohlenstoff portionsweise zugegeben. Es wurde auf dem Eisbad weitergerührt und über Nacht auf RT erwärmt. Die Reaktionslösung wurde in gesättigte Natriumhydrogencarbonatlösung gegossen, die Phasen wurden getrennt und die wäßrige Phase wurde zweimal mit Essigsäureethylester extrahiert. Die vereinigten organischen Phasen wurden einmal mit gesättigter Natriumchloridlösung gewaschen, über Natriumsulfat getrocknet und eingeengt. Es wurde über Kieselgel 60 (Gradient Hexan, Hexan/Essigsäureethylester) gereinigt. Es fielen 9.40 g (97% d. Th.) Produkt an. 8.2 g (24.1 mmol) of 8- (4-fluorophenyl) -9- (5-hydroxypentyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol in 150 ml of anhydrous THF were added at 0-5 ° C with 12.64 g (48.2 mmol) of triphenylphosphine. At 0-5 ° C 15.98 g (48.2 mmol) of carbon tetrabromide were added in portions. It was further stirred on the ice bath and warmed to RT overnight. The reaction solution was poured into saturated sodium bicarbonate solution, the phases were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride solution, dried over sodium sulfate and concentrated. It was purified over silica gel 60 (gradient hexane, hexane / ethyl acetate). There were 9.40 g (97% of theory) of product.
'H-NMR (300 MHz, DMSO-de): δ = 1.08 - 1.24 (m, 4H), 1.48 - 1.63 (m, 2H), 1.92 - 2.11 (m, 4H), 2.23 - 2.37 (m, 2H), 2.53 - 2.60 (m, 2H), 3.34 - 3.39 (m, 2H), 6.63 - 6.69 (m, 2H), 7.11 - 7.32 (m, 5H), 9.32 (s, 1H). 'H-NMR (300 MHz, DMSO-de): δ = 1.08-1.24 (m, 4H), 1.48-1.63 (m, 2H), 1.92-2.11 (m, 4H), 2.23-2.37 (m, 2H) , 2.53-2.60 (m, 2H), 3.34-3.39 (m, 2H), 6.63-6.69 (m, 2H), 7.11-7.32 (m, 5H), 9.32 (s, 1H).
Intermediate 12: Intermediate 12:
Allgemeine Vorschrift 12 für die Herstellung von 12 unter Schutzgas und Luftfeuchtigkeitsausschluß: General regulation 12 for the preparation of 12 under protective gas and exclusion of atmospheric moisture:
(Methylsulfanyl)methan-boran(l : l) wurde zur Carbonsäure 11 in wasserfreiem THF zugetropft. Es wurde 5 Stunden unter Rückfluss und über Nacht bei RT gerührt. Erst wurde mit tert-Butyl- methylether verdünnt, bevor vorsichtig gesättigte Natriumhydrogencarbonatlösung zugegeben wurde. Nach dem Ende der Gasentwicklung wurden die Phasen separiert und die wässrige Phase wurde zweimal mit tert-Butyl-methylether extrahiert. Die vereinigten organischen Phasen wurden über Magnesiumsulfat getrocknet und eingeengt. (Methylsulfanyl) methaneborane (1: 1) was added dropwise to the carboxylic acid 11 in anhydrous THF. The mixture was stirred under reflux for 5 hours and at RT overnight. It was first diluted with tert-butyl methyl ether before carefully saturated sodium bicarbonate solution was added. After the gas evolution ceased, the phases were separated and the aqueous phase was extracted twice with tert-butyl methyl ether. The combined organic phases were dried over magnesium sulfate and concentrated.
Intermediat 1-12
tert-But l-(2S)-2-(2-hydroxyethyl)pyrrolidin-l-carboxylat Intermediate 1-12 tert-Butyl (2S) -2- (2-hydroxyethyl) pyrrolidine-1-carboxylate
7.24 ml (76.3 mmol) Borandimethylsulfidkomplex wurden zu 10 g (43.6 mmol) [(2S)-l-(tert- Butoxycarbonyl)pyrrolidin-2-yl] essigsaure in 120 ml THF zugetropft und entsprechend der allgemeinen Vorschrift 12 umgesetzt und aufgearbeitet. Es wurden 8.89 g (95% d. Th.) Produkt isoliert. 7.24 ml (76.3 mmol) Borandimethylsulfidkomplex were added dropwise to 10 g (43.6 mmol) of [(2S) -1- (tert-butoxycarbonyl) pyrrolidin-2-yl] acetic acid in 120 ml THF and reacted according to the general procedure 12 and worked up. 8.89 g (95% of theory) of product were isolated.
'H-NMR (300 MHz, Chloroform-di): δ = 1.46 (s, 9H), 1.55-1.76 (m, 2H), 1.79-2.05 (m, 3H), 3.25- 3.39 (m, 2H), 3.48-3.70 (m, 2H), 4.15 (mc, 1H), 4.43 (mc, 1H). Intermediat 2-12 'H NMR (300 MHz, chloroform-di): δ = 1.46 (s, 9H), 1.55-1.76 (m, 2H), 1.79-2.05 (m, 3H), 3.25-3.39 (m, 2H), 3.48 -3.70 (m, 2H), 4.15 (mc, 1H), 4.43 (mc, 1H). Intermediate 2-12
tert-But l-(2R)-2-(2-hydroxyethyl)pyrrolidin-l-carboxylat tert-Butyl (2R) -2- (2-hydroxyethyl) pyrrolidine-1-carboxylate
3.62 ml (38.2 mmol) Borandimethylsulfidkomplex wurden zu 5 g (21.8 mmol) [(2R)-l -(tert- Butoxycarbonyl)pyrrolidin-2-yl] essigsaure in 60 ml THF zugetropft und entsprechend der allgemeinen Vorschrift 12 umgesetzt und aufgearbeitet. Es wurden 4.04 g (86% d. Th.) Produkt isoliert. 3.62 ml (38.2 mmol) Borandimethylsulfidkomplex were added dropwise to 5 g (21.8 mmol) of [(2R) -1- (tert-butoxycarbonyl) pyrrolidin-2-yl] acetic acid in 60 ml THF and reacted according to the general procedure 12 and worked up. 4.04 g (86% of theory) of product were isolated.
'H-NMR (300 MHz, Chloroform-di): δ = 1.46 (s, 9H), 1.55-1.75 (m, 2H), 1.76-2.08 (m, 3H), 3.24- 3.71 (m, 4H), 4.15 (mc, 1H), 4.42 (mc, 1H). 'H-NMR (300 MHz, chloroform-di): δ = 1.46 (s, 9H), 1.55-1.75 (m, 2H), 1.76-2.08 (m, 3H), 3.24-3.71 (m, 4H), 4.15 (mc, 1H), 4.42 (mc, 1H).
Intermediate 13: Intermediate 13:
Allgemeine Vorschrift 13 für die Herstellung von 13 unter Schutzgas und Luftfeuchtigkeitsausschluß: General rule 13 for the preparation of 13 under protective gas and exclusion of atmospheric moisture:
Zu 1 g Alkohol 12 in 15.5 ml Dichlormethan wurden 1.3 Äquivalente Triethylamin zugegeben. Bei -5 °C wurden 1.3 Äquivalente Methansulfonsäurechlorid zugetropft. Es wurde bei 0 °C 1.5-3 Stunden nachgerührt, bevor gesättigte Ammoniumchloridlösung zugegeben wurde. Die Phasen wurden separiert und die wässrige Phase wurde zweimal mit Dichlormethan extrahiert. Die vereinigten organischen Phasen wurden einmal mit gesättigter Natriumchloridlösung gewaschen, über Magnesiumsulfat getrocknet und eingeengt. To 1 g of alcohol 12 in 15.5 ml of dichloromethane was added 1.3 equivalents of triethylamine. At -5 ° C, 1.3 equivalents of methanesulfonyl chloride were added dropwise. The mixture was stirred at 0 ° C for 1.5-3 hours before saturated ammonium chloride solution was added. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated.
Intermediat 1-13 Intermediate 1-13
tert-Butyl-(2S)-2-{2-[(methylsulfonyl)oxy]ethyl}pyrrolidine-l-carboxylat
tert-butyl (2S) -2- {2 - [(methylsulfonyl) oxy] ethyl} pyrrolidine-l-carboxylate
8.48 g (39.4 mmol) tert-Butyl-(2S)-2-(2-hydroxyethyl)pyrrolidin-l-carboxylat wurden entsprechend der allgemeinen Vorschrift 13 umgesetzt und aufgearbeitet. Es wurden 11.48 g (99% d. Th.) Produkt isoliert. 8.48 g (39.4 mmol) of tert-butyl (2S) -2- (2-hydroxyethyl) pyrrolidine-1-carboxylate were reacted and worked up in accordance with general procedure 13. 11.48 g (99% of theory) of product were isolated.
'H-NMR (300 MHz, Chloroform-di): δ = 1.46 (s, 9H), 1.60-2.20 (m, 6H), 3.00 + 3.02 (s, 3H), 3.25- 3.48 (m, 2H), 3.86-4.08 (m, 1H), 4.20-4.42 (m, 2H). 'H-NMR (300 MHz, chloroform-di): δ = 1.46 (s, 9H), 1.60-2.20 (m, 6H), 3.00 + 3.02 (s, 3H), 3.25- 3.48 (m, 2H), 3.86 -4.08 (m, 1H), 4.20-4.42 (m, 2H).
Intermediat 2-13 Intermediate 2-13
tert-Butyl-(2R)-2-{2-[(methylsulfonyl)oxy]ethyl}pyrrolidine-l-carboxylat tert-butyl (2R) -2- {2 - [(methylsulfonyl) oxy] ethyl} pyrrolidine-l-carboxylate
4.05 g (18.8 mmol) tert-Butyl-(2R)-2-(2-hydroxyethyl)pyrrolidin-l-carboxylat wurden entsprechend der allgemeinen Vorschrift 13 umgesetzt und aufgearbeitet. Es wurden 5.13 g (93% d. Th.) Produkt isoliert. 4.05 g (18.8 mmol) of tert-butyl (2R) -2- (2-hydroxyethyl) pyrrolidine-1-carboxylate were reacted in accordance with general procedure 13 and worked up. 5.13 g (93% of theory) of product were isolated.
'H-NMR (300 MHz, Chloroform-di): δ = 1.46 (s, 9H), 1.60-2.23 (m, 6H), 3.00 + 3.02 (s, 3H), 3.26- 3.47 (m, 2H), 3.87-4.07 (m, 1H), 4.21-4.42 (m, 2H). 'H-NMR (300 MHz, chloroform-di): δ = 1.46 (s, 9H), 1.60-2.23 (m, 6H), 3.00 + 3.02 (s, 3H), 3.26- 3.47 (m, 2H), 3.87 -4.07 (m, 1H), 4.21-4.42 (m, 2H).
Intermediate 14: Intermediate 14:
Allgemeine Vorschrift 14 für die Herstellung von 14 unter Schutzgas und Luftfeuchtigkeitsausschluß: General rule 14 for the preparation of 14 under protective gas and exclusion of atmospheric moisture:
2.1 Äquivalente einer käuflichen 30%igen Natriummethanolatlösung in Methanol wurden mit Methanol (1-2 ml Methanol pro 1 ml Natriummethanolatlösung) verdünnt. Zu dieser Natriummethanolatlösung wurden bei 5 °C 2.1 Äquivalente Thioacetat in Methanol (0.3-0.5 ml/mmol Thioacetat) zugetropft und 30 Minuten nachgerührt. Bei RT wurde das Mesylat in DMF (1.5 ml/mmol Mesylat) zugetropft und über Nacht nachgerührt. Es wurde 0.2 M Salzsäure (0.15-0.30 mmol/mmol Natriummethanolat) zugegeben und eingeengt. Der Rückstand wurde in Diethylether oder tert-Butyl- methylether aufgenommen, viermal mit Wasser gewaschen, über Magnesiumsulfat getrocknet und eingeengt. 2.1 equivalents of a commercially available 30% sodium methoxide solution in methanol were diluted with methanol (1-2 ml of methanol per 1 ml of sodium methoxide solution). 2.1 equivalents of thioacetate in methanol (0.3-0.5 ml / mmol of thioacetate) were added dropwise at 5 ° C. to this sodium methoxide solution and the mixture was stirred for a further 30 minutes. At RT, the mesylate in DMF (1.5 ml / mmol mesylate) was added dropwise and stirred overnight. 0.2 M hydrochloric acid (0.15-0.30 mmol / mmol sodium methoxide) was added and concentrated. The residue was taken up in diethyl ether or tert-butyl methyl ether, washed four times with water, dried over magnesium sulfate and concentrated.
Intermediat 1-14
tert-But l-(2S)-2-{2-[(3,3,3-trifluorpropyl)sulfanyl]ethyl}pyrrolidin-l-carboxylat Intermediate 1-14 tert-Butyl (2S) -2- {2 - [(3,3,3-trifluoropropyl) sulfanyl] ethyl} pyrrolidine-1-carboxylate
3.25 g (11.1 mmol) tert-Butyl-(2S)-2- {2-[(methylsulfonyl)oxy]ethyl}pyrrolidin-l-carboxylat und 4 g (23.2 mmol) S-(3,3,3-Trifluorpropyl)ethanthioat wurden mit 4.4 ml einer 30%igen Natriummethanolatlösung und 4.4 ml Methanol entsprechend der allgemeinen Vorschrift 14 umgesetzt und aufgearbeitet. Es wurde über Kieselgel 60 (Laufmittel: Hexan, Hexan-Essigsäureethylester 99: 1, 98:2 und 95:5) gereinigt. Es wurden 2.14 g (59% d. Th.) Produkt isoliert. Tert-Butyl (2S) -2- {2 - [(methylsulfonyl) oxy] ethyl} pyrrolidine-1-carboxylate (3.25 g, 11.1 mmol) and S- (3,3,3-trifluoropropyl) (4 g, 23.2 mmol). ethanthioate were reacted with 4.4 ml of a 30% sodium methoxide solution and 4.4 ml of methanol according to general procedure 14 and worked up. It was purified over silica gel 60 (eluent: hexane, hexane-ethyl acetate 99: 1, 98: 2 and 95: 5). 2.14 g (59% of theory) of product were isolated.
'H-NMR (300 MHz, Chloroform-di): δ = 1.46 (s, 9H), 1.55-1.70 (m, 2H), 1.77-2.05 (m, 4H), 2.28- 2.61 (m, 4H), 2.63-2.74 (m, 2H), 3.24-3.45 (m, 2H), 3.85 (mc, 1H). 'H-NMR (300 MHz, chloroform-di): δ = 1.46 (s, 9H), 1.55-1.70 (m, 2H), 1.77-2.05 (m, 4H), 2.28-2.61 (m, 4H), 2.63 -2.74 (m, 2H), 3.24-3.45 (m, 2H), 3.85 (mc, 1H).
Intermediat 2-14 Intermediate 2-14
tert-But l-(2S)-2-{2-[(4,4,4-trifluorbutyl)sulfanyl]ethyl}pyrrolidin-l-carboxylat tert -But 1- (2S) -2- {2 - [(4,4,4-trifluorobutyl) sulfanyl] ethyl} pyrrolidine-1-carboxylate
4.97 g (16.9 mmol) tert-Butyl-(2S)-2- {2-[(methylsulfonyl)oxy]ethyl}pyrrolidin-l-carboxylat und 6.62 g (35.6 mmol) S-(4,4,4-Trifluorbutyl)ethanthioat wurden mit 6.8 ml einer 30%igen Natriummethanolatlösung und 12 ml Methanol entsprechend der allgemeinen Vorschrift 14 umgesetzt und aufgearbeitet. Es wurde über Kieselgel 60 (Laufmittel: Hexan, Hexan-Essigsäureethylester 99: 1, 98:2, 95:5, 93:7 und 90: 10) gereinigt. Es wurden 3.42 g (59% d. Th.) Produkt isoliert. Tert-Butyl (2S) -2- {2 - [(methylsulfonyl) oxy] ethyl} pyrrolidine-1-carboxylate (4.97 g, 16.9 mmol) and S- (4,4,4-trifluorobutyl) (6.62 g, 35.6 mmol). ethanethioate were reacted with 6.8 ml of a 30% sodium methoxide solution and 12 ml of methanol according to general procedure 14 and worked up. It was purified over silica gel 60 (eluent: hexane, hexane-ethyl acetate 99: 1, 98: 2, 95: 5, 93: 7 and 90:10). 3.42 g (59% of theory) of product were isolated.
'H-NMR (300 MHz, Chloroform-di): δ = 1.46 (s, 9H), 1.52-1.70 (m, 2H), 1.77-2.06 (m, 6H), 2.13- 2.31 (m, 2H), 2.43-2.64 (m, 4H), 3.25-3.46 (m, 2H), 3.85 (mc, 1H). 'H NMR (300 MHz, chloroform-di): δ = 1.46 (s, 9H), 1.52-1.70 (m, 2H), 1.77-2.06 (m, 6H), 2.13-2.31 (m, 2H), 2.43 -2.64 (m, 4H), 3.25-3.46 (m, 2H), 3.85 (mc, 1H).
Intermediat 3-14 Intermediate 3-14
tert-But l-(2S)-2-{2-[(4,4,5,5,5-pentafluorpentyl)sulfanyl]ethyl}pyrrolidin-l-carboxylat tert-Butyl (2S) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfanyl] ethyl} pyrrolidine-1-carboxylate
6.5 g (22.2 mmol) tert-Butyl-(2S)-2- {2-[(methylsulfonyl)oxy]ethyl}pyrrolidin-l-carboxylat und 11 g (46.5 mmol) S-(4,4,5,5,5-Pentafluorpentyl)ethanthioat wurden mit 8.9 ml einer 30%>igen
Natriummethanolatlösung und 9 ml Methanol entsprechend der allgemeinen Vorschrift 14 umgesetzt und aufgearbeitet. Es wurde über Kieselgel 60 (Laufmittel: Hexan, Hexan-Essigsäureethylester 95:5, 90: 10 und 80:20) gereinigt. Es wurden 4.6 g (53% d. Th.) Produkt isoliert. Tert-Butyl (2S) -2- {2 - [(methylsulfonyl) oxy] ethyl} pyrrolidine-1-carboxylate (6.5 g, 22.2 mmol) and 11 g (46.5 mmol) of S- (4,4,5,5, 5-pentafluoropentyl) ethanethioate were mixed with 8.9 ml of a 30%> Sodium methoxide and 9 ml of methanol according to the general procedure 14 reacted and worked up. It was purified over silica gel 60 (eluent: hexane, hexane-ethyl acetate 95: 5, 90:10 and 80:20). 4.6 g (53% of theory) of product were isolated.
'H-NMR (300 MHz, Chloroform-di): δ = 1.46 (s, 9H), 1.52-1.70 (m, 2H), 1.77-2.04 (m, 6H), 2.07- 2.27 (m, 2H), 2.40-2.67 (m, 4H), 3.24-3.49 (m, 2H), 3.85 (mc, 1H). 'H-NMR (300 MHz, chloroform-di): δ = 1.46 (s, 9H), 1.52-1.70 (m, 2H), 1.77-2.04 (m, 6H), 2.07-2.27 (m, 2H), 2.40 -2.67 (m, 4H), 3.24-3.49 (m, 2H), 3.85 (mc, 1H).
Intermediat 4-14 Intermediate 4-14
tert-But l-(2R)-2-{2-[(3,3,3-trifluorpropyl)sulfanyl]ethyl}pyrrolidin-l-carboxylat tert-Butyl (2R) -2- {2 - [(3,3,3-trifluoropropyl) sulfanyl] ethyl} pyrrolidine-1-carboxylate
6.3 g (21.5 mmol) tert-Butyl-(2R)-2- {2-[(methylsulfonyl)oxy]ethyl}pyrrolidin-l-carboxylat und 7.76 g (45.1 mmol) S-(3,3,3-Trifluorpropyl)ethanthioat wurden mit 8.6 ml einer 30%igen Natriummethanolatlösung und 9 ml Methanol entsprechend der allgemeinen Vorschrift 14 umgesetzt und aufgearbeitet. Es wurde über Kieselgel 60 (Laufmittel: Hexan, Hexan-Essigsäureethylester 95:5, 90: 10 und 80:20) gereinigt. Es wurden 2.97 g (42% d. Th.) Produkt isoliert. Tert-butyl- (2R) -2- {2 - [(methylsulfonyl) oxy] ethyl} pyrrolidine-1-carboxylate (6.3 g, 21.5 mmol) and 7.76 g (45.1 mmol) of S- (3,3,3-trifluoropropyl) ethanethioate were reacted with 8.6 ml of a 30% sodium methoxide solution and 9 ml of methanol according to general procedure 14 and worked up. It was purified over silica gel 60 (eluent: hexane, hexane-ethyl acetate 95: 5, 90:10 and 80:20). 2.97 g (42% of theory) of product were isolated.
'H-NMR (300 MHz, Chloroform-di): δ = 1.46 (s, 9H), 1.56-1.70 (m, 2H), 1.77-2.08 (m, 4H), 2.28- 2.61 (m, 4H), 2.64-2.74 (m, 2H), 3.24-3.51 (m, 2H), 3.86 (mc, 1H). 'H-NMR (300 MHz, chloroform-di): δ = 1.46 (s, 9H), 1.56-1.70 (m, 2H), 1.77-2.08 (m, 4H), 2.28-2.61 (m, 4H), 2.64 -2.74 (m, 2H), 3.24-3.51 (m, 2H), 3.86 (mc, 1H).
Intermediat 5-14 tert-Butyl-(2R)-2-{2-[(4,4,4-trifluorbutyl)sulfanyl]ethyl}pyrrolidin-l- carbox lat Intermediate 5-14 tert -Butyl (2R) -2- {2 - [(4,4,4-trifluorobutyl) sulfanyl] ethyl} pyrrolidine-1-carboxylate lat
5.13 g (17.5 mmol) tert-Butyl-(2R)-2- {2-[(methylsulfonyl)oxy]ethyl}pyrrolidin-l-carboxylat und 6.8 g (36.7 mmol) S-(4,4,4-Trifluorbutyl)ethanthioat wurden mit 7 ml einer 30%>igen Natriummethanolatlösung und 7 ml Methanol entsprechend der allgemeinen Vorschrift 14 umgesetzt und aufgearbeitet. Es wurden 4 g (67% d. Th.) Produkt isoliert. Tert-Butyl (2R) -2- {2 - [(methylsulfonyl) oxy] ethyl} pyrrolidine-1-carboxylate (5.13 g, 17.5 mmol) and S- (4,4,4-trifluorobutyl) (6.8 g, 36.7 mmol). ethanethioate were reacted with 7 ml of a 30% solution of sodium methoxide and 7 ml of methanol according to general procedure 14 and worked up. 4 g (67% of theory) of product were isolated.
'H-NMR (300 MHz, Chloroform-di): δ = 1.46 (s, 9H), 1.55-1.70 (m, 2H), 1.77-2.06 (m, 6H), 2.13- 2.31 (m, 2H), 2.44-2.66 (m, 2H), 2.73 (t, 2H), 3.25-3.47 (m, 2H), 3.85 (mc, 1H). 'H NMR (300 MHz, chloroform-di): δ = 1.46 (s, 9H), 1.55-1.70 (m, 2H), 1.77-2.06 (m, 6H), 2.13-2.31 (m, 2H), 2.44 -2.66 (m, 2H), 2.73 (t, 2H), 3.25-3.47 (m, 2H), 3.85 (mc, 1H).
Intermediat 6-14 Intermediate 6-14
tert-Butyl-(2R)-2-{2-[(4,4,5,5,5-pentafluorpentyl)sulfanyl]ethyl}pyrrolidin-l-carboxylat
tert-butyl (2R) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfanyl] ethyl} pyrrolidine-l-carboxylate
4.71 g (16.1 mmol) tert-Butyl-(2R)-2- {2-[(methylsulfonyl)oxy]ethyl}pyrrolidin-l-carboxylat und 8 g (33.9 mmol) S-(4,4,5,5,5-Pentafluorpentyl)ethanthioat wurden mit 6.5 ml einer 30%igen Natriummethanolatlösung und 7 ml Methanol entsprechend der allgemeinen Vorschrift 14 umgesetzt und aufgearbeitet. Es wurde über Kieselgel 60 (Laufmittel: Hexan, Hexan-Essigsäureethylester 99: 1, 98:2, 95:5, 94:6, 92:8 und 90: 10) gereinigt. Es wurden 1.93 g (31% d. TL) Produkt isoliert. Tert-Butyl- (2R) -2- {(2- (methylsulfonyl) oxy] ethyl} pyrrolidine-1-carboxylate (4.71 g, 16.1 mmol) and S- (4,4,5,5, 5-pentafluoropentyl) ethanethioate were reacted with 6.5 ml of a 30% sodium methoxide solution and 7 ml of methanol according to general procedure 14 and worked up. It was purified over silica gel 60 (eluent: hexane, hexane-ethyl acetate 99: 1, 98: 2, 95: 5, 94: 6, 92: 8 and 90:10). 1.93 g (31% of theory) of product were isolated.
'H-NMR (300 MHz, Chloroform-di): δ = 1.46 (s, 9H), 1.53-1.69 (m, 2H), 1.77-2.05 (m, 6H), 2.06- 2.26 (m, 2H), 2.40-2.66 (m, 4H), 3.24-3.49 (m, 2H), 3.85 (mc, 1H). Intermediate 15: 'H-NMR (300 MHz, chloroform-di): δ = 1.46 (s, 9H), 1.53-1.69 (m, 2H), 1.77-2.05 (m, 6H), 2.06-2.26 (m, 2H), 2.40 -2.66 (m, 4H), 3.24-3.49 (m, 2H), 3.85 (mc, 1H). Intermediate 15:
Allgemeine Vorschrift 15 für die Herstellung von 15: General rule 15 for the preparation of 15:
1 Moläquivalent Thioether wurde in Chloroform gelöst. Auf dem Eisbad wurde meta- Chlorperbenzoesäure (ca. 80-90%ig) in Portionen so zugegeben, dass die Temperatur bei 5 °C blieb. Es wurde 1.5-3 Stunden bei RT nachgerührt, bevor mit Dichlormethan verdünnt wurde. Überschüssige Persäure wurde durch Waschen mit 39%iger Natriumhydrogensulfitlösung (ein- oder zweimal) reduziert. Die organische Phase wurde mit gesättigter Natriumhydrogencarbonatlösung (ein- oder zweimal) und gegebenenfalls mit Wasser gewaschen, über Magnesiumsulfat getrocknet und eingeengt. 1 molar equivalent of thioether was dissolved in chloroform. On the ice bath, meta-chloroperbenzoic acid (about 80-90%) was added in portions such that the temperature remained at 5 ° C. The mixture was stirred for 1.5-3 hours at RT, before being diluted with dichloromethane. Excess peracid was reduced by washing with 39% sodium bisulfite solution (once or twice). The organic phase was washed with saturated sodium bicarbonate solution (once or twice) and optionally with water, dried over magnesium sulfate and concentrated.
Intermediat 1-15Intermediate 1-15
,3,3-trifluorpropyl)sulfonyl] ethyl}pyrrolidin-l-carboxylat , 3,3-trifluoropropyl) sulfonyl] ethyl} pyrrolidine-1-carboxylate
2.14 g (6.54 mmol) tert-Butyl-(2S)-2- {2-[(3,3,3-trifluorpropyl)sulfanyl]ethyl}pyrrolidin-l-carboxylat in 21 ml Chloroform wurden mit 3.61 g (20.92 mmol) meta-Chlorperbenzoesäure entsprechend der allgemeinen Vorschrift 15 umgesetzt. Es wurden 2.19 g (93% d. Th.) Produkt gewonnen. Tert-Butyl (2S) -2- {2 - [(3,3,3-trifluoropropyl) sulfanyl] ethyl} pyrrolidine-1-carboxylate (2.14 g, 6.54 mmol) in 21 ml of chloroform was mixed with 3.61 g (20.92 mmol). reacted meta-chloroperbenzoic acid according to general rule 15. 2.19 g (93% of theory) of product were obtained.
'H-NMR (400 MHz, Chloroform-di): δ = 1.46 (s, 9H), 1.58-1.71 (m, 1H), 1.82-2.20 (m, 5H), 2.60- 2.75 (m, 2H), 2.79-3.25 (m, 4H), 3.28-3.54 (m, 2H), 3.84-4.00 (m, 1H). 'H NMR (400 MHz, chloroform-di): δ = 1.46 (s, 9H), 1.58-1.71 (m, 1H), 1.82-2.20 (m, 5H), 2.60-275 (m, 2H), 2.79 -3.25 (m, 4H), 3.28-3.54 (m, 2H), 3.84-4.00 (m, 1H).
Intermediat 2-15 Intermediate 2-15
tert-Butyl-(2S)-2-{2-[(4,4,4-trifluorbutyl)sulfonyl]ethyl}pyrrolidin-l-carboxylat
tert-butyl (2S) -2- {2 - [(4,4,4-trifluorobutyl) sulfonyl] ethyl} pyrrolidine-l-carboxylate
3.4 g (9.96 mmol) tert-Butyl-(2S)-2- {2-[(4,4,4-trifluorbutyl)sulfanyl]ethyl}pyrrolidin-l-carboxylat in 35 ml Chloroform wurden mit 5.5 g (31.87 mmol) meta-Chlorperbenzoesäure entsprechend der allgemeinen Vorschrift 15 umgesetzt. Es wurden 3.59 g (97% d. Th.) Produkt gewonnen. 3.4 g (9.96 mmol) of tert-butyl (2S) -2- {2 - [(4,4,4-trifluorobutyl) sulfanyl] ethyl} pyrrolidine-1-carboxylate in 35 ml of chloroform were mixed with 5.5 g (31.87 mmol). reacted meta-chloroperbenzoic acid according to general rule 15. There was recovered 3.59 g (97% of theory) of product.
'H-NMR (300 MHz, Chloroform-di): δ = 1.45 (s, 9H), 1.60-1.70 (m, 1H), 1.81-2.21 (m, 7H), 2.32 (mc, 2H), 2.92-3.15 (m, 4H), 3.26-3.55 (m, 2H), 3.92 (mc, 1H). 'H-NMR (300 MHz, chloroform-di): δ = 1.45 (s, 9H), 1.60-1.70 (m, 1H), 1.81-2.21 (m, 7H), 2.32 (mc, 2H), 2.92-3.15 (m, 4H), 3.26-3.55 (m, 2H), 3.92 (mc, 1H).
Intermediat 3-15Intermediate 3-15
5,5,5-pentafluorpentyl)sulfonyl]ethyl}pyrrolidin-l-carboxylat 5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidine-l-carboxylate
4.6 g (11.75 mmol) tert-Butyl-(2S)-2- {2-[(4,4,5,5,5-pentafluorpentyl)sulfanyl]ethyl}pyrrolidin-l - carboxylat in 40 ml Chloroform wurden mit 6.49 g (37.60 mmol) meta-Chlorperbenzoesäure entsprechend der allgemeinen Vorschrift 15 umgesetzt, wobei noch über Nacht bei RT nachgerührt wurde. Es wurden 4.33 g (87% d. Th.) Produkt gewonnen. 4.6 g (11.75 mmol) of tert-butyl (2S) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfanyl] ethyl} pyrrolidine-1-carboxylate in 40 ml of chloroform were mixed with 6.49 g (37.60 mmol) meta-chloroperbenzoic acid according to the general procedure 15, while stirring was continued at RT overnight. 4.33 g (87% of theory) of product were obtained.
'H-NMR (400 MHz, Chloroform-di): δ = 1.44 (s, 9H), 1.61-1.69 (m, 1H), 1.81-2.35 (m, 9H), 2.94- 3.15 (m, 4H), 3.27-3.54 (m, 2H), 3.83-3.98 (m, 1H). 'H-NMR (400 MHz, chloroform-di): δ = 1.44 (s, 9H), 1.61-1.69 (m, 1H), 1.81-2.35 (m, 9H), 2.94-3.15 (m, 4H), 3.27 -3.54 (m, 2H), 3.83-3.98 (m, 1H).
Intermediat 4-15Intermediate 4-15
(3,3,3-trifluorpropyl)sulfonyl]ethyl}pyrrolidin-l-carboxylat (3,3,3-trifluoropropyl) sulfonyl] ethyl} pyrrolidine-l-carboxylate
2.97 g (9.07 mmol) tert-Butyl-(2R)-2- {2-[(3,3,3-trifluorpropyl)sulfanyl]ethyl}pyrrolidin-l-carboxylat in 32 ml Chloroform wurden mit 5 g (28.97 mmol) meta-Chlorperbenzoesäure entsprechend der allgemeinen Vorschrift 15 umgesetzt. Nach Zugabe von Dichlormethan wurde der Niederschlag abgesaugt. Das Filtrat wurde entsprechend der Vorschrift 15 aufgearbeitet. Es wurde über Kieselgel 60 (Laufmittel: Hexan, Hexan-Essigsäureethylester 95:5, 80:20 und 75:25) gereinigt. Es wurden 2.3 g (71 ) d. Th.) Produkt gewonnen.
'H-NMR (300 MHz, Chloroform-di): δ = 1.46 (s, 9H), 1.60-1.71 (m, 1H), 1.81-2.23 (m, 5H), 2.68 (mc, 2H), 2.97-3.25 (m, 4H), 3.27-3.57 (m, 2H), 3.94 (mc, 1H). 2.97 g (9.07 mmol) of tert-butyl (2R) -2- {2 - [(3,3,3-trifluoropropyl) sulfanyl] ethyl} pyrrolidine-1-carboxylate in 32 ml of chloroform were mixed with 5 g (28.97 mmol). reacted meta-chloroperbenzoic acid according to general rule 15. After addition of dichloromethane, the precipitate was filtered off with suction. The filtrate was worked up according to procedure 15. It was purified over silica gel 60 (eluent: hexane, hexane-ethyl acetate 95: 5, 80:20 and 75:25). There were 2.3 g (71) d. Th.) Product recovered. 'H-NMR (300 MHz, chloroform-di): δ = 1.46 (s, 9H), 1.60-1.71 (m, 1H), 1.81-2.23 (m, 5H), 2.68 (mc, 2H), 2.97-3.25 (m, 4H), 3.27-3.57 (m, 2H), 3.94 (mc, 1H).
Intermediat 5-15Intermediate 5-15
,4-trifluorbutyl)sulfonyl]ethyl}pyrrolidin-l-carboxylat , 4-trifluorobutyl) sulfonyl] ethyl} pyrrolidine-l-carboxylate
4 g (11.72 mmol) tert-Butyl-(2R)-2- {2-[(4,4,4-trifluorbutyl)sulfanyl]ethyl}pyrrolidin-l-carboxylat in 40 ml Chloroform wurden mit 6.47 g (37.49 mmol) meta-Chlorperbenzoesäure entsprechend der allgemeinen Vorschrift 15 umgesetzt. Es wurde über Kieselgel 60 (Laufmittel: Hexan, Hexan- Essigsäureethylester 99: 1, 98:2, 95:5, 93:7 und 90: 10) gereinigt. Es wurden 1.02 g (23% d. Th.) Produkt gewonnen. 4 g (11.72 mmol) of tert-butyl (2R) -2- {2 - [(4,4,4-trifluorobutyl) sulfanyl] ethyl} pyrrolidine-1-carboxylate in 40 ml of chloroform were treated with 6.47 g (37.49 mmol). reacted meta-chloroperbenzoic acid according to general rule 15. It was purified over silica gel 60 (eluent: hexane, hexane-ethyl acetate 99: 1, 98: 2, 95: 5, 93: 7 and 90:10). 1.02 g (23% of theory) of product was recovered.
'H-NMR (300 MHz, Chloroform-di): δ = 1.45 (s, 9H), 1.57-1.72 (m, 1H), 1.80-2.22 (m, 7H), 2.23- 2.42 (m, 2H), 2.92-3.17 (m, 4H), 3.26-3.54 (m, 2H), 3.93 (mc, 1H). Intermediat 6-15 'H-NMR (300 MHz, chloroform-di): δ = 1.45 (s, 9H), 1.57-1.72 (m, 1H), 1.80-2.22 (m, 7H), 2.23-2.42 (m, 2H), 2.92 -3.17 (m, 4H), 3.26-3.54 (m, 2H), 3.93 (mc, 1H). Intermediate 6-15
,5,5,5-pentafluorpentyl)sulfonyl]ethyl}pyrrolidin-l-carboxylat , 5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidine-l-carboxylate
2.23 g (5.70 mmol) tert-Butyl-(2R)-2- {2-[(4,4,5,5,5-pentafluorpentyl)sulfanyl]ethyl}pyrrolidin-l - carboxylat in 20 ml Chloroform wurden mit 3.15 g (18.23 mmol) meta-Chlorperbenzoesäure entsprechend der allgemeinen Vorschrift 15 umgesetzt. Nach Zugabe von Dichlormethan wurde der Niederschlag abgesaugt. Das Filtrat wurde entprechend der Vorschrift 15 aufgearbeitet. Es wurde über Kieselgel 60 (Laufmittel: Hexan, Hexan-Essigsäureethylester 80:20 und 75:25) gereinigt. Es wurden 2.04 g (85% d. Th.) Produkt gewonnen. 2.23 g (5.70 mmol) of tert-butyl (2R) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfanyl] ethyl} pyrrolidine-1-carboxylate in 20 ml of chloroform were mixed with 3.15 g (18.23 mmol) meta-chloroperbenzoic acid according to general rule 15 implemented. After addition of dichloromethane, the precipitate was filtered off with suction. The filtrate was worked up according to procedure 15. It was purified over silica gel 60 (eluent: hexane, hexane-ethyl acetate 80:20 and 75:25). There was recovered 2.04 g (85% of theory) of product.
'H-NMR (300 MHz, Chloroform-di): δ = 1.45 (s, 9H), 1.60-1.71 (m, 1H), 1.80-2.37 (m, 9H), 2.92- 3.16 (m, 4H), 3.25-3.54 (m, 2H), 3.92 (mc, 1H). 'H-NMR (300 MHz, chloroform-di): δ = 1.45 (s, 9H), 1.60-1.71 (m, 1H), 1.80-2.37 (m, 9H), 2.92-3.16 (m, 4H), 3.25 -3.54 (m, 2H), 3.92 (mc, 1H).
Intermediate 16: Intermediate 16:
Allgemeine Vorschrift 16 für die Herstellung von 16:
1 Moläquivalent Carbamat wurde in 10-14 Moläquivalenten Trifluoressigsäure gelöst. Hierzu wurden ca. 10 Vol % (bezogen auf Trifluoressigsäure) Triisopropylsilan und ca. 20 Vol % (bezogen auf Trifluoressigsäure) Wasser zugegeben. Es wurde bei RT bis zu 24 Stunden gerührt. Das Reaktionsgemisch wurde in gesättigte Natriumhydrogencarbonatlösung gegosssen und 1 Stunde gerührt. Mit 0.2 M Natronlauge wurde ein pH von 10 eingestellt und dreimal mit Dichlormethan extrahiert. Mit 2 M oder 4 M Salzsäure wurden die vereinigten organischen Phasen extrahiert. Diese wässrige Phase wurde mit Natronlauge basisch gestellt (> pH 10) und dreimal mit Dichlormethan extrahiert. Die vereinigten organischen Phasen wurden über Magnesiumsulfat getrocknet und eingeengt. General rule 16 for the preparation of 16: 1 molar equivalent of carbamate was dissolved in 10-14 molar equivalents of trifluoroacetic acid. About 10% by volume (based on trifluoroacetic acid) of triisopropylsilane and about 20% by volume (based on trifluoroacetic acid) of water were added thereto. It was stirred at RT for up to 24 hours. The reaction mixture was poured into saturated sodium bicarbonate solution and stirred for 1 hour. A pH of 10 was adjusted with 0.2 M sodium hydroxide solution and extracted three times with dichloromethane. With 2 M or 4 M hydrochloric acid, the combined organic phases were extracted. This aqueous phase was basified with sodium hydroxide solution (> pH 10) and extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated.
Intermediat 1-16Intermediate 1-16
-2-{2-[(3,3,3-Trifluorpropyl)sulfonyl]ethyl}pyrrolidin -2- {2 - [(3,3,3-trifluoropropyl) sulfonyl] ethyl} pyrrolidine
2.19 g (6.09 mmol) tert-Butyl-(2S)-2- {2-[(3,3,3-trifluorpropyl)sulfonyl]ethyl}pyrrolidin-l-carboxylat in 4.7 ml Trifluoressigsäure wurden entsprechend der allgemeinen Vorschrift 16 umgesetzt. Es wurden 0.62 g (39% d. Th.) Produkt gewonnen. 2.19 g (6.09 mmol) of tert-butyl (2S) -2- {2 - [(3,3,3-trifluoropropyl) sulfonyl] ethyl} pyrrolidine-1-carboxylate in 4.7 ml of trifluoroacetic acid were reacted in accordance with general procedure 16. 0.62 g (39% of theory) of product were obtained.
'H-NMR (400 MHz, Chloroform-di): δ = 1.31-1.41 (m, 1H), 1.66-2.08 (m, 5H), 2.61-2.75 (m, 2H), 2.88-2.98 (m, 2H), 3.07-3.28 (m, 5H). Intermediat 2-16 'H-NMR (400 MHz, chloroform-di): δ = 1.31-1.41 (m, 1H), 1.66-2.08 (m, 5H), 2.61-2.75 (m, 2H), 2.88-2.98 (m, 2H) , 3.07-3.28 (m, 5H). Intermediate 2-16
-2-{2-[(4,4,4-Trifluorbutyl)sulfonyl]ethyl}pyrrolidin -2- {2 - [(4,4,4-trifluorobutyl) sulfonyl] ethyl} pyrrolidine
3.59 g (9.61 mmol) tert-Butyl-(2S)-2- {2-[(4,4,4-trifluorbutyl)sulfonyl]ethyl}pyrrolidin-l-carboxylat in 7.5 ml Trifluoressigsäure wurden entsprechend der allgemeinen Vorschrift 16 umgesetzt. Es wurden 0.80 g (30% d. Th.) Produkt gewonnen. 3.59 g (9.61 mmol) of tert-butyl (2S) -2- {2 - [(4,4,4-trifluorobutyl) sulfonyl] ethyl} pyrrolidine-1-carboxylate in 7.5 ml of trifluoroacetic acid were reacted in accordance with general procedure 16. There were obtained 0.80 g (30% of theory) of product.
'H-NMR (300 MHz, Chloroform-di): δ = 1.26-1.42 (m, 1H), 1.63-2.21 (m, 7H), 2.23-2.41 (m, 2H), 2.83-3.26 (m, 7H). 'H-NMR (300 MHz, chloroform-di): δ = 1.26-1.42 (m, 1H), 1.63-2.21 (m, 7H), 2.23-2.41 (m, 2H), 2.83-3.26 (m, 7H) ,
Intermediat 3-16 Intermediate 3-16
(2S)-2-{2-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]ethyl}pyrrolidin
(2S) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidine
4.3 g (10.16 mmol) tert-Butyl-(2S)-2- {2-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]ethyl}pyrrolidin-l- carboxylat in 10 ml Trifluoressigsäure wurden 5 Stunden bei 0 °C entsprechend der allgemeinen Vorschrift 16 umgesetzt und aufgearbeitet. Es wurden 3.2 g (97% d. Th.) Produkt gewonnen. 4.3 g (10.16 mmol) of tert-butyl (2S) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidine-1-carboxylate in 10 ml of trifluoroacetic acid were added for 5 hours 0 ° C implemented in accordance with general rule 16 and worked up. 3.2 g (97% of theory) of product were obtained.
'H-NMR (300 MHz, Chloroform-di): δ = 1.27-1.41 (m, 1H), 1.63-2.08 (m, 5H), 2.12-2.37 (m, 4H), 2.84-2.99 (m, 2H), 3.01-3.24 (m, 5H). 'H-NMR (300 MHz, chloroform-di): δ = 1.27-1.41 (m, 1H), 1.63-2.08 (m, 5H), 2.12-2.37 (m, 4H), 2.84-2.99 (m, 2H) , 3.01-3.24 (m, 5H).
Intermediat 4-16Intermediate 4-16
-2-{2-[(3,3,3-Trifluorpropyl)sulfonyl]ethyl}pyrrolidin -2- {2 - [(3,3,3-trifluoropropyl) sulfonyl] ethyl} pyrrolidine
2.3 g (6.40 mmol) tert-Butyl-(2R)-2- {2-[(3,3,3-trifluorpropyl)sulfonyl]ethyl}pyrrolidin-l-carboxylat in 5.7 ml Trifluoressigsäure wurden entsprechend der allgemeinen Vorschrift 16 umgesetzt. Bei der Aufarbeitung wurde nur bei pH 10 extrahiert und über Magnesiumsulfat getrocknet und eingeengt. Es wurden 1.22 g (74% d. Th.) Produkt gewonnen. 2.3 g (6.40 mmol) of tert-butyl (2R) -2- {2 - [(3,3,3-trifluoropropyl) sulfonyl] ethyl} pyrrolidine-1-carboxylate in 5.7 ml of trifluoroacetic acid were reacted in accordance with general procedure 16. The work-up was extracted only at pH 10 and dried over magnesium sulfate and concentrated. 1.22 g (74% of theory) of product were recovered.
'H-NMR (300 MHz, Chloroform-di): δ = 1.30-1.44 (m, 1H), 1.65-2.11 (m, 5H), 2.58-2.77 (m, 2H), 2.87-3.02 (m, 2H), 3.06-3.32 (m, 5H). 'H-NMR (300 MHz, chloroform-di): δ = 1.30-1.44 (m, 1H), 1.65-2.11 (m, 5H), 2.58-2.77 (m, 2H), 2.87-3.02 (m, 2H) , 3.06-3.32 (m, 5H).
Intermediat 5-16Intermediate 5-16
-2-{2-[(4,4,4-Trifluorbutyl)sulfonyl]ethyl}pyrrolidin -2- {2 - [(4,4,4-trifluorobutyl) sulfonyl] ethyl} pyrrolidine
1.02 g (2.73 mmol) tert-Butyl-(2R)-2- {2-[(4,4,4-trifluorbutyl)sulfonyl]ethyl}pyrrolidin-l-carboxylat in 2.1 ml Trifluoressigsäure wurden entsprechend der allgemeinen Vorschrift 16 umgesetzt. Es wurden 0.49 g (66% d. Th.) Produkt gewonnen. 1.02 g (2.73 mmol) of tert-butyl (2R) -2- {2 - [(4,4,4-trifluorobutyl) sulfonyl] ethyl} pyrrolidine-1-carboxylate in 2.1 ml of trifluoroacetic acid were reacted according to general procedure 16. 0.49 g (66% of theory) of product was recovered.
'H-NMR (400 MHz, Chloroform-di): δ = 1.29-1.39 (m, 1H), 1.66-1.88 (m 3H), 1.89-2.05 (m, 2H), 2.10-2.20 (m, 2H), 2.26-2.39 (m, 2H), 2.85-2.98 (m, 2H), 3.01-3.11 (m, 3H), 3.13-3.22 (m, 2H). 'H-NMR (400 MHz, chloroform-di): δ = 1.29-1.39 (m, 1H), 1.66-1.88 (m 3H), 1.89-2.05 (m, 2H), 2.10-2.20 (m, 2H), 2.26-2.39 (m, 2H), 2.85-2.98 (m, 2H), 3.01-3.11 (m, 3H), 3.13-3.22 (m, 2H).
Intermediat 6-16 Intermediate 6-16
(2R)-2-{2-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]ethyl}pyrrolidin
(2R) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidine
2.02 g (4.77 mmol) tert-Butyl-(2R)-2- {2-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]ethyl}pyrrolidin-l- carboxylat in 5 ml Trifluoressigsäure wurden entsprechend der allgemeinen Vorschrift 16 umgesetzt. Das Reaktionsgemisch wurde in gesättigte Natriumhydrogencarbonatlösung gegosssen und 1 Stunde gerührt. Mit 0.2 M Natronlauge wurde ein pH von 10 eingestellt und dreimal mit Dichlormethan extrahiert. Die vereinigten organischen Phasen wurde über Magnesiumsulfat getrocknet, eingeengt und mit Diethylether digeriert. Es wurden 1.21 g (78% d. Th.) Produkt gewonnen. 2.02 g (4.77 mmol) of tert-butyl (2R) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidine-1-carboxylate in 5 ml of trifluoroacetic acid were added according to the general procedure Regulation 16 implemented. The reaction mixture was poured into saturated sodium bicarbonate solution and stirred for 1 hour. A pH of 10 was adjusted with 0.2 M sodium hydroxide solution and extracted three times with dichloromethane. The combined organic phases were dried over magnesium sulfate, concentrated and digested with diethyl ether. 1.21 g (78% of theory) of product were recovered.
'H-NMR (300 MHz, Chloroform-di): δ = 1.44 (mc, 1H), 1.71-2.36 (m, 9H), 2.94-3.15 (m, 5H), 3.17- 3.35 (m, 2H). 'H-NMR (300 MHz, chloroform-di): δ = 1.44 (mc, 1H), 1.71-2.36 (m, 9H), 2.94-3.15 (m, 5H), 3.17-3.35 (m, 2H).
Intermediat 17 Intermediate 17
{3-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]propyl}(triphenyl)phosphoniumiodid {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} (triphenyl) phosphonium iodide
Man rührte eine Mischung aus 2.22 g (8.46 mmol) Triphenylphosphin und 3.33 g (8.45 mmol) l,l,l,2,2-Pentafluor-5-[(3-iodpropyl)sulfonyl]pentan (CAS 199730-82-0) in 10 ml Acetontril unter Stickstoff bei 95°C Badtemperatur 18 h. Man engte ein und kristallisierte aus Diethylether. Man erhielt 7.2 g der Titelverbindung. A mixture of 2.22 g (8.46 mmol) of triphenylphosphine and 3.33 g (8.45 mmol) of 1,1,2,2-pentafluoro-5 - [(3-iodopropyl) sulfonyl] pentane (CAS 199730-82-0) was stirred. in 10 ml of acetone tril under nitrogen at 95 ° C bath temperature 18 h. It was concentrated and crystallized from diethyl ether. 7.2 g of the title compound were obtained.
1H-NMR (300MHz, DMSO-de): δ [ppm]= 1.80 - 2.02 (m, 4H), 2.22 - 2.44 (m, 2H), 3.19 - 3.43 (m, 4H), 3.60 - 3.76 (m, 2H), 7.69 - 7.97 (m, 15H). 1H-NMR (300MHz, DMSO-de): δ [ppm] = 1.80 - 2.02 (m, 4H), 2.22 - 2.44 (m, 2H), 3.19 - 3.43 (m, 4H), 3.60 - 3.76 (m, 2H ), 7.69 - 7.97 (m, 15H).
Intermediat 18 Intermediate 18
tert-Butyl-(25)-2-{(lE)-4-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]but-l-en-l-yl}pyrrolidin-l- carboxylat
tert -Butyl (25) -2 - {(LE) -4 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] but-1-en-1-yl} pyrrolidine 1-carboxylate
5.60 g (8.53 mmol) {3-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]propyl}(triphenyl)phosphoniumiodid wurden in 100 ml THF vorgelegt. Man kühlte auf -30°C ab, addierte 7.53 ml einer Kalium-tert- butanolatlösung (IM in THF) und rührte 2 h bei -30°C. Man addierte 1.00 g tert-Butyl-(2S)-2- formylpyrrolidin-l-carboxylat, ließ über Nacht auf RT kommen, addierte 100 ml Hexan, saugte ab und wusch mit Diethylether und Hexan nach. Das Filtrat wurde eingeengt und der Rückstand säulenchromatographisch an Kieselgel gereinigt. Man erhielt 1.56 g der Titelverbindung. 5.60 g (8.53 mmol) of {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} (triphenyl) phosphonium iodide were initially charged in 100 ml of THF. The mixture was cooled to -30 ° C, added 7.53 ml of a potassium tert-butoxide solution (IM in THF) and stirred for 2 h at -30 ° C. 1.00 g of tert-butyl (2S) -2-formylpyrrolidine-1-carboxylate was added, the mixture was allowed to come to RT overnight, 100 ml of hexane were added, the mixture was filtered off with suction and washed with diethyl ether and hexane. The filtrate was concentrated and the residue was purified by column chromatography on silica gel. 1.56 g of the title compound were obtained.
'H-NMR (300MHZ, CHLOROFORM-d, ausgewählte Signale): δ [ppm]= 1.42 (s, 9H), 2.52 - 2.66 (m, 1H), 2.80 (br. s, 1H), 2.98 - 3.42 (m, 6H), 4.52 (td, 1H), 5.29 - 5.51 (m, 2H). 'H-NMR (300MHZ, CHLOROFORM-d, selected signals): δ [ppm] = 1.42 (s, 9H), 2.52 - 2.66 (m, 1H), 2.80 (brs s, 1H), 2.98 - 3.42 (m , 6H), 4.52 (td, 1H), 5.29 - 5.51 (m, 2H).
Intermediat 19 Intermediate 19
tert-Butyl-(2R)-2-{4-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]butyl}pyrrolidin-l-carboxylat tert-butyl (2R) -2- {4 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] butyl} pyrrolidin-l-carboxylate
1.56 g (3.47 mmol) tert-Butyl-(2S)-2- {(lE)-4-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]but-l-en-l- yl}pyrrolidin-l-carboxylat wurden in 40 ml Methanol und 10 ml Wasser in Gegenwart von 318 mg Palladium auf Kohlenstoff (10 prozentig) unter eine Wasserstoffatmosphäre gesetzt. Man filtrierte und engte ein. 1.56 g (3.47 mmol) of tert-butyl (2S) -2- {(IE) -4 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] but-1-en-1-yl} pyrrolidine -l-carboxylate was placed in 40 ml of methanol and 10 ml of water in the presence of 318 mg of palladium on carbon (10%) under a hydrogen atmosphere. It was filtered and concentrated.
'H-NMR (300MHZ, CHLOROFORM-di, ausgewählte Signale): δ = 1 .45 (s, 9H), 2.88 - 3.14 (m, 5H), 3.23 - 3.41 (m, 2H), 3.69 - 3.82 (m). 'H-NMR (300MHZ, CHLOROFORM-di, selected signals): δ = 1.45 (s, 9H), 2.88-3.14 (m, 5H), 3.23-3.41 (m, 2H), 3.69-3.82 (m) ,
Intermediat 20 Intermediate 20
(2R)-2-{4-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]butyl}pyrrolidin (2R) -2- {4 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] butyl} pyrrolidin
Eine Lösung aus 1.42 g (3.15 mmol) tert-Butyl-(2R)-2- {4-[(4,4,5,5,5- pentafluorpentyl)sulfonyl]butyl}pyrrolidin-l -carboxylat in 10 ml Dichlormethan wurden mit 2.5 ml TFA versetzt und über Nacht bei RT gerührt. Man addierte gesättigte Natriumhydrogen- carbonatlösung, rührte 1 h, trennte die organische Phase ab und extrahierte dreimal mit Dichlormethan. Die vereinigten organischen Phasen wurden mit Natriumchloridlösung gewaschen, über Natriumsulfat getrocknet und eingeengt. Man erhielt 1.17 g eines Rohrproduktes, das ohne weitere Reinigung eingesetzt wurde. A solution of 1.42 g (3.15 mmol) of tert -butyl (2R) -2- {4 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] butyl} pyrrolidine 1-carboxylate in 10 ml of dichloromethane mixed with 2.5 ml of TFA and stirred overnight at RT. Saturated sodium bicarbonate solution was added, stirred for 1 h, the organic phase separated and extracted three times with dichloromethane. The combined organic phases were washed with sodium chloride solution, dried over sodium sulfate and concentrated. This gave 1.17 g of a tube product which was used without further purification.
Intermediat 1-21 Intermediate 1-21
tert-Butyl-(2S,4R)-2-[(lE)-3-ethoxy-3-oxoprop-l-en-l-yl]-4-fluorpyrrolidin-l-carboxylat tert-butyl (2S, 4R) -2 - [(lE) -3-ethoxy-3-oxoprop-l-en-l-yl] -4-fluoropyrrolidine-l-carboxylate
8.18 g (19.1 mmol) (2-Ethoxy-2-oxoethyl)(triphenyl)phosphoniumbromid wurden in 60 ml Dichlormethan unter Stickstoff vorgelegt und mit 4.0 ml Triethylamin versetzt. Man ließ 15 min bei RT rühren, addierte 2.07 g (9.53 mmol) tert-Butyl-(2S,4R)-4-fluor-2-formylpyrro lidin- 1-carboxylat (CAS 1299466-02-6) gelöst in 20 ml Dichlormethan und rührte 18 h bei RT. Man addierte Diethylether und Wasser, trennte die organische Phase ab, extrahierte zweimal mit Diethylether, wusch die vereinigten organischen Phasen mit gesättigter Natriumchloridlösung, trocknete über Natriumsulfat, engte ein und reinigte durch Säulenchromatographie an Kieselgel (Hexan/Ethylacetat). Man erhielt 1.44 g der Titelverbindung. 8.18 g (19.1 mmol) of (2-ethoxy-2-oxoethyl) (triphenyl) phosphonium bromide were introduced into 60 ml of dichloromethane under nitrogen and treated with 4.0 ml of triethylamine. The mixture was stirred at RT for 15 min, and 2.07 g (9.53 mmol) of tert-butyl (2S, 4R) -4-fluoro-2-formylpyrrolidine-1-carboxylate (CAS 1299466-02-6) were added in 20 ml of dichloromethane and stirred for 18 h at RT. Diethyl ether and water were added, the organic phase separated, extracted twice with diethyl ether, the combined organic phases washed with saturated sodium chloride solution, dried over sodium sulfate, concentrated and purified by column chromatography on silica gel (hexane / ethyl acetate). This gave 1.44 g of the title compound.
'H-NMR (300MHZ, CHLOROFORM-di): δ [ppm]= 1.28 (t, 3H), 1.42 (s, 9H), 1.74 - 2.02 (m, 1H), 2.38 - 2.55 (m, 1H), 3.38 - 3.59 (m, 1H), 3.78 - 4.06 (m, 1H), 4.1 1 - 4.26 (m, 1H), 3.92 (d, 1H), 4.08 - 4.27 (m, 2H), 4.42 - 4.68 (m, 1H), 5.02 - 5.27 (m, 1H), 5.90 (d, 1H), 6.72 - 6.91 (m, 1H). 'H NMR (300MHZ, CHLOROFORM-di): δ [ppm] = 1.28 (t, 3H), 1.42 (s, 9H), 1.74-2.02 (m, 1H), 2.38-2.55 (m, 1H), 3.38 - 3.59 (m, 1H), 3.78 - 4.06 (m, 1H), 4.1 1 - 4.26 (m, 1H), 3.92 (d, 1H), 4.08 - 4.27 (m, 2H), 4.42 - 4.68 (m, 1H ), 5.02 - 5.27 (m, 1H), 5.90 (d, 1H), 6.72 - 6.91 (m, 1H).
Intermdiat 2-21Intermediate 2-21
3-ethoxy-3-oxoprop-l-en-l-yl]-4,4-difluorpyrrolidin-l-carboxylat 3-ethoxy-3-oxoprop-l-en-l-yl] -4,4-difluoropyrrolidine-l-carboxylate
Analog zur Herstellung von Intermediat 1 -21 wurde (2-Ethoxy-2- oxoethyl)(triphenyl)phosphoniumbromid mit tert-Butyl-(2S)-4,4-difluor-2-formylpyrro lidin- 1 -
carboxylat (CAS 1 194032-45-5) umgesetzt. Nach säulenchromatographischer Reinigung an Kieselgel erhielt man 620 mg (27% d. Th.) der Titelverbindung. Analogously to the preparation of Intermediate 1 -21, (2-ethoxy-2-oxoethyl) (triphenyl) phosphonium bromide was treated with tert-butyl (2S) -4,4-difluoro-2-formylpyrrolidine 1 - carboxylate (CAS 1 194032-45-5) implemented. After purification by column chromatography on silica gel, 620 mg (27% of theory) of the title compound were obtained.
'H-NMR (400MHZ, CHLOROFORM-di): δ [ppm]= 1.29 (t, 3H), 1.44 (s, 9H), 1 .62 (br. s, 1H), 2.17 - 2.31 (m, 1H), 2.55 - 2.71 (m, 1H), 3.71 (q, 1 H), 3.83 (br. s, 1H), 4.14 - 4.28 (m, 2H), 4.50 - 4.77 (m, 1H), 5.90 (d, 1H), 6.82 (dd, 1H). 'H-NMR (400MHZ, CHLOROFORM-di): δ [ppm] = 1.29 (t, 3H), 1.44 (s, 9H), 1.62 (br.s, 1H), 2.17-2.31 (m, 1H) , 2.55 - 2.71 (m, 1H), 3.71 (q, 1H), 3.83 (brs s, 1H), 4.14 - 4.28 (m, 2H), 4.50 - 4.77 (m, 1H), 5.90 (d, 1H ), 6.82 (dd, 1H).
Intermediat 3-21 Intermediate 3-21
tert-Butyl-(2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[(lE)-3-ethoxy-3-oxoprop-l-en-l- tert-butyl (2S, 4R) -4 - {[tert-butyl (dimethyl) silyl] oxy} -2 - [(lE) -3-ethoxy-3-oxoprop-l-en-l-
Analog zur Herstellung von Intermediat 1-21 wurden 6.10 g (18.5 mmol) tert-Butyl-(2S,4R)-4- {[tert- butyl(dimethyl)silyl]oxy}-2-formylpyrrolidin-l -carboxylat (CAS: 137955-35-2) mit 15.9 g (37.0 mmol) (2-Ethoxy-2-oxoethyl)(triphenyl)phosphoniumbromid umgesetzt. Nach säulenchromatographischer Reinigung an Kieselgel (Hexan/Ethylacetat) erhielt man 3.30 g (45% d. Th.) der Titelverbindung. Analogously to the preparation of Intermediate 1-21, 6.10 g (18.5 mmol) of tert-butyl (2S, 4R) -4- [[tert-butyl (dimethyl) silyl] oxy} -2-formylpyrrolidine 1-carboxylate (CAS: 137955-35-2) with 15.9 g (37.0 mmol) of (2-ethoxy-2-oxoethyl) (triphenyl) phosphonium bromide. After purification by column chromatography on silica gel (hexane / ethyl acetate), 3.30 g (45% of theory) of the title compound were obtained.
'H-NMR (400MHZ, CHLOROFORM-di): δ [ppm]= 0.06 (s, 6H), 0.87 (s, 9H), 1.29 (t, 3H), 1.34 - 1.52 (m, 9H), 1.77 - 1.86 (m, 1H), 2.03 - 2.12 (m, 1H), 3.31 - 3.51 (m, 2H), 4.14 - 4.25 (m, 2H), 4.29 - 4.37 (m, 1H), 4.39 - 4.62 (m, 1H), 5.86 (d, 1H), 6.82 (br. s, 1H). 'H-NMR (400MHZ, CHLOROFORM-di): δ [ppm] = 0.06 (s, 6H), 0.87 (s, 9H), 1.29 (t, 3H), 1.34 - 1.52 (m, 9H), 1.77 - 1.86 (m, 1H), 2.03 - 2.12 (m, 1H), 3.31 - 3.51 (m, 2H), 4.14 - 4.25 (m, 2H), 4.29 - 4.37 (m, 1H), 4.39 - 4.62 (m, 1H) , 5.86 (d, 1H), 6.82 (br s, 1H).
Intermediat 4-21 Intermediate 4-21
tert-Butyl-(2S)-2-[(lE)-3-methoxy-3-oxoprop-l-en-l-yl]pyrrolidin-l-carboxylat tert-butyl (2S) -2 - [(lE) -3-methoxy-3-oxoprop-l-en-l-yl] pyrrolidin-l-carboxylate
Analog zu Intermediat 1-21 wurde tert-Butyl-(2S)-2-formylpyrro lidin- 1 -carboxylat (CAS 69610-41-9) mit Methyl(diethoxyphosphoryl)acetat (CAS 1067-74-9) umgesetzt. Die Titelverbindung wurde als farbloses Öl erhalten. Analogously to Intermediate 1-21, tert-butyl (2S) -2-formylpyrrolidine-1-carboxylate (CAS 69610-41-9) was reacted with methyl (diethoxyphosphoryl) acetate (CAS 1067-74-9). The title compound was obtained as a colorless oil.
'H-NMR (300MHZ, DMSO-de): δ [ppm]= 1.31 - 1.42 (m, 9H), 1.65 - 1.82 (m, 3H), 1.95 - 2.12 (m, 1H), 3.24 - 3.32 (m, 2H), 3.66 (s, 3H), 4.25 - 4.44 (m, 1H), 5.77 (d, 1H), 6.78 (dd, 1H). 'H-NMR (300MHZ, DMSO-de): δ [ppm] = 1.31-1.42 (m, 9H), 1.65-1.82 (m, 3H), 1.95-2.12 (m, 1H), 3.24-3.32 (m, 2H), 3.66 (s, 3H), 4.25-4.44 (m, 1H), 5.77 (d, 1H), 6.78 (dd, 1H).
Drehwert: [a] = - 77,8 ° (c = 1.0, CHC13).
Intermediat 5-21 Rotation: [a] = - 77.8 ° (c = 1.0, CHC1 3 ). Intermediate 5-21
tert-Butyl-(2R)-2-[(lE)-3-methoxy-3-oxoprop-l-en-l-yl]pyrrolidin-l-carboxylat tert-butyl (2R) -2 - [(lE) -3-methoxy-3-oxoprop-l-en-l-yl] pyrrolidin-l-carboxylate
Analog zu Intermediat 1-21 wurde tert-Butyl-(2R)-2-formylpyrrolidin-l-carboxylat (CAS 73365-02-3) mit Methyl(diethoxyphosphoryl)acetat (CAS 1067-74-9) umgesetzt. Die Titelverbindung wurde als farbloses Öl erhalten. Analogously to Intermediate 1-21, tert-butyl (2R) -2-formylpyrrolidine-1-carboxylate (CAS 73365-02-3) was reacted with methyl (diethoxyphosphoryl) acetate (CAS 1067-74-9). The title compound was obtained as a colorless oil.
'H-NMR (300MHZ, DMSO-de): δ [ppm]= 1.31 - 1.42 (m, 9H), 1.65 - 1.82 (m, 3H), 1.95 - 2.12 (m, 1H), 3.24 - 3.32 (m, 2H), 3.66 (s, 3H), 4.25 - 4.44 (m, 1H), 5.77 (d, 1H), 6.78 (dd, 1H). 'H-NMR (300MHZ, DMSO-de): δ [ppm] = 1.31-1.42 (m, 9H), 1.65-1.82 (m, 3H), 1.95-2.12 (m, 1H), 3.24-3.32 (m, 2H), 3.66 (s, 3H), 4.25-4.44 (m, 1H), 5.77 (d, 1H), 6.78 (dd, 1H).
Drehwert: [a] = 62,5 ° (c = 1.0, CHC13). Rotation: [a] = 62.5 ° (c = 1.0, CHC1 3 ).
Intermediat 1-22 Intermediate 1-22
tert-Butyl-(2R,4R)-2-(3-ethoxy-3-oxopropyl)-4-fluorpyrrolidin-l-carboxylat tert-butyl (2R, 4R) -2- (3-ethoxy-3-oxopropyl) -4-fluoropyrrolidine-l-carboxylate
1.80 g (6.26 mmol) tert-Butyl-(2S,4R)-2-[(lE)-3-ethoxy-3-oxoprop-l-en-l-yl]-4-fluorpyrrolidin-l- carboxylat wurden in 30 ml Ethylacetat und 10 ml Ethanol vorgelegt. Man addierte 1.0 g Palladium auf Kohlenstoff (10 prozentig), evakuierte dreimal und belüftete mit Stickstoff. Danach erhitzte man unter Rückfluß, addierte portionsweise je 1 ml 1 ,4-Cyclohexadien (insgesamt 10 ml), erhitzte 30 min unter Rückfluß, ließ auf RT kommen und filtrierte. Nach Einengen im Vakuum erhielt man 1.7 g der Titelverbindung. 1.80 g (6.26 mmol) of tert-butyl (2S, 4R) -2 - [(1E) -3-ethoxy-3-oxoprop-1-en-1-yl] -4-fluoropyrrolidine-1-carboxylate were added in 30 ml of ethyl acetate and 10 ml of ethanol. 1.0 g of palladium on carbon (10 percent) was added, evacuated three times and aerated with nitrogen. Thereafter, it was heated under reflux, added in portions each 1 ml of 1, 4-cyclohexadiene (10 ml total), heated for 30 min under reflux, allowed to come to RT and filtered. Concentration in vacuo gave 1.7 g of the title compound.
'H-NMR (300MHZ, CHLOROFORM-d): δ [ppm]= 1.25 (t, 3H), 1.47 (s, 9H), 1.63 - 1.90 (m), 2.09 - 2.47 (m, 4H), 3.22 - 3.44 (m, 1H), 3.40 (dd, 1H), 3.80 - 4.07 (m, 2H), 4.12 (q, 2H), 4.98 - 5.22 (m, 1H). Intermediat 2-22 'H NMR (300MHZ, CHLOROFORM-d): δ [ppm] = 1.25 (t, 3H), 1.47 (s, 9H), 1.63-1.90 (m), 2.09-2.47 (m, 4H), 3.22-3.44 (m, 1H), 3.40 (dd, 1H), 3.80 - 4.07 (m, 2H), 4.12 (q, 2H), 4.98 - 5.22 (m, 1H). Intermediate 2-22
tert-Butyl-(2R)-2-(3-ethoxy-3-oxopropyl)-4,4-difluorpyrrolidin-l-carboxylat
tert-butyl (2R) -2- (3-ethoxy-3-oxopropyl) -4,4-difluoropyrrolidine-l-carboxylate
Analog zur Herstellung von Intermediat 1-22 wurde tert-Butyl-(2S)-2-[(lE)-3-ethoxy-3-oxoprop-l-en- l-yl]-4,4-difluorpyrrolidin-l-carboxylat mit Wasserstoff in Gegenwart von Palladium auf Kohlenstoff zu 1.4 g der Titelverbindung umgesetzt. Analogously to the preparation of Intermediate 1-22, tert-butyl (2S) -2 - [(1E) -3-ethoxy-3-oxoprop-1-en-1-yl] -4,4-difluoropyrrolidine-1-carboxylate reacted with hydrogen in the presence of palladium on carbon to 1.4 g of the title compound.
'H-NMR (300MHZ, CHLOROFORM-di): δ [ppm]= 1.25 (t, 3H), 1.46 (s, 9H), 1.76 - 1.90 (m, 1H), 2.03 - 2.21 (m, 2H), 2.24 - 2.38 (m, 2H), 2.38 - 2.60 (m, 1H), 3.59 (q, 1H), 3.84 (br. s, 1H), 3.99 - 4.18 (m, 3H). 'H NMR (300MHZ, CHLOROFORM-di): δ [ppm] = 1.25 (t, 3H), 1.46 (s, 9H), 1.76-1.90 (m, 1H), 2.03-2.21 (m, 2H), 2.24 - 2.38 (m, 2H), 2.38 - 2.60 (m, 1H), 3.59 (q, 1H), 3.84 (br, s, 1H), 3.99 - 4.18 (m, 3H).
Intermediat 3-22 Intermediate 3-22
tert-Butyl-(2R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-ethoxy-3-oxopropyl)pyrrolidin-l- tert-butyl (2R, 4R) -4 - {[tert-butyl (dimethyl) silyl] oxy} -2- (3-ethoxy-3-oxopropyl) pyrrolidin-l-
Analog zur Herstellung von Intermediat 1-22 wurden 3.30 g (8.26 mmol) tert-Butyl-(2S,4R)-4- {[tert- butyl(dimethyl)silyl]oxy}-2-[(lE)-3-ethoxy-3-oxoprop-l-en-l-yl]pyrrolidin-l-carboxylat mit Wasser- stoff in Gegenwart von Palladium auf Kohlenstoff zu 2.90 g (87% d. Th.) der Titelverbindung umge- setzt. Analogously to the preparation of Intermediate 1-22, 3.30 g (8.26 mmol) of tert-butyl (2S, 4R) -4- {[tert-butyl (dimethyl) silyl] oxy} -2 - [(IE) -3-ethoxy 3-oxoprop-1-en-1-yl] pyrrolidine-1-carboxylate with hydrogen in the presence of palladium on carbon to give 2.90 g (87% of theory) of the title compound.
'H-NMR (400MHZ, CHLOROFORM-di): δ [ppm]= 0.05 (s, 6H), 0.86 (s, 9H), 1.25 (t, 3H), 1.46 (s, 9H), 1.65 - 1.83 (m, 2H), 1.89 - 2.00 (m, 1H), 2.06 (br. s, 1H), 2.21 - 2.36 (m, 2H), 3.26 - 3.60 (m, 2H), 3.92 (br. s, 1H), 4.12 (q, 2H), 4.33 (quin, 1H). 'H-NMR (400MHZ, CHLOROFORM-di): δ [ppm] = 0.05 (s, 6H), 0.86 (s, 9H), 1.25 (t, 3H), 1.46 (s, 9H), 1.65 - 1.83 (m , 2H), 1.89 - 2.00 (m, 1H), 2.06 (br s, 1H), 2.21 - 2.36 (m, 2H), 3.26 - 3.60 (m, 2H), 3.92 (br s, 1H), 4.12 (q, 2H), 4.33 (quin, 1H).
Intermediat 4-22 Intermediate 4-22
tert-Butyl-(2S)-2-(3-methoxy-3-oxopropyl)pyrrolidin-l-carboxylat tert-butyl (2S) -2- (3-methoxy-3-oxopropyl) pyrrolidine-l-carboxylate
Analog zur Herstellung von Intermediat 1-22 wurden 17 g (66.8 mmol) tert-Butyl (2S)-2-[(lE)-3- methoxy-3-oxoprop-l-en-l -yl]pyrrolidin-l-carboxylat mit Wasserstoff in Gegenwart von Palladium auf Kohlenstoff zu 16.9 g (93% d. Th.) der Titelverbindung umgesetzt. Analogously to the preparation of Intermediate 1-22, 17 g (66.8 mmol) of tert-butyl (2S) -2 - [(IE) -3-methoxy-3-oxoprop-1-en-1-yl] pyrrolidine-1-carboxylate reacted with hydrogen in the presence of palladium on carbon to give 16.9 g (93% of theory) of the title compound.
'H-NMR (300MHZ, DMSO-de): δ [ppm]= 1.38 (s, 9H), 1.59 (d, 2H), 1.66 - 1.94 (m, 4H), 2.21 - 2.33 (m, 2H), 3.10 - 3.31 (m, 2H), 3.58 (s, 3H), 3.67 (d, 1H). 'H-NMR (300MHZ, DMSO-de): δ [ppm] = 1.38 (s, 9H), 1.59 (d, 2H), 1.66 - 1.94 (m, 4H), 2.21 - 2.33 (m, 2H), 3.10 - 3.31 (m, 2H), 3.58 (s, 3H), 3.67 (d, 1H).
Drehwert: [a] = - 34,3 ° (c = 1.0, CHC13). Rotation: [a] = - 34.3 ° (c = 1.0, CHC1 3 ).
Intermediat 5-22Intermediate 5-22
thoxy-3-oxopropyl)pyrrolidin-l-carboxylat thoxy-3-oxopropyl) pyrrolidine-l-carboxylate
Analog zur Herstellung von Intermediat 1-22 wurden 18.8 g (73.6 mmol) tert-Butyl (2R)-2-[(lE)-3- methoxy-3-oxoprop-l-en-l -yl]pyrrolidin-l-carboxylat mit Wasserstoff in Gegenwart von Palladium auf Kohlenstoff zu 18.58 g (93% d. Th.) der Titelverbindung umgesetzt. Analogously to the preparation of Intermediate 1-22, 18.8 g (73.6 mmol) of tert-butyl (2R) -2 - [(IE) -3-methoxy-3-oxoprop-1-en-1-yl] pyrrolidine-1-carboxylate reacted with hydrogen in the presence of palladium on carbon to give 18.58 g (93% of theory) of the title compound.
'Η-ΝΜΡν (300MHZ, DMSO-de): δ [ppm]= 1.38 (s, 9H), 1.59 (d, 2H), 1.66 - 1.94 (m, 4H), 2.21 - 2.33 (m, 2H), 3.10 - 3.31 (m, 2H), 3.58 (s, 3H), 3.67 (d, 1H). 'Η-ΝΜΡν (300MHZ, DMSO-en): δ [ppm] = 1.38 (s, 9H), 1.59 (d, 2H), 1.66 - 1.94 (m, 4H), 2.21 - 2.33 (m, 2H), 3.10 - 3.31 (m, 2H), 3.58 (s, 3H), 3.67 (d, 1H).
Drehwert: [a] = 33,2 0 (c = 1.0, CHCI3). Rotation: [a] = 33.2 0 (c = 1.0, CHCI3).
Intermediat 1-23 Intermediate 1-23
tert-Butyl-(2R,4R)-4-fluor-2-(3-hydroxypropyl)pyrrolidin-l-carboxylattert-butyl (2R, 4R) -4-fluoro-2- (3-hydroxypropyl) pyrrolidine-l-carboxylate
H H
Eine Lösung aus 1.68 g (5.81 mmol) tert-Butyl-(2R,4R)-2-(3-ethoxy-3-oxopropyl)-4-fluorpyrrolidin- 1-carboxylat in 84 ml THF wurde auf -40°C abgekühlt, vorsichtig 14.5 ml Diisobutylaluminiumhydridlösung (IM in THF) zugetropft und 3 h gerührt. Man ließ auf RT kommen, addierte vorsichtig 1.9 ml Methanol, kühlte erneut ab und gab vorsichtig 1.9 ml Wasser und anschließend 1.9 ml Natriumhydroxidlösung (2M) zu. Man engte ein, versetzte mit Wasser und Ethylacetat, trennte die organische Phase ab und extrahierte dreimal mit Ethylacetat. Die vereinigten organischen Phasen wurden mit Wasser (Zugabe von verdünnter Salzlsäurelösung zur Phasentrennung), gesättiger Natriumhydrogencarbonatlösung und Natriumchloridlösung gewaschen, über Natriumsulfat getrocknet und eingeengt. Nach Reinigung durch Säulenchromatographie an Kieselgel (Hexan/Ethylacetat) wurden 0.84 g der Titelverbindung erhalten.
'H-NMR (300MHZ, CHLOROFORM-di): δ [ppm]= 1 .37 - 1.61 (m, 1 1H), 1.63 - 1.92 (m, 3H), 1.93 - 2.07 (m, 1 H), 2.31 - 2.50 (m, 1H), 3.24 - 3.47 (m, 1H), 3.60 - 3.72 (m, 2H), 3.78 - 4.08 (m, 2H), 4.98 - 5.23 (m, 1H). Intermediat 2-23A solution of 1.68 g (5.81 mmol) of tert-butyl (2R, 4R) -2- (3-ethoxy-3-oxopropyl) -4-fluoropyrrolidine-1-carboxylate in 84 ml of THF was cooled to -40 ° C. Carefully added dropwise 14.5 ml Diisobutylaluminiumhydridlösung (IM in THF) and stirred for 3 h. It was allowed to come to RT, carefully added 1.9 ml of methanol, cooled again and carefully added 1.9 ml of water and then 1.9 ml of sodium hydroxide solution (2M). 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. 'H-NMR (300MHZ, CHLOROFORM-di): δ [ppm] = 1 .37-1.61 (m, 11H), 1.63-1.92 (m, 3H), 1.93-2.07 (m, 1H), 2.31- 2.50 (m, 1H), 3.24 - 3.47 (m, 1H), 3.60 - 3.72 (m, 2H), 3.78 - 4.08 (m, 2H), 4.98 - 5.23 (m, 1H). Intermediate 2-23
-difluor-2-(3-hydroxypropyl)pyrrolidin-l-carboxylat difluoro-2- (3-hydroxypropyl) pyrrolidine-l-carboxylate
Analog zur Herstellung von Intermediat 1-23 wurde tert-Butyl-(2R)-2-(3-ethoxy-3-oxopropyl)-4,4- difluorpyrrolidin-l-carboxylat mit Diisobutylaluminiumhydridlösung (IM in THF) umgesetzt. Nach säulenchromatographischer Reinigung an Kieselgel (Hexan/Ethylacetat) erhielt man 0.35 g (29% d. Th.) der Titelverbindung. Analogously to the preparation of Intermediate 1-23, tert-butyl (2R) -2- (3-ethoxy-3-oxopropyl) -4,4-difluoropyrrolidine-1-carboxylate was reacted with diisobutylaluminum hydride solution (III in THF). After purification by column chromatography on silica gel (hexane / ethyl acetate), 0.35 g (29% of theory) of the title compound were obtained.
'H-NMR (300MHZ, CHLOROFORM-di, ausgewählte Signale): δ [ppm]= 1.46 (s, 9H), 1.92 (br. s, 1H), 2.03 - 2.20 (m, 2H), 2.35 - 2.62 (m, 1H), 3.51 - 3.73 (m, 3H), 3.83 (br. s, 1H), 3.97 - 4.21 (d, 1H). Intermediat 3-23 'H-NMR (300MHZ, CHLOROFORM-di, selected signals): δ [ppm] = 1.46 (s, 9H), 1.92 (brs s, 1H), 2.03 - 2.20 (m, 2H), 2.35 - 2.62 (m , 1H), 3.51 - 3.73 (m, 3H), 3.83 (br s, 1H), 3.97 - 4.21 (d, 1H). Intermediate 3-23
tert-Butyl-(2R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-hydroxypropyl)pyrrolidin-l- tert-butyl (2R, 4R) -4 - {[tert-butyl (dimethyl) silyl] oxy} -2- (3-hydroxypropyl) pyrrolidin-l-
Analog zur Herstellung von Intermediat 1-23 wurden 1.8 g (4.48 mmol) tert-Butyl-(2R,4R)-4- {[tert- butyl(dimethyl)silyl]oxy}-2-(3-ethoxy-3-oxopropyl)pyrrolidin-l -carboxylat mit Diisobutylaluminium- hydridlösung (IM in THF) umgesetzt. Nach säulenchromatographischer Reinigung an Kieselgel (Hexan/Ethylacetat) erhielt man 0.59 g (37% d. Th.) der Titelverbindung. Analogously to the preparation of Intermediate 1-23, 1.8 g (4.48 mmol) of tert-butyl (2R, 4R) -4- {[tert-butyl (dimethyl) silyl] oxy} -2- (3-ethoxy-3-oxopropyl ) pyrrolidine-1-carboxylate with diisobutylaluminum hydride solution (IM in THF). After purification by column chromatography on silica gel (hexane / ethyl acetate), 0.59 g (37% of theory) of the title compound were obtained.
'H-NMR (300MHZ, CHLOROFORM-di, ausgewählte Signale): δ [ppm]= 0.05 (s, 6H), 0.86 (s, 9H), 1.45 (s, 9H), 3.35 (d, 2H), 3.66 (t, 2H), 3.87 - 3.98 (m, 1H), 4.32 (quin, 1H). 'H-NMR (300MHZ, CHLOROFORM-di, selected signals): δ [ppm] = 0.05 (s, 6H), 0.86 (s, 9H), 1.45 (s, 9H), 3.35 (d, 2H), 3.66 ( t, 2H), 3.87-3.98 (m, 1H), 4.32 (quin, 1H).
Intermediat 4-23 Intermediate 4-23
tert-Butyl-(2S)-2-(3-hydroxypropyl)pyrrolidin-l-carboxylat
tert-butyl (2S) -2- (3-hydroxypropyl) pyrrolidine-l-carboxylate
Analog zur Herstellung von Intermediat 1 -23 wurden 16.9 g (65.6 mmol) tert-Butyl-(2S)-2-(3- methoxy-3-oxopropyl)pyrrolidine-l -carboxylat mit Diisobutylaluminiumhydridlösung (IM in THF) umgesetzt. Analogously to the preparation of Intermediate 1 -23, 16.9 g (65.6 mmol) of tert-butyl (2S) -2- (3-methoxy-3-oxopropyl) -pyrrolidine-1-carboxylate were reacted with diisobutylaluminum hydride solution (III in THF).
Nach säulenchromatographischer Reinigung an Kieselgel (Hexan/Ethylacetat) erhielt man 9.76 g (61 % d. Th.) der Titelverbindung. After purification by column chromatography on silica gel (hexane / ethyl acetate), 9.76 g (61% of theory) of the title compound were obtained.
'H-NMR (300MHZ, DMSO-d6): δ [ppm]= 1.17 - 1.44 (m, 12H), 1.51 - 1.94 (m, 5H), 3.10 - 3.30 (m, 2H), 3.37 (q, 2H), 3.57 - 3.68 (m, 1H), 4.38 (t, 1H). 'H-NMR (300MHz, DMSO-d 6): δ [ppm] = 1:17 to 1:44 (m, 12H), 1:51 - 1.94 (m, 5 H) 3.10 - 3.30 (m, 2H), 3:37 (q, 2H ), 3.57 - 3.68 (m, 1H), 4.38 (t, 1H).
Drehwert: [a] = - 46,6 ° (c = 1.0, CHC13). Rotation: [a] = - 46.6 ° (c = 1.0, CHC1 3 ).
Intermediat 5-23 Intermediate 5-23
tert-Butyl-(2R)-2-(3-hydroxypropyl)pyrrolidin-l-carboxylat tert-butyl (2R) -2- (3-hydroxypropyl) pyrrolidine-l-carboxylate
Analog zur Herstellung von Intermediat 1 -23 wurden 18.4 g (71.5 mmol) tert-Butyl-(2R)-2-(3- methoxy-3-oxopropyl)pyrrolidine-l -carboxylat mit Diisobutylaluminiumhydridlösung (IM in THF) umgesetzt. Analogously to the preparation of Intermediate 1 -23, 18.4 g (71.5 mmol) of tert-butyl (2R) -2- (3-methoxy-3-oxopropyl) pyrrolidine-1-carboxylate were reacted with diisobutylaluminum hydride solution (III in THF).
Nach säulenchromatographischer Reinigung an Kieselgel (Hexan/Ethylacetat) erhielt man 1 1.1 g (64 % d. Th.) der Titelverbindung. After purification by column chromatography on silica gel (hexane / ethyl acetate), 1.1 g (64% of theory) of the title compound were obtained.
'H-NMR (300MHZ, DMSO-d6): δ [ppm]= 1.17 - 1.44 (m, 12H), 1.51 - 1.94 (m, 5H), 3.10 - 3.30 (m, 2H), 3.37 (q, 2H), 3.57 - 3.68 (m, 1H), 4.38 (t, 1H). 'H-NMR (300MHz, DMSO-d 6): δ [ppm] = 1:17 to 1:44 (m, 12H), 1:51 - 1.94 (m, 5 H) 3.10 - 3.30 (m, 2H), 3:37 (q, 2H ), 3.57 - 3.68 (m, 1H), 4.38 (t, 1H).
Drehwert: [a] = 44,7 0 (c = 1.0, CHCI3). Rotation: [a] = 44,7 0 (c = 1.0, CHCI3).
Intermediat 6-23Intermediate 6-23
-(2-hydroxyethyl)morpholin-4-carboxylat - (2-hydroxyethyl) morpholine-4-carboxylate
2.00 g [(3R)-4-(tert-Butoxycarbonyl)morpholin-3-yl]essigsäure in 50 ml THF wurden mit 1.14 ml Boran-Dimethylsulfid-Komplex (2M Lösung in THF, CAS 13292-87-0) versetzt. Man erhitzte 4 h unter Rückfluß, addierte Diethylether, gab vorsichtig gesättigte Natriumhydrogencarbonatlösung zu, trennte die organische Phase ab und extrahierte mit Diethylether. Die vereinigten organischen Phasen wurden mit gesättigter Natriumchloridlösung gewaschen, über Natriumsulfat getrocknet, eingeengt und im Vakuum getrocknet. Man erhielt 1.0 g eines Rohproduktes, welches ohne Reinigung eingesetzt wurde. 2.00 g of [(3R) -4- (tert-butoxycarbonyl) morpholin-3-yl] acetic acid in 50 ml of THF were admixed with 1.14 ml of borane-dimethyl sulfide complex (2M solution in THF, CAS 13292-87-0). The mixture was refluxed for 4 h, added diethyl ether, carefully added saturated sodium bicarbonate solution, the organic phase was separated and extracted with diethyl ether. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, concentrated and dried in vacuo. 1.0 g of a crude product was obtained which was used without purification.
Intermediat 1-24Intermediate 1-24
-{[(4-methylphenyl)sulfonyl]oxy}propyl)pyrrolidin-l-carboxylat - {[(4-methylphenyl) sulfonyl] oxy} propyl) pyrrolidin-l-carboxylate
Eine Lösung aus 840 mg (3.40 mmol) tert-Butyl-(2R,4R)-4-fluor-2-(3-hydroxypropyl)pyrro lidin- 1 - carboxylat, 0.57 ml Triethylamin und 2 mg DMAP in 8.4 ml Dichlormethan wurde auf 3°C abgekült. 777 mg (4.08 mmol) 4-Methylbenzolsulfonylchlorid wurden zugegeben und die Mischung über Nacht bei RT gerührt. Man addierte erneut 648 mg 4-Methylbenzolsulfonylchlorid und 415 mg DMAP und rührte über Nacht. Das Reaktionsgemisch wurde auf gesättigte Natriumhydrogencarbonatlösung gegeben, die organische Phase wurde abgetrennt und die wässrige Phase zweimal mit Dichlormethan extrahiert. Die vereinigten organischen Phasen wurden zweimal mit Wasser und gesättigter Natriumchloridlösung gewaschen, über Natriumsulfat getrocknet und eingeengt. Nach Reinigung des Rückstandes durch Säulenchromatographie an Kieselgel (Hexan/Ethylacetat) wurden 1.05 g (77% d. Th.) der Titelverbindung erhalten. A solution of 840 mg (3.40 mmol) of tert-butyl (2R, 4R) -4-fluoro-2- (3-hydroxypropyl) pyrrolidine-1-carboxylate, 0.57 ml of triethylamine and 2 mg of DMAP in 8.4 ml of dichloromethane was added 3 ° C cooled. 777 mg (4.08 mmol) of 4-methylbenzenesulfonyl chloride were added and the mixture was stirred at RT overnight. 648 mg of 4-methylbenzenesulfonyl chloride and 415 mg of DMAP were again added, and the mixture was stirred overnight. The reaction mixture was added to saturated sodium bicarbonate solution, the organic phase was separated and the aqueous phase extracted twice with dichloromethane. The combined organic phases were washed twice with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated. After purification of the residue by column chromatography on silica gel (hexane / ethyl acetate), 1.05 g (77% of theory) of the title compound were obtained.
'H-NMR (400MHZ, CHLOROFORM-di): δ [ppm]= 1.44 (s, 9H), 1.45 - 1.55 (m und Wassersignal), 1.55 - 1.79 (m und Wassersignal), 1.88 (br. s, 1H), 2.26 - 2.42 (m, 1H), 2.45 (s, 3H), 3.22 - 3.39 (m, 1H), 3.35 (dd, 1H), 3.92 (br. s, 2H), 3.95 - 4.08 (m, 3H), 4.99 - 5.17 (m, 1H), 7.26 (s, 1H), 7.34 (d, 2H), 7.75 - 7.81 (m, 2H). 'H-NMR (400MHZ, CHLOROFORM-di): δ [ppm] = 1.44 (s, 9H), 1.45 - 1.55 (m and water signal), 1.55 - 1.79 (m and water signal), 1.88 (brs s, 1H) , 2.26 - 2.42 (m, 1H), 2.45 (s, 3H), 3.22 - 3.39 (m, 1H), 3.35 (dd, 1H), 3.92 (br, s, 2H), 3.95 - 4.08 (m, 3H) , 4.99 - 5.17 (m, 1H), 7.26 (s, 1H), 7.34 (d, 2H), 7.75 - 7.81 (m, 2H).
Intermediat 2-24 Intermediate 2-24
tert-Butyl-(2R)-4,4-difluor-2-(3-{[(4-methylphenyl)sulfonyl]oxy}propyl)pyrrolidin-l-carboxylat
tert-butyl (2R) -4,4-difluoro-2- (3 - {[(4-methylphenyl) sulfonyl] oxy} propyl) pyrrolidin-l-carboxylate
Analog zur Herstellung von Intermediat 1-24 wurden 350 mg (1.32 mmol) tert-Butyl-(2R)-4,4-difluor- 2-(3-hydroxypropyl)pyrro lidin- 1 -carboxylat mit 302 mg 4-Methylbenzolsulfonylchlorid umgesetzt. Nach Reinigung durch Säulenchromatogaphie an Kieselgel (Hexan/Ethylacetat) erhielt man 343 mg der Titelverbindung. Analogously to the preparation of Intermediate 1-24, 350 mg (1.32 mmol) of tert-butyl (2R) -4,4-difluoro-2- (3-hydroxypropyl) pyrrolidine-1-carboxylate were reacted with 302 mg of 4-methylbenzenesulfonyl chloride. After purification by column chromatography on silica gel (hexane / ethyl acetate), 343 mg of the title compound were obtained.
'H-NMR (300MHZ, CHLOROFORM-di): δ [ppm]= 1.44 (s, 9H), 1.49 - 1.72 (m), 1.81 (br. s, 1H), 1.94 - 2.10 (m, 1H), 2.34 - 2.54 (m, 4H, enthält Singulett bei 2.45), 3.56 (q, 1H), 3.80 (br. s, 1H), 3.91 - 4.09 (m, 3H), 7.30 - 7.40 (m, 2H), 7.73 - 7.84 (m, 2H). Intermediat 3-24 'H-NMR (300MHZ, CHLOROFORM-di): δ [ppm] = 1.44 (s, 9H), 1.49-1.72 (m), 1.81 (br.s, 1H), 1.94-2.10 (m, 1H), 2.34 - 2.54 (m, 4H, contains singlet at 2.45), 3.56 (q, 1H), 3.80 (br, s, 1H), 3.91 - 4.09 (m, 3H), 7.30 - 7.40 (m, 2H), 7.73 - 7.84 (m, 2H). Intermediate 3-24
tert-Butyl-(2R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-{[(4- )pyrrolidin-l-carboxylat tert -Butyl (2R, 4R) -4 - {[tert -butyl (dimethyl) silyl] oxy} -2- (3 - {[(4) pyrrolidine-1-carboxylate
Analog zur Herstellung von Intermediat 1-24 wurden 590 mg (1.64 mmol) tert-Butyl-(2R,4R)-4- {[tert- butyl(dimethyl)silyl] oxy} -2-(3-hydroxypropyl)pyrro lidin- 1 -carboxylat mit 438 mg 4-Methylbenzolsulfonylchlorid umgesetzt. Nach Reinigung durch Säulenchromatogaphie an Kieselgel (Hexan/Ethylacetat) erhielt man 414 mg (49% d. Th.) der Titelverbindung. Analogously to the preparation of Intermediate 1-24, 590 mg (1.64 mmol) of tert-butyl (2R, 4R) -4- [[tert-butyl (dimethyl) silyl] oxy} -2- (3-hydroxypropyl) pyrrolidine were used. 1-carboxylate reacted with 438 mg of 4-methylbenzenesulfonyl chloride. After purification by column chromatography on silica gel (hexane / ethyl acetate), 414 mg (49% of theory) of the title compound were obtained.
'H-NMR (300MHZ, CHLOROFORM-di): δ [ppm]= 0.04 (s, 6H), 0.85 (s, 9H), 1.42 (s, 9H), 1.52 - 1.83 (m), 1.74 (br. s, 1H), 1.86 - 2.00 (m, 1H), 2.45 (s, 3H), 3.21 - 3.32 (m, 1H), 3.32 - 3.47 (m, 1H), 3.77 - 3.90 (m, 1H), 3.95 - 4.08 (m, 2H), 4.24 - 4.31 (m, 1H), 7.30 - 7.37 (m, 2H), 7.72 - 7.83 (m, 2H). 'H-NMR (300MHZ, CHLOROFORM-di): δ [ppm] = 0.04 (s, 6H), 0.85 (s, 9H), 1.42 (s, 9H), 1.52 - 1.83 (m), 1.74 (br , 1H), 1.86 - 2.00 (m, 1H), 2.45 (s, 3H), 3.21 - 3.32 (m, 1H), 3.32 - 3.47 (m, 1H), 3.77 - 3.90 (m, 1H), 3.95 - 4.08 (m, 2H), 4.24-4.31 (m, 1H), 7.30-7.37 (m, 2H), 7.72-7.83 (m, 2H).
Intermediat 4-24 Intermediate 4-24
tert-Butyl-(2S)-2-(3-{[(4-methylphenyl)sulfonyl]oxy}propyl)pyrrolidin-l-carboxylat
tert-butyl (2S) -2- (3 - {[(4-methylphenyl) sulfonyl] oxy} propyl) pyrrolidin-l-carboxylate
Analog zur Herstellung von Intermediat 1-24 wurden 4.73 g (20.6 mmol) tert-Butyl (2S)-2-(3- hydroxypropyl)pyrrolidin-l-carboxylat mit 4.72 g 4-Methylbenzolsulfonylchlorid umgesetzt. Nach Reinigung durch Säulenchromatogaphie an Kieselgel (Hexan/Ethylacetat) erhielt man 6.24 g (75 % d. Th.) der Titelverbindung. Analogously to the preparation of Intermediate 1-24, 4.73 g (20.6 mmol) of tert-butyl (2S) -2- (3-hydroxypropyl) pyrrolidine-1-carboxylate were reacted with 4.72 g of 4-methylbenzenesulfonyl chloride. After purification by column chromatography on silica gel (hexane / ethyl acetate), 6.24 g (75% of theory) of the title compound were obtained.
'H-NMR (300MHZ, DMSO-de): δ [ppm]= 1.13 - 1.28 (m, 1H), 1.32 - 1.40 (m, 9H), 1.42 - 1.60 (m, 4H), 1.63 - 1.87 (m, 3H), 2.42 (s, 3H), 3.06 - 3.26 (m, 2H), 3.49 - 3.63 (m, 1H), 3.97 - 4.06 (m, 2H), 7.48 (d, 2H), 7.78 (d, 2H). 'H-NMR (300MHZ, DMSO-de): δ [ppm] = 1.13-1.28 (m, 1H), 1.32-1.40 (m, 9H), 1.42-1.60 (m, 4H), 1.63-1.87 (m, 3H), 2.42 (s, 3H), 3.06 - 3.26 (m, 2H), 3.49 - 3.63 (m, 1H), 3.97 - 4.06 (m, 2H), 7.48 (d, 2H), 7.78 (d, 2H) ,
Drehwert: [a] = - 29,1 ° (c = 1.0, CHC13). Rotation: [a] = - 29.1 ° (c = 1.0, CHC1 3 ).
Intermediat 5-24Intermediate 5-24
henyl)sulfonyl]oxy}propyl)pyrrolidin-l-carboxylat henyl) sulfonyl] oxy} propyl) pyrrolidin-l-carboxylate
Analog zur Herstellung von Intermediat 1-24 wurden 11 g (47.9 mmol) tert-Butyl (2R)-2-(3- hydroxypropyl)pyrrolidin-l-carboxylat mit 10.97 g 4-Methylbenzolsulfonylchlorid umgesetzt. Nach Reinigung durch Säulenchromatogaphie an Kieselgel (Hexan/Ethylacetat) erhielt man 14.89 g (77 % d. Th.) der Titelverbindung. Analogously to the preparation of Intermediate 1-24, 11 g (47.9 mmol) of tert-butyl (2R) -2- (3-hydroxypropyl) pyrrolidine-1-carboxylate were reacted with 10.97 g of 4-methylbenzenesulfonyl chloride. Purification by column chromatography on silica gel (hexane / ethyl acetate) gave 14.89 g (77% of theory) of the title compound.
'H-NMR (300MHZ, DMSO-de): δ [ppm]= 1.13 - 1.28 (m, 1H), 1.32 - 1.40 (m, 9H), 1.42 - 1.60 (m, 4H), 1.63 - 1.87 (m, 3H), 2.42 (s, 3H), 3.06 - 3.26 (m, 2H), 3.49 - 3.63 (m, 1H), 3.97 - 4.06 (m, 2H), 7.48 (d, 2H), 7.78 (d, 2H). 'H-NMR (300MHZ, DMSO-de): δ [ppm] = 1.13-1.28 (m, 1H), 1.32-1.40 (m, 9H), 1.42-1.60 (m, 4H), 1.63-1.87 (m, 3H), 2.42 (s, 3H), 3.06 - 3.26 (m, 2H), 3.49 - 3.63 (m, 1H), 3.97 - 4.06 (m, 2H), 7.48 (d, 2H), 7.78 (d, 2H) ,
Drehwert: [a] = 29,3 0 (c = 1.0, CHCI3). Rotation: [a] = 29.3 0 (c = 1.0, CHCI3).
Intermediat 6-24Intermediate 6-24
ylphenyl)sulfonyl]oxy}ethyl)morpholin-4-carboxylat ylphenyl) sulfonyl] oxy} ethyl) morpholine-4-carboxylate
1.90 g (8.21 mmol) tert-Butyl-(3R)-3-(2-hydroxyethyl)morpholin-4-carboxylat wurden analog mit 4.02 g (1.5 Äquivalente) /jara-Toluolsulfonsäureanhydrid (CAS 4124-41-8) (anstelle von 4-
Methylbenzolsulfonylchlorid) umgesetzt. Nach Reinigung an Kieselgel (Hexan/Ethylacetat) wurden 2.35 g (74% d. Th.) der Titelverbindung erhalten. 1.90 g (8.21 mmol) of tert-butyl (3R) -3- (2-hydroxyethyl) morpholine-4-carboxylate were reacted analogously with 4.02 g (1.5 equivalents) / jaran-toluenesulfonic anhydride (CAS 4124-41-8) (instead of 4 Methylbenzenesulfonyl chloride). Purification on silica gel (hexane / ethyl acetate) gave 2.35 g (74% of theory) of the title compound.
'H-NMR (400MHZ, CHLOROFORM-di): δ [ppm]= 1 .44 (s, 9H), 1 .76 (br. s, 1 H), 1 .89 - 2.00 (m, 1H), 2. 17 (br. s, 1 H), 2.44 (s, 3H), 3.00 (br. s, 1 H), 3.41 (td, 1 H), 3.52 (dd, 1 H), 3.57 - 3.88 (m, 3H, verbreiterte Signale), 3.71 - 3.93 (m, 2H), 3.98 - 4.1 1 (m, 3H), 7.3 1 - 7.39 (m, 2H), 7.76 - 7.82 (m, 2H). 'H-NMR (400MHZ, CHLOROFORM-di): δ [ppm] = 1 .44 (s, 9H), 1 .76 (br. S, 1H), 1 .89 - 2.00 (m, 1H), 2 17 (brs s, 1 H), 2.44 (s, 3H), 3.00 (brs s, 1 H), 3.41 (td, 1 H), 3.52 (dd, 1 H), 3.57 - 3.88 (m, 3H, broadened signals), 3.71 - 3.93 (m, 2H), 3.98 - 4.1 1 (m, 3H), 7.3 1 - 7.39 (m, 2H), 7.76 - 7.82 (m, 2H).
Intermediat 1-25 Intermediate 1-25
tert-Butyl-(2R,4R)-4-fluor-2-{3-[(4,4,4-trifluorbutyl)sulfanyl]propyl}pyrrolidin-l-carboxylat tert-butyl (2R, 4R) -4-fluoro-2- {3 - [(4,4,4-trifluorobutyl) sulfanyl] propyl} pyrrolidin-l-carboxylate
642 mg Natriummethanolat wurden in 15 ml Methanol unter Stickstoff vorgelegt und 553 mg (2.97 mmol) S-(4,4,4-Trifluorbutyl)ethanthioat in 5 ml Methanol zugetropft. Die Mischung wurde 45 min bei RT gerührt, dann wurden 0.96 g (2.38 mmol) tert-Butyl-(2R,4R)-4-fluor-2-(3- {[(4- methylphenyl)sulfonyl]oxy}propyl)pyrro lidin- 1 -carboxylat in 5 ml Methanol zugetropft und unter Rückfluß erhitzt. Man engte ein, nahm den Rückstand in Wasser und Ethylaceat auf, trennte die organische Phase ab und extrahierte dreimal mit Ethylacetat. Die vereinigten organischen Phasen wurden mit gesättigter Natriumchloridlösung gewaschen, über Natriumsulfat getrocknet, eingeengt und durch säulenchromatographische Reinigung an Kieselgel (Hexan/Ethylacetat) gereinigt. Man erhielt 0.77 g (87% d. Th.) der Titelverbindung. 642 mg of sodium methoxide were initially charged in 15 ml of methanol under nitrogen, and 553 mg (2.97 mmol) of S- (4,4,4-trifluorobutyl) ethanethioate in 5 ml of methanol were added dropwise. The mixture was stirred at RT for 45 min, then 0.96 g (2.38 mmol) of tert -butyl (2R, 4R) -4-fluoro-2- (3 - [(4-methylphenyl) sulfonyl] oxy} propyl) pyrrole lidin-1-carboxylate in 5 ml of methanol was added dropwise and heated under reflux. The mixture was concentrated, the residue was taken up in water and ethyl acetate, and the organic phase was separated off and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, concentrated and purified by column chromatography on silica gel (hexane / ethyl acetate). 0.77 g (87% of theory) of the title compound were obtained.
'H-NMR (300MHZ, CHLOROFORM-di): δ [ppm]= 1 .41 - 1 .91 (m, 15H), 1 .93 - 2.1 1 (m, 1 H), 2. 13 - 2.63 (m, 7H), 3.34 (ddd, 1 H), 3.91 - 4.06 (m, 2H), 4.98 - 5.24 (m, 1 H). 'H-NMR (300MHZ, CHLOROFORM-di): δ [ppm] = 1 .41 - 1 .91 (m, 15H), 1 .93 - 2.1 1 (m, 1H), 2. 13 - 2.63 (m , 7H), 3.34 (ddd, 1H), 3.91 - 4.06 (m, 2H), 4.98 - 5.24 (m, 1H).
Intermediat 2-25 Intermediate 2-25
tert-Butyl-(2R)-4,4-difluor-2-{3-[(4,4,4-trifluorbutyl)sulfanyl]propyl}pyrrolidin-l-carboxylat tert-butyl (2R) -4,4-difluoro-2- {3 - [(4,4,4-trifluorobutyl) sulfanyl] propyl} pyrrolidin-l-carboxylate
Analog zu Intermediat 1-25 wurden 343 mg (0.818 mmol) tert-Butyl-(2R)-4,4-difluor-2-(3- {[(4- methylphenyl)sulfonyl]oxy}propyl)pyrro lidin- 1-carboxylat mit 198 mg S-(4,4,4-Trifluor- butyl)ethanthioat umgesetzt. Nach Reinigung durch Säulenchromatogaphie an Kieselgel (Hexan/Ethylacetat) erhielt man 266 mg der Titelverbindung. Analogously to Intermediate 1-25, 343 mg (0.818 mmol) of tert-butyl (2R) -4,4-difluoro-2- (3- {[(4-methylphenyl) sulfonyl] oxy} propyl) pyrrolidine 1- carboxylate with 198 mg of S- (4,4,4-trifluoro-butyl) ethanethioate. After purification by column chromatography on silica gel (hexane / ethyl acetate), 266 mg of the title compound were obtained.
'H-NMR (300MHZ, CHLOROFORM-di): δ [ppm]= 1.46 (s, 9H), 1.51 - 1.63 (m, 4H), 1.78 - 2.00 (m, 3H), 2.00 - 2.31 (m, 3H), 2.36 - 2.64 (m, 4H), 3.51 - 3.69 (m, 1H), 3.82 (br. s, 1H), 4.02 (br. s, 1H). 'H NMR (300MHZ, CHLOROFORM-di): δ [ppm] = 1.46 (s, 9H), 1.51-1.63 (m, 4H), 1.78-2.00 (m, 3H), 2.00-2.21 (m, 3H) , 2.36 - 2.64 (m, 4H), 3.51 - 3.69 (m, 1H), 3.82 (br, s, 1H), 4.02 (br, s, 1H).
Intermediat 3-25 Intermediate 3-25
tert-Butyl-(2R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-{3-[(4,4,4- idin-l-carboxylat tert -Butyl (2R, 4R) -4 - {[tert -Butyl (dimethyl) silyl] oxy} -2- {3 - [(4,4,4-Idyn-1-carboxylate
Analog zu Intermediat 1-25 wurden 414 mg (0.81 mmol) tert-Butyl-(2R,4R)-4- {[tert- butyl(dimethyl)silyl] oxy } -2-(3 - { [(4-methylphenyl)sulfonyl] oxy } propyl)pyrro lidin- 1 -carboxylat mit 195 mg S-(4,4,4-Trifluorbutyl)ethanthioat umgesetzt. Nach Reinigung durch Säulenchromatogaphie an Kieselgel (Hexan/Ethylacetat) erhielt man 221 mg (56% d. Th.) der Titelverbindung. Analogously to Intermediate 1-25, 414 mg (0.81 mmol) of tert-butyl (2R, 4R) -4- {[tert-butyl (dimethyl) silyl] oxy} -2- (3 - {[(4-methylphenyl) sulfonyl] oxy} propyl) pyrrolidine-1-carboxylate reacted with 195 mg of S- (4,4,4-trifluorobutyl) ethanethioate. After purification by column chromatography on silica gel (hexane / ethyl acetate), 221 mg (56% of theory) of the title compound were obtained.
'H-NMR (300MHZ, CHLOROFORM-di): δ [ppm]= 0.05 (s, 6H), 0.86 (s, 9H), 1.36 - 1.74 (m, enthält Wassersignal), 1.75 - 2.02 (m, 4H), 2.12 - 2.30 (m, 2H), 2.43 - 2.62 (m, 4H), 3.28 - 3.46 (m, 2H), 3.82 - 3.95 (m, 1H), 4.31 (quin, 1H). Intermediat 4-25 'H-NMR (300MHZ, CHLOROFORM-di): δ [ppm] = 0.05 (s, 6H), 0.86 (s, 9H), 1.36 - 1.74 (m, contains water signal), 1.75 - 2.02 (m, 4H), 2.12-2.30 (m, 2H), 2.43-2.62 (m, 4H), 3.28-3.46 (m, 2H), 3.82-3.95 (m, 1H), 4.31 (quin, 1H). Intermediate 4-25
,5,5-pentafluorpentyl)sulfanyl]ethyl}morpholin-4-carboxylat , 5,5-pentafluoropentyl) sulfanyl] ethyl} morpholine-4-carboxylate
1.16 g (4.93 mmol) S-(4,4,5,5,5-Pentafluorpentyl)ethanthioat, beschrieben in WO 2011/16101 AI, wurden analog zur Herstellung des Intermediates 1-25 mit Natriummethanolat und dann mit 1.90 g (4.93 mmmol, 1 Äquivatent) tert-Butyl-(3R)-3-(2- {[(4-methylphenyl)sulfonyl]oxy}ethyl)morpholin-4-
carboxylat umgesetzt. Nach säulenchromatographischer Reinigung an Kieselgel (Hexan/Ethylacetat) wurden 1.60 g (80% der Theorie) der Titelverbindung erhalten. 1.16 g (4.93 mmol) of S- (4,4,5,5,5-pentafluoropentyl) ethanethioate, described in WO 2011/16101 Al, were prepared analogously to the preparation of the intermediate 1-25 with sodium methoxide and then with 1.90 g (4.93 mmol , 1 equiv.) Tert -Butyl (3R) -3- (2- {[(4-methylphenyl) sulfonyl] oxy} ethyl) morpholine-4 reacted carboxylate. After purification by column chromatography on silica gel (hexane / ethyl acetate), 1.60 g (80% of theory) of the title compound were obtained.
'H-NMR (300MHZ, CHLOROFORM-di): δ [ppm]= 1.46 (s, 9H), 1.81 - 1.95 (m, 3H), 2.01 - 2.27 (m, 3H), 2.39 - 2.67 (m, 4H), 3.02 - 3.17 (m, 1H), 3.44 (td, 1H), 3.52 - 3.62 (m, 1H), 3.66 - 3.89 (m, 3H), 3.99 - 4.12 (m, 1H). 'H NMR (300MHZ, CHLOROFORM-di): δ [ppm] = 1.46 (s, 9H), 1.81-1.95 (m, 3H), 2.01-2.27 (m, 3H), 2.39-2.27 (m, 4H) , 3.02 - 3.17 (m, 1H), 3.44 (td, 1H), 3.52 - 3.62 (m, 1H), 3.66 - 3.89 (m, 3H), 3.99 - 4.12 (m, 1H).
Intermediat 5-25Intermediate 5-25
orbutyl)sulfanyl]propyl}pyrrolidin-l-carboxylat orbutyl) sulfanyl] propyl} pyrrolidin-l-carboxylate
Analog zur Herstellung von Intermediat 1-25 wurden 11 g (28.6 mmol) tert-Butyl-(2S)-2-(3- {[(4- methylphenyl)sulfonyl]oxy}propyl)pyrro lidin- 1 -carboxylat mit 4.27 g (22.94 mmol) S-(4,4,4- Trifluorbutyl)ethanthioat umgesetzt. Nach Reinigung durch Säulenchromatogaphie an Kieselgel (Hexan/Ethylacetat) erhielt man 7,47 g (69% d. Th.) der Titelverbindung. Analogously to the preparation of Intermediate 1-25, 11 g (28.6 mmol) of tert-butyl (2S) -2- (3- {[(4-methylphenyl) sulfonyl] oxy} propyl) pyrrolidine-1-carboxylate with 4.27 g (22.94 mmol) reacted S- (4,4,4-trifluorobutyl) ethanethioate. Purification by column chromatography on silica gel (hexane / ethyl acetate) gave 7.47 g (69% of theory) of the title compound.
'H-NMR (400MHZ, DMSO-d6): δ [ppm]= 1.26 - 1.66 (m, 14H), 1.66 - 1.94 (m, 6H), 2.26 - 2.41 (m, 2H), 2.56 (t, 2H), 3.12 - 3.28 (m, 2H), 3.64 (br. s, 1H). 'H-NMR (400MHz, DMSO-d 6): δ [ppm] = 1.26 - 1.66 (m, 14H), 1.66 - 1.94 (m, 6H), 2:26 to 2:41 (m, 2H), 2:56 (t, 2H ), 3.12 - 3.28 (m, 2H), 3.64 (brs s, 1H).
Drehwert: [a] = - 38,6 ° (c = 1.0, CHC13). Rotation: [a] = - 38.6 ° (c = 1.0, CHC1 3 ).
Intermediat 6-25Intermediate 6-25
orbutyl)sulfanyl]propyl}pyrrolidin-l-carboxylat orbutyl) sulfanyl] propyl} pyrrolidin-l-carboxylate
Analog zur Herstellung von Intermediat 1-25 wurden 4 g (10.4 mmol) tert-Butyl-(2R)-2-(3- {[(4- methylphenyl)sulfonyl]oxy}propyl)pyrro lidin- 1 -carboxylat mit 1.76 g (9.48 mmol) S-(4,4,4- Trifluorbutyl)ethanthioat umgesetzt. Nach Reinigung durch Säulenchromatogaphie an Kieselgel (Hexan/Ethylacetat) erhielt man 1.54 g (39 % d. Th.) der Titelverbindung. Analogously to the preparation of Intermediate 1-25, 4 g (10.4 mmol) of tert-butyl (2R) -2- (3- {[(4-methylphenyl) sulfonyl] oxy} propyl) pyrrolidine-1-carboxylate with 1.76 g (9.48 mmol) reacted S- (4,4,4-trifluorobutyl) ethanethioate. After purification by column chromatography on silica gel (hexane / ethyl acetate), 1.54 g (39% of theory) of the title compound were obtained.
'H-NMR (400MHZ, DMSO-d6): δ [ppm]= 1.26 - 1.66 (m, 14H), 1.66 - 1.94 (m, 6H), 2.26 - 2.41 (m, 2H), 2.56 (t, 2H), 3.12 - 3.28 (m, 2H), 3.64 (br. s, 1H). 'H-NMR (400MHz, DMSO-d 6): δ [ppm] = 1.26 - 1.66 (m, 14H), 1.66 - 1.94 (m, 6H), 2:26 to 2:41 (m, 2H), 2:56 (t, 2H ), 3.12 - 3.28 (m, 2H), 3.64 (brs s, 1H).
Drehwert: [a] = 35,5 0 (c = 1.0, CHCI3).
Intermediat 7-25Rotation: [a] = 35.5 0 (c = 1.0, CHCl 3). Intermediate 7-25
tafluorbutyl)sulfanyl]propyl}pyrrolidin-l-carboxylat tafluorbutyl) sulfanyl] propyl} pyrrolidin-l-carboxylate
Analog zur Herstellung von Intermediat 1-25 wurden 6.69 g (17.45 mmol) tert-Butyl-(2S)-2-(3- {[(4- methylphenyl)sulfonyl]oxy}propyl)pyrro lidin- 1-carboxylat mit 3.1 g (13.96 mmol) S-(3,3,4,4,4- Pentafluorbutyl)ethanthioat umgesetzt. Nach Reinigung durch Säulenchromatogaphie an Kieselgel (Hexan/Ethylacetat) erhielt man 4.51 g (62% d. Th.) der Titelverbindung. Analogously to the preparation of Intermediate 1-25, 6.69 g (17.45 mmol) of tert-butyl (2S) -2- (3 - [(4-methylphenyl) sulfonyl] oxy} propyl) pyrrolidine-1-carboxylate with 3.1 g (13.96 mmol) reacted S- (3,3,4,4,4-pentafluorobutyl) ethanethioate. After purification by column chromatography on silica gel (hexane / ethyl acetate), 4.51 g (62% of theory) of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 1.39 (s, 9H), 1.42 - 1.94 (m, 8H), 2.40 - 2.52 (m, 2H), 2.59 (t, 2H), 2.66 - 2.73 (m, 2H), 3.12 - 3.30 (m, 2H), 3.65 (br. s, 1H). 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 1.39 (s, 9H), 1.42 - 1.94 (m, 8H), 2.40 - 2.52 (m, 2H), 2.59 (t, 2H), 2.66 - 2.73 (m, 2H), 3.12 - 3.30 (m, 2H), 3.65 (br, s, 1H).
Drehwert: [a] = - 33,3 ° (c = 1.0, CHC13). Rotation: [a] = - 33.3 ° (c = 1.0, CHC1 3 ).
Intermediat 8-25Intermediate 8-25
tafluorbutyl)sulfanyl]propyl}pyrrolidin-l-carboxylat tafluorbutyl) sulfanyl] propyl} pyrrolidin-l-carboxylate
Analog zur Herstellung von Intermediat 1-25 wurden 3.0 g (7.8 mmol) tert-Butyl-(2R)-2-(3- {[(4- methylphenyl)sulfonyl]oxy}propyl)pyrro lidin- 1-carboxylat mit 1.58 g (7.1 mmol) S-(3,3,4,4,4- Pentafluorbutyl)ethanthioat umgesetzt. Nach Reinigung durch Säulenchromatogaphie an Kieselgel (Hexan/Ethylacetat) erhielt man 2.09 g (64 % d. Th.) der Titelverbindung. Analogously to the preparation of Intermediate 1-25, 3.0 g (7.8 mmol) tert-butyl- (2R) -2- (3- {[(4-methylphenyl) sulfonyl] oxy} propyl) pyrrolidine-1-carboxylate at 1.58 g (7.1 mmol) of S- (3,3,4,4,4-pentafluorobutyl) ethanethioate reacted. After purification by column chromatography on silica gel (hexane / ethyl acetate), 2.09 g (64% of theory) of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 1.39 (s, 9H), 1.42 - 1.94 (m, 8H), 2.40 - 2.52 (m, 2H), 2.59 (t, 2H), 2.66 - 2.73 (m, 2H), 3.12 - 3.30 (m, 2H), 3.65 (br. s, 1H). 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 1.39 (s, 9H), 1.42 - 1.94 (m, 8H), 2.40 - 2.52 (m, 2H), 2.59 (t, 2H), 2.66 - 2.73 (m, 2H), 3.12 - 3.30 (m, 2H), 3.65 (br, s, 1H).
Drehwert: [a] = 29,9 0 (c = 1.0, CHCI3). Rotation: [a] = 29.9 0 (c = 1.0, CHCI3).
Intermediat 9-25 Intermediate 9-25
tert-Butyl-(2S)-2-{3-[(4,4,5,5,5-Pentafluorpentyl)sulfanyl]propyl}pyrrolidin-l-carboxylat tert-butyl (2S) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfanyl] propyl} pyrrolidin-l-carboxylate
Analog zur Herstellung von Intermediat 1-25 wurden 6.0 g (15.64 mmol) tert-Butyl-(2S)-2-(3- {[(4- methylphenyl)sulfonyl]oxy}propyl)pyrro lidin- 1-carboxylat mit 3.36 g (14.22 mmol) S-(4,4,5,5,5- Pentafluorpentyl)ethanthioat umgesetzt. Nach Reinigung durch Säulenchromatogaphie an Kieselgel (Hexan/Ethylacetat) erhielt man 4.25 g (63% d. Th.) der Titelverbindung. Analogously to the preparation of Intermediate 1-25, 6.0 g (15.64 mmol) of tert-butyl (2S) -2- (3- {[(4-methylphenyl) sulfonyl] oxy} propyl) pyrrolidine-1-carboxylate with 3.36 g (14.22 mmol) reacted S- (4,4,5,5,5-pentafluoropentyl) ethanethioate. Purification by column chromatography on silica gel (hexane / ethyl acetate) gave 4.25 g (63% of theory) of the title compound.
'H-NMR (400MHZ, DMSO-d6): δ [ppm]= 1.24 - 1.64 (m, 12H), 1.64 - 1.94 (m, 5H), 2.21 - 2.38 (m, 2H), 2.59 (t, 2H), 3.11 - 3.28 (m, 2H), 3.64 (br. s, 1H). 'H-NMR (400MHz, DMSO-d 6): δ [ppm] = 1.24 - 1.64 (m, 12H), 1.64 - 1.94 (m, 5H), 2:21 to 2:38 (m, 2H), 2:59 (t, 2H ), 3.11 - 3.28 (m, 2H), 3.64 (brs s, 1H).
Drehwert: [a] = - 31,5 ° (c = 1.0, CHC13). Rotation: [a] = - 31.5 ° (c = 1.0, CHC1 3 ).
Intermediat 10-25 Intermediate 10-25
tert-Butyl-(2R)-2-{3-[(4,4,5,5,5-Pentafluorpentyl)sulfanyl]propyl}pyrrolidin-l-carboxylat tert-butyl (2R) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfanyl] propyl} pyrrolidin-l-carboxylate
Analog wurden zur Herstellung von Intermediat 1-25 wurden 3.0 g (7.82 mmol) tert-Butyl-(2R)-2-(3- {[(4-methylphenyl)sulfonyl]oxy}propyl)pyrrolidin-l-carboxylat mit 1.68 g (7.1 mmol) S-(4,4,5,5,5- Pentafluorpentyl)ethanthioat umgesetzt. Nach Reinigung durch Säulenchromatogaphie (Hexan/Ethylacetat) an Kieselgel erhielt man 1.66 g (49 % d. Th.) der Titelverbindung. Analogously, to prepare Intermediate 1-25, 3.0 g (7.82 mmol) of tert -butyl (2R) -2- (3 - [(4-methylphenyl) sulfonyl] oxy} propyl) pyrrolidine-1-carboxylate at 1.68 g (7.1 mmol) of S- (4,4,5,5,5-pentafluoropentyl) ethanethioate reacted. After purification by column chromatography (hexane / ethyl acetate) on silica gel, 1.66 g (49% of theory) of the title compound were obtained.
'H-NMR (400MHZ, DMSO-d6): δ [ppm]= 1.24 - 1.64 (m, 12H), 1.64 - 1.94 (m, 5H), 2.21 - 2.38 (m, 2H), 2.59 (t, 2H), 3.11 - 3.28 (m, 2H), 3.64 (br. s, 1H). 'H-NMR (400MHz, DMSO-d 6): δ [ppm] = 1.24 - 1.64 (m, 12H), 1.64 - 1.94 (m, 5H), 2:21 to 2:38 (m, 2H), 2:59 (t, 2H ), 3.11 - 3.28 (m, 2H), 3.64 (brs s, 1H).
Drehwert: [a] = 30,4 0 (c = 1.0, CHCI3). Intermediat 11-25Rotation: [a] = 30,4 0 (c = 1.0, CHCI3). Intermediate 11-25
orpropyl)sulfanyl]propyl}pyrrolidin-l-carboxylat orpropyl) sulfanyl] propyl} pyrrolidin-l-carboxylate
Analog wurden zur Herstellung von Intermediat 1-25 wurden 12.0 g (31.29 mmol) tert-Butyl-(2S)-2- (3 - {[(4-methylphenyl)sulfonyl]oxy}propyl)pyrro lidin- 1-carboxylat mit 4.31 g (25.03 mmol) S-(3,3,3- Trifluorpropyl)ethanthioat umgesetzt. Nach Reinigung durch Säulenchromatogaphie (Hexan/Ethylacetat) an Kieselgel erhielt man 7.84 g (69 % d. Th.) der Titelverbindung. Similarly, to prepare Intermediate 1-25, 12.0 g (31.29 mmol) of tert-butyl (2S) -2- (3 - {[(4-methylphenyl) sulfonyl] oxy} propyl) pyrrolidine-1-carboxylate with 4.31 g (25.03 mmol) of S- (3,3,3-trifluoropropyl) ethanethioate. After purification by column chromatography (hexane / ethyl acetate) on silica gel, 7.84 g (69% of theory) of the title compound were obtained.
'H-NMR (400MHZ, DMSO-d6): δ [ppm]= 1.28 - 1.64 (m, 13H), 1.64 - 1.94 (m, 4H), 2.52 - 2.61 (m, 4H), 2.61 - 2.69 (m, 2H), 3.11 - 3.29 (m, 2H), 3.65 (br. s, 1H). 'H-NMR (400MHz, DMSO-d 6): δ [ppm] = 1.28 - 1.64 (m, 13H), 1.64 - 1.94 (m, 4H), 2:52 - 2.61 (m, 4H), 2.61 - 2.69 (m , 2H), 3.11 - 3.29 (m, 2H), 3.65 (br s, 1H).
Drehwert: [a] = - 40,4 0 (c = 1.0, CHCI3).
Intermediat 12-25 Rotation: [a] = - 40.4 0 (c = 1.0, CHCI3). Intermediate 12-25
tert-Butyl-(2R)-2-{3-[(3,3,3-trifluorpropyl)sulfanyl]propyl}pyrrolidin-l-carboxylat tert-butyl (2R) -2- {3 - [(3,3,3-trifluoropropyl) sulfanyl] propyl} pyrrolidin-l-carboxylate
Analog zur Herstellung von Intermediat 1-25 wurden 3 g (7.8 mmol) tert-Butyl-(2R)-2-(3- {[(4- methylphenyl)sulfonyl] oxy} propyl)pyrro lidin- 1-carboxylat mit 1.22 g (7.11 mmol) S-(3,3,3- Trifluorpropyl)ethanthioat umgesetzt. Nach Reinigung durch Säulenchromatogaphie (Hexan/Ethylacetat) an Kieselgel erhielt man 620 mg (22 % d. Th.) der Titelverbindung. Analogously to the preparation of Intermediate 1-25, 3 g (7.8 mmol) of tert-butyl (2R) -2- (3 - [(4-methylphenyl) sulfonyl] oxy} propyl) pyrrolidine-1-carboxylate with 1.22 g (7.11 mmol) reacted S- (3,3,3-trifluoropropyl) ethanethioate. After purification by column chromatography (hexane / ethyl acetate) on silica gel, 620 mg (22% of theory) of the title compound were obtained.
'H-NMR (400MHZ, DMSO-d6): δ [ppm]= 1.28 - 1.64 (m, 13H), 1.64 - 1.94 (m, 4H), 2.52 - 2.61 (m, 4H), 2.61 - 2.69 (m, 2H), 3.11 - 3.29 (m, 2H), 3.65 (br. s, 1H). 'H-NMR (400MHz, DMSO-d 6): δ [ppm] = 01.28 - 1.64 (m, 13H), 1.64 - 1.94 (m, 4H), 2:52 - 2.61 (m, 4H), 2.61 - 2.69 (m , 2H), 3.11 - 3.29 (m, 2H), 3.65 (br s, 1H).
Drehwert: [a] = 33,8 ° (c = 1.0, CHC13). Rotation: [a] = 33.8 ° (c = 1.0, CHC1 3 ).
Intermediat 13-25 Intermediate 13-25
tert-Butyl-(2S)-2-{3-[(5,5,5-trifluoopentyl)sulfanyl]propyl}pyrrolidin-l-carboxylat tert-butyl (2S) -2- {3 - [(5,5,5-trifluoopentyl) sulfanyl] propyl} pyrrolidin-l-carboxylate
Analog zur Herstellung von Intermediat 1-25 wurden 6 g (15.64 mmol) tert-Butyl-(2S)-2-(3- {[(4- methylphenyl)sulfonyl] oxy} propyl)pyrro lidin- 1-carboxylat mit 2.51 g (12.51 mmol) S-(5,5,5- Trifluorpentyl)ethanthioat umgesetzt. Nach Reinigung durch Säulenchromatogaphie an Kieselgel (Hexan/Ethylacetat) erhielt man 3.83 g (63 % d. Th.) der Titelverbindung. Analogously to the preparation of Intermediate 1-25, 6 g (15.64 mmol) of tert-butyl (2S) -2- (3- {[(4-methylphenyl) sulfonyl] oxy} propyl) pyrrolidine-1-carboxylate with 2.51 g (12.51 mmol) of S- (5,5,5-trifluoropentyl) ethanethioate. Purification by column chromatography on silica gel (hexane / ethyl acetate) gave 3.83 g (63% of theory) of the title compound.
'H-NMR (400MHZ, DMSO-d6): δ [ppm]= 1.25 - 1.64 (m, 17H), 1.64 - 1.93 (m, 4H), 2.17 - 2.35 (m, 2H), 2.43 - 2.52 (m, 4H), 3.11 - 3.28 (m, 2H), 3.64 (br. s, 1H). 'H-NMR (400MHz, DMSO-d 6): δ [ppm] = 1.25 - 1.64 (m, 17H), 1.64 - 1.93 (m, 4H), 2:17 to 2:35 (m, 2H), 2:43 to 2:52 (m , 4H), 3.11 - 3.28 (m, 2H), 3.64 (br s, 1H).
Drehwert: [a] = - 39,6 0 (c = 1.0, CHCI3). Rotation: [a] = - 39.6 0 (c = 1.0, CHCI3).
Intermediat 14-25Intermediate 14-25
lbutyl)sulfanyl]propyl}pyrrolidin-l-carboxylat lbutyl) sulfanyl] propyl} pyrrolidin-l-carboxylate
Analog zur Herstellung von Intermediat 1-25 wurden 10 g (26.08 mmol) tert-Butyl-(2S)-2-(3- {[(4- methylphenyl)sulfonyl]oxy}propyl)pyrrolidin-l-carboxylat mit 3.80 g (23.70 mmol) S-(3,3-
Dimethylbutyl)ethanthioat umgesetzt. Nach Reinigung durch Säulenchromatogaphie an Kieselgel (Hexan/Ethylacetat) erhielt man 5.66 g (63 % d. Th.) der Titelverbindung. Analogously to the preparation of Intermediate 1-25, 10 g (26.08 mmol) of tert-butyl (2S) -2- (3- {[(4-methylphenyl) sulfonyl] oxy} propyl) pyrrolidine-1-carboxylate with 3.80 g ( 23.70 mmol) S- (3,3- Dimethylbutyl) ethanethioate reacted. After purification by column chromatography on silica gel (hexane / ethyl acetate), 5.66 g (63% of theory) of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.87 (s, 9H), 1.25 - 1.92 (m, 19H), 2.38 - 2.46 (m, 2H), 3.11 - 3.28 (m, 2H), 3.59 - 3.70 (m, 1H). 'H NMR (400MHZ, DMSO-de): δ [ppm] = 0.87 (s, 9H), 1.25-1.92 (m, 19H), 2.38-2.46 (m, 2H), 3.11-3.38 (m, 2H) , 3.59 - 3.70 (m, 1H).
Drehwert: [a] = - 40 ° (c = 1.0, CHC13). Rotation: [a] = - 40 ° (c = 1.0, CHC1 3 ).
Intermediat 1-26 Intermediate 1-26
tert-Butyl-(2R,4R)-4-fluor-2-{3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-l-carboxylat tert-butyl (2R, 4R) -4-fluoro-2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin-l-carboxylate
0.80 g (2.14 mmol) tert-Butyl-(2R,4R)-4-fluor-2- {3-[(4,4,4 rifluorbutyl)sulfanyl]propyl}pyrrolidin-l- carboxylat wurden entsprechend der allgemeinen Vorschrift 15 mit 1.11 g meta-Chlorperbenzoesäure umgesetzt. Man erhielt nach säulenchromatographischer Reinigung an Kieselgel (Hexan/Ethylacetat) 0.77 g (89% d. Th.) der Titelverbindung. 0.80 g (2.14 mmol) of tert-butyl (2R, 4R) -4-fluoro-2- {3 - [(4,4,4-trifluorobutyl) sulfanyl] propyl} pyrrolidine-1-carboxylate were obtained according to general procedure 15 Reacted 1.11 g of meta-chloroperbenzoic acid. After purification by column chromatography on silica gel (hexane / ethyl acetate), 0.77 g (89% of theory) of the title compound were obtained.
'H-NMR (300MHZ, CHLOROFORM-di): δ [ppm]= 1.46 (s, 9H), 1.53 - 2.20 (m, und Wassersignal), 2.23 - 2.51 (m, 3H), 2.92 - 3.17 (m, 4H), 3.34 (ddd, 1H), 3.78 - 4.09 (m, 2H), 4.99 - 5.24 (m, 1H). 'H-NMR (300MHZ, CHLOROFORM-di): δ [ppm] = 1.46 (s, 9H), 1.53 - 2.20 (m, and water signal), 2.23 - 2.51 (m, 3H), 2.92 - 3.17 (m, 4H ), 3.34 (ddd, 1H), 3.78 - 4.09 (m, 2H), 4.99 - 5.24 (m, 1H).
Intermediat 2-26 Intermediate 2-26
tert-Butyl-(2R)-4,4-difluor-2-{3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-l-carboxylat tert-butyl (2R) -4,4-difluoro-2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin-l-carboxylate
266 mg (0.68 mmol) tert-Butyl-(2R)-4,4-difluor-2- {3-[(4,4,4 rifluorbutyl)sulfanyl]propyl}pyrrolidin- 1-carboxylat wurden entsprechend der allgemeinen Vorschrift 15 mit 352 mg meta- Chlorperbenzoesäure umgesetzt. Man erhielt nach wässriger Aufarbeitung 293 mg eines Rohproduktes, welches ohne weitere Reinigung umgesetzt wurde. 266 mg (0.68 mmol) of tert-butyl (2R) -4,4-difluoro-2- {3 - [(4,4,4-trifluorobutyl) sulfanyl] propyl} pyrrolidine-1-carboxylate were obtained according to general procedure 15 Reacted 352 mg meta-chloroperbenzoic acid. After aqueous workup, 293 mg of a crude product were obtained, which was reacted without further purification.
Intermediat 3-26 Intermediate 3-26
tert-Butyl-(2R,4R)-4-hydroxy-2-{3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-l-carboxylat
tert-butyl (2R, 4R) -4-hydroxy-2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin-l-carboxylate
Stufe 1 : Step 1 :
tert-Butyl-(2R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-{3-[(4,4,4- rrolidin-l-carboxylat tert -Butyl (2R, 4R) -4 - {[tert -butyl (dimethyl) silyl] oxy} -2- {3 - [(4,4,4-rrolidine-1-carboxylate
220 mg (0.45 mmol) tert-Butyl-(2R,4R)-4- {[tert-butyl(dimethyl)silyl]oxy} -2- {3-[(4,4,4- trifluorbutyl)sulfanyl]propyl}pyrrolidin-l -carboxylat wurden entsprechend der allgemeinen Vorschrift 15 mit 156 mg meta-Chlorperbenzoesäure umgesetzt. Man erhielt nach wässriger Aufarbeitung und säulenchromatographischer Reinigung an Kieselgel (Hexan/Ethylacetat) 175 mg (75% d. Th.) tert- Butyl-(2R,4R)-4- {[tert-butyl(dimethyl)silyl]oxy} -2- {3-[(4,4,4- trifluorbutyl)sulfonyl]propyl}pyrrolidin-l-carboxylat. 220 mg (0.45 mmol) of tert-butyl (2R, 4R) -4- {[tert-butyl (dimethyl) silyl] oxy} -2- {3 - [(4,4,4-trifluorobutyl) sulfanyl] propyl} Pyrrolidine-1-carboxylate was reacted according to general procedure 15 with 156 mg meta-chloroperbenzoic acid. After aqueous work-up and purification by column chromatography on silica gel (hexane / ethyl acetate), 175 mg (75% of theory) of tert-butyl (2R, 4R) -4- {[tert-butyl (dimethyl) silyl] oxy} 2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidine-1-carboxylate.
'H-NMR (300MHZ, CHLOROFORM-di): δ [ppm]= 0.05 (s, 6H), 0.86 (s, 9H), 1.45 (s, 9H), 1.48 - 2.06 (m, 5H), 2.09 - 2.20 (m, 2H), 2.22 - 2.41 (m, 2H), 2.94 - 3.15 (m, 4H), 3.36 - 3.48 (m, 1 H), 3.87 - 3.99 (m, 1H), 4.26 - 4.35 (m, 1H). 'H-NMR (300MHZ, CHLOROFORM-di): δ [ppm] = 0.05 (s, 6H), 0.86 (s, 9H), 1.45 (s, 9H), 1.48 - 2.06 (m, 5H), 2.09 - 2.20 (m, 2H), 2.22 - 2.41 (m, 2H), 2.94 - 3.15 (m, 4H), 3.36 - 3.48 (m, 1H), 3.87 - 3.99 (m, 1H), 4.26 - 4.35 (m, 1H ).
Stufe 2: Level 2:
170 mg (0.33 mmol) tert-Butyl-(2R,4R)-4- {[tert-butyl(dimethyl)silyl]oxy} -2- {3-[(4,4,4- trifluorbutyl)sulfonyl]propyl}pyrrolidin-l-carboxylat in 5.0 ml THF wurden mit Tetrabutylammoniumfluorid-Lösung (IM in THF) versetzt, die Mischung wurde 18 h bei RT gerührt und auf Wasser gegossen. Man extrahierte dreimal mit tert-Butyl-methylether, wusch mit gesättigter Natriumchloridlösung, trocknete über Natriumsulfat und engte ein. Nach säulenchromatographischer Reinigung an Kieselgel (Hexan/Ethylacetat) erhielt man 117 mg (88% d. Th.) tert-Butyl-(2R,4R)-4- hydroxy-2- {3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-l -carboxylat (Intermediat 3-26). Tert-Butyl (2R, 4R) -4- {[tert-butyl (dimethyl) silyl] oxy} -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl 170 mg (0.33 mmol) pyrrolidine-1-carboxylate in 5.0 ml of THF were treated with tetrabutylammonium fluoride solution (III in THF), the mixture was stirred at RT for 18 h and poured into water. It was extracted three times with tert-butyl methyl ether, washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. After purification by column chromatography on silica gel (hexane / ethyl acetate), 117 mg (88% of theory) of tert-butyl (2R, 4R) -4-hydroxy-2- {3 - [(4,4,4-trifluorobutyl ) sulfonyl] propyl} pyrrolidine-1-carboxylate (Intermediate 3-26).
'H-NMR (400MHZ, CHLOROFORM-di): δ [ppm]= 1.46 (s, 9H), 1.49 - 1.91 (m, enthält Singulett bei 1.64 ppm), 1.91 -2.02 (m, 1H), 2.06 - 2.20 (m, 3H), 2.26 - 2.39 (m, 2H), 2.96 - 3.13 (m, 4H), 3.39 (dd, 1H), 3.46 - 3.62 (m, 1H), 3.92 - 4.04 (m, 1H), 4.41 (br. s, 1H).
Intermediat 4-26'H-NMR (400MHZ, CHLOROFORM-di): δ [ppm] = 1.46 (s, 9H), 1.49 - 1.91 (m, contains singlet at 1.64 ppm), 1.91 -2.02 (m, 1H), 2.06 - 2.20 ( m, 3H), 2.26-2.39 (m, 2H), 2.96-3.13 (m, 4H), 3.39 (dd, 1H), 3.46-3.62 (m, 1H), 3.92-4.04 (m, 1H), 4.41 ( br. s, 1H). Intermediate 4-26
,5,5-pentafluorpentyl)sulfonyl]ethyl}morpholin-4-carboxylat , 5,5-pentafluoropentyl) sulfonyl] ethyl} morpholine-4-carboxylate
1.6 g (3.93 mmol) tert-Butyl-(3R)-3- {2-[(4,4,5,5,5-pentafluorpentyl)sulfanyl]ethyl}morpholin-4- carboxylat wurden mit 2.03 g meta-Chlorperbenzoesäure in Dichlormethan analog zur allgmeinen Vorschrift 15 umgesetzt. Man erhielt nach Einengen im Vakuum 2.35 g Rohprodukt. Tert-Butyl (3R) -3- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfanyl] ethyl} morpholine-4-carboxylate (1.6 g, 3.93 mmol) was treated with 2.03 g of meta-chloroperbenzoic acid in Dichloromethane implemented analogously to General rule 15. Concentration in vacuo gave 2.35 g of crude product.
'H-NMR (400MHZ, CHLOROFORM-di): δ [ppm]= 1.47 (s, 9H), 2.00 - 2.10 (m, 1 H), 2.14 - 2.35 (m, 4H), 2.44 - 2.55 (m, 1 H), 2.84 - 2.95 (m, 1 H), 2.98 - 3.19 (m, 4H), 3.44 (td, 1H), 3.61 (dd, 1H), 3.67 - 3.92 (m, 3H), 4.01 - 4.19 (m, 1H), 5.30 (s, 2H). 'H NMR (400MHZ, CHLOROFORM-di): δ [ppm] = 1.47 (s, 9H), 2.00-2.10 (m, 1H), 2.14-2.35 (m, 4H), 2.44-2.55 (m, 1 H), 2.84-2.95 (m, 1H), 2.98-3.19 (m, 4H), 3.44 (td, 1H), 3.61 (dd, 1H), 3.67-3.92 (m, 3H), 4.01-4.19 (m , 1H), 5.30 (s, 2H).
Intermediat 5-26 Intermediate 5-26
tert-Butyl-(2S)-2-{3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-l-carboxylat tert-butyl (2S) -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin-l-carboxylate
7.46 g (19.9 mmol) tert-Butyl-(2S)-2- {3-[(4,4,4-trifluorbutyl)sulfanyl]propyl}pyrrolidin-l-carboxylat wurden entsprechend der allgemeinen Vorschrift 15 mit 15.29 g meta-Chlorperbenzoesäure umgesetzt. Man erhielt nach säulenchromatographischer Reinigung an Kieselgel (Hexan/Ethylacetat) 7.96 g (97 % d. Th.) der Titelverbindung. 7.46 g (19.9 mmol) of tert-butyl (2S) -2- {3 - [(4,4,4-trifluorobutyl) sulfanyl] propyl} pyrrolidine-1-carboxylate were obtained according to general procedure 15 with 15.29 g of meta-chloroperbenzoic acid implemented. After purification by column chromatography on silica gel (hexane / ethyl acetate), 7.96 g (97% of theory) of the title compound were obtained.
'H-NMR (400MHZ, DMSO-d6): δ [ppm]= 1.32 - 1.50 (m, 10H), 1.52 - 1.96 (m, 9H), 2.35 - 2.47 (m, 2H), 3.05 - 3.29 (m, 6H), 3.67 (br. s, 1H). 'H-NMR (400MHz, DMSO-d 6): δ [ppm] = 1:32 to 1:50 (m, 10H), 1:52 - 1.96 (m, 9H), 2:35 to 2:47 (m, 2H), 3:05 to 3:29 (m , 6H), 3.67 (brs s, 1H).
Drehwert: [a] = - 25,3 ° (c = 1.0, CHC13). Rotation: [a] = - 25.3 ° (c = 1.0, CHC1 3 ).
Intermediat-6-26 Intermediate-6-26
tert-Butyl-(2R)-2-{3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-l-carboxylat
tert-butyl (2R) -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin-l-carboxylate
1.5 g (4,2 mmol) tert-Butyl-(2R)-2- {3-[(4,4,4-trifluorbutyl)sulfanyl]propyl}pyrrolidin-l-carboxylat wurden entsprechend der allgemeinen Vorschrift 15 mit 2.11 g meta-Chlorperbenzoesäure umgesetzt. Man erhielt nach säulenchromatographischer Reinigung an Kieselgel (Hexan/Ethylacetat) 1.56 g (90 % d. Th.) der Titelverbindung. 1.5 g (4.2 mmol) of tert-butyl (2R) -2- {3 - [(4,4,4-trifluorobutyl) sulfanyl] propyl} pyrrolidine-1-carboxylate were obtained according to general procedure 15 with 2.11 g of meta -Chlorperbenzoesäure implemented. After purification by column chromatography on silica gel (hexane / ethyl acetate), 1.56 g (90% of theory) of the title compound were obtained.
'H-NMR (400MHZ, DMSO-d6): δ [ppm]= 1.32 - 1.50 (m, 10H), 1.52 - 1.96 (m, 9H), 2.35 - 2.47 (m, 2H), 3.05 - 3.29 (m, 6H), 3.67 (br. s, 1H). 'H-NMR (400MHz, DMSO-d 6): δ [ppm] = 1:32 to 1:50 (m, 10H), 1:52 - 1.96 (m, 9H), 2:35 to 2:47 (m, 2H), 3:05 to 3:29 (m , 6H), 3.67 (brs s, 1H).
Drehwert: [a] = 22,4 ° (c = 1.0, CHC13). Intermediat 7-26Rotation: [a] = 22.4 ° (c = 1.0, CHC1 3 ). Intermediate 7-26
tafluorbutyl)sulfonyl]propyl}pyrrolidin-l-carboxylat tafluorbutyl) sulfonyl] propyl} pyrrolidin-l-carboxylate
4.5 g (11.49 mmol) tert-Butyl-(2S)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfanyl]-propyl}pyrrolidine-l - carboxylat wurden entsprechend der allgemeinen Vorschrift 15 mit 9.06 g meta-Chlorperbenzoesäure umgesetzt. Man erhielt nach säulenchromatographischer Reinigung an Kieselgel (Hexan/Ethylacetat) 4.24 g (82 % d. Th.) der Titelverbindung. 4.5 g (11.49 mmol) of tert-butyl (2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfanyl] propyl} pyrrolidine-1-carboxylate were obtained according to general procedure 15 Reacted 9.06 g of meta-chloroperbenzoic acid. After purification by column chromatography on silica gel (hexane / ethyl acetate), 4.24 g (82% of theory) of the title compound were obtained.
'H-NMR (400MHZ, DMSO-d6): δ [ppm]= 1.30 - 1.50 (m, 10H), 1.53 - 1.96 (m, 7H), 2.57 - 2.75 (m, 2H), 3.12 - 3.31 (m, 4H), 3.37 - 3.47 (m, 2H), 3.68 (br. s, 1H). 'H-NMR (400MHz, DMSO-d 6): δ [ppm] = 1:30 to 1:50 (m, 10H), 1:53 - 1.96 (m, 7H), 2:57 - 2.75 (m, 2H), 3:12 to 3:31 (m , 4H), 3.37 - 3.47 (m, 2H), 3.68 (br, s, 1H).
Drehwert: [a] = - 19,8 0 (c = 1.0, CHCI3). Rotation: [a] = - 19.8 0 (c = 1.0, CHCI3).
Intermediat 8-26Intermediate 8-26
tafluorbutyl)sulfonyl]propyl}pyrrolidin-l-carboxylat tafluorbutyl) sulfonyl] propyl} pyrrolidin-l-carboxylate
2 g (4.9 mmol) tert-Butyl-(2R)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfanyl]-propyl}pyrrolidine-l - carboxylat wurden entsprechend der allgemeinen Vorschrift 15 mit 3.56 g meta-Chlorperbenzoesäure
umgesetzt. Man erhielt nach säulenchromatographischer Reinigung an Kieselgel (Hexan/Ethylacetat) 2.10 g (94 % d. Th.) der Titelverbindung. 2 g (4.9 mmol) of tert-butyl (2R) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfanyl] -propyl} pyrrolidine-1-carboxylate were obtained in accordance with general procedure 15 3.56 g meta-chloroperbenzoic acid implemented. After purification by column chromatography on silica gel (hexane / ethyl acetate), 2.10 g (94% of theory) of the title compound were obtained.
'H-NMR (400MHZ, DMSO-d6): δ [ppm]= 1.30 - 1.50 (m, 10H), 1.53 - 1.96 (m, 7H), 2.57 - 2.75 (m, 2H), 3.12 - 3.31 (m, 4H), 3.37 - 3.47 (m, 2H), 3.68 (br. s, 1H). 'H-NMR (400MHz, DMSO-d 6): δ [ppm] = 1:30 to 1:50 (m, 10H), 1:53 - 1.96 (m, 7H), 2:57 - 2.75 (m, 2H), 3:12 to 3:31 (m , 4H), 3.37 - 3.47 (m, 2H), 3.68 (br, s, 1H).
Drehwert: [a] = 17,2 ° (c = 1.0, CHC13). Rotation: [a] = 17.2 ° (c = 1.0, CHC1 3 ).
Intermediat 9-26Intermediate 9-26
uorpentyl)sulfonyl]propyl}pyrrolidin-l-carboxylat uorpentyl) sulfonyl] propyl} pyrrolidin-l-carboxylate
4.18 g (9.8 mmol) tert-Butyl-(2S)-2- {3-[(4,4,5,5,5-pentafluorpentyl)sulfanyl]-propyl}pyrrolidin-l - carboxylat wurden entsprechend der allgemeinen Vorschrift 15 mit 3.2 g meta-Chlorperbenzoesäure umgesetzt. Man erhielt nach säulenchromatographischer Reinigung an Kieselgel (Hexan/Ethylacetat) 4.26 g (94 % d. Th.) der Titelverbindung. 4.18 g (9.8 mmol) of tert-butyl (2S) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfanyl] propyl} pyrrolidine-1-carboxylate were obtained in accordance with general procedure 15 3.2 g reacted meta-chloroperbenzoic acid. After purification by column chromatography on silica gel (hexane / ethyl acetate), 4.26 g (94% of theory) of the title compound were obtained.
'H-NMR (400MHZ, DMSO-d6): δ [ppm]= 1.35 - 1.46 (m, 10H), 1.52 - 2.02 (m, 9H), 2.31 - 2.48 (m, 2H), 3.03 - 3.30 (m, 6H), 3.67 (br. s, 1H). 'H-NMR (400MHz, DMSO-d 6): δ [ppm] = 1:35 to 1:46 (m, 10H), 1:52 to 2:02 (m, 9H), 2:31 to 2:48 (m, 2H), 3:03 to 3:30 (m , 6H), 3.67 (brs s, 1H).
Drehwert: [a] = - 22,2 0 (c = 1.0, CHCI3). Rotation: [a] = - 22.2 0 (c = 1.0, CHCI3).
Intermediat 10-26Intermediate 10-26
fluorpentyl)sulfonyl]propyl}pyrrolidin-l-carboxylat fluoropentyl) sulfonyl] propyl} pyrrolidin-l-carboxylate
1.6 g (9.8 mmol) tert-Butyl-(2R)-2- {3-[(4,4,5,5,5-pentafluorpentyl)sulfanyl]-propyl}pyrrolidin-l - carboxylat wurden entsprechend der allgemeinen Vorschrift 15 mit 2.68 g meta-Chlorperbenzoesäure umgesetzt. Man erhielt nach säulenchromatographischer Reinigung an Kieselgel (Hexan/Ethylacetat) 1.55 g (98 % d. Th.) der Titelverbindung. 1.6 g (9.8 mmol) of tert-butyl (2R) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfanyl] propyl} pyrrolidine-1-carboxylate were obtained in accordance with general procedure 15 2.68 g reacted meta-chloroperbenzoic acid. After purification by column chromatography on silica gel (hexane / ethyl acetate), 1.55 g (98% of theory) of the title compound were obtained.
'H-NMR (400MHZ, DMSO-d6): δ [ppm]= 1.35 - 1.46 (m, 10H), 1.52 - 2.02 (m, 9H), 2.31 - 2.48 (m, 2H), 3.03 - 3.30 (m, 6H), 3.67 (br. s, 1H). 'H-NMR (400MHz, DMSO-d 6): δ [ppm] = 1:35 to 1:46 (m, 10H), 1:52 to 2:02 (m, 9H), 2:31 to 2:48 (m, 2H), 3:03 to 3:30 (m , 6H), 3.67 (brs s, 1H).
Drehwert: [a] = 20,6 0 (c = 1.0, CHCI3). Rotation: [a] = 20.6 0 (c = 1.0, CHCI3).
Intermediat 11-26
tert-Butyl-(2S)-2-{3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l-carboxylat Intermediate 11-26 tert-butyl (2S) -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidin-l-carboxylate
7.83 g (22.9 mmol) tert-Butyl-(2S)-2- {3-[(3,3,3-trifluorpropyl)sulfanyl]propyl}pyrrolidin-l-carboxylat wurden entsprechend der allgemeinen Vorschrift 15 mit 12.66 g meta-Chlorperbenzoesäure umgesetzt. Man erhielt nach säulenchromatographischer Reinigung an Kieselgel (Hexan/Ethylacetat) 8.27 g (91 % d. Th.) der Titelverbindung. 7.83 g (22.9 mmol) of tert-butyl (2S) -2- {3 - [(3,3,3-trifluoropropyl) sulfanyl] propyl} pyrrolidine-1-carboxylate were obtained according to general procedure 15 with 12.66 g of meta-chloroperbenzoic acid implemented. After purification by column chromatography on silica gel (hexane / ethyl acetate), 8.27 g (91% of theory) of the title compound were obtained.
'H-NMR (400MHZ, DMSO-d6): δ [ppm]= 1.34 - 1.48 (m, 10H), 1.51 - 1.94 (m, 7H), 2.65 - 2.82 (m, 2H), 3.12 - 3.31 (m, 4H), 3.35 - 3.43 (m, 2H), 3.68 (br. s, 1H). 'H-NMR (400MHz, DMSO-d 6): δ [ppm] = 1:34 to 1:48 (m, 10H), 1:51 - 1.94 (m, 7H), 2.65 - 2.82 (m, 2H), 3:12 to 3:31 (m , 4H), 3.35 - 3.43 (m, 2H), 3.68 (br s, 1H).
Drehwert: [a] = - 25,3 ° (c = 1.0, CHC13). Rotation: [a] = - 25.3 ° (c = 1.0, CHC1 3 ).
Intermediat 12-26 Intermediate 12-26
tert-Butyl-(2R)-2-{3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l-carboxylat tert-butyl (2R) -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidin-l-carboxylate
620 mg (1.81 mmol) tert-Butyl-(2R)-2- {3-[(3,3,3-trifluorpropyl)sulfanyl]propyl}pyrrolidin-l - carboxylat wurden entsprechend der allgemeinen Vorschrift 15 mit 1 g meta-Chlorperbenzoesäure umgesetzt. Man erhielt nach säulenchromatographischer Reinigung an Kieselgel (Hexan/Ethylacetat) 685 mg (96 % d. Th.) der Titelverbindung. 620 mg (1.81 mmol) of tert-butyl (2R) -2- {3 - [(3,3,3-trifluoropropyl) sulfanyl] propyl} pyrrolidine-1-carboxylate were obtained according to general procedure 15 with 1 g of meta-chloroperbenzoic acid implemented. After purification by column chromatography on silica gel (hexane / ethyl acetate), 685 mg (96% of theory) of the title compound were obtained.
'H-NMR (400MHZ, DMSO-d6): δ [ppm]= 1.34 - 1.48 (m, 10H), 1.51 - 1.94 (m, 7H), 2.65 - 2.82 (m, 2H), 3.12 - 3.31 (m, 4H), 3.35 - 3.43 (m, 2H), 3.68 (br. s, 1H). 'H-NMR (400MHz, DMSO-d 6): δ [ppm] = 1:34 to 1:48 (m, 10H), 1:51 - 1.94 (m, 7H), 2.65 - 2.82 (m, 2H), 3:12 to 3:31 (m , 4H), 3.35 - 3.43 (m, 2H), 3.68 (br s, 1H).
Drehwert: [a] = 17,6 0 (c = 1.0, CHCI3). Rotation: [a] = 17.6 0 (c = 1.0, CHCI3).
Intermediat 13-26 Intermediate 13-26
tert-Butyl-(2S)-2-{3-[(5,5,5-trifluorpentyl)sulfonyl]propyl}pyrrolidin-l-carboxylat tert-butyl (2S) -2- {3 - [(5,5,5-trifluoropentyl) sulfonyl] propyl} pyrrolidin-l-carboxylate
3.82 g (10.33 mmol) tert-Butyl-(2S)-2- {3-[(5,5,5-trifluorpentyl)sulfanyl]propyl}pyrrolidin-l- carboxylat wurden entsprechend der allgemeinen Vorschrift 15 mit 5.71 g meta-Chlorperbenzoesäure
umgesetzt. Man erhielt nach säulenchromatographischer Reinigung an Kieselgel (Hexan/Ethylacetat) 2.35 g (53 % d. Th.) der Titelverbindung. 3.82 g (10.33 mmol) of tert-butyl (2S) -2- {3 - [(5,5,5-trifluoropentyl) sulfanyl] propyl} pyrrolidine-1-carboxylate were obtained according to general procedure 15 with 5.71 g of meta-chloroperbenzoic acid implemented. After purification by column chromatography on silica gel (hexane / ethyl acetate), 2.35 g (53% of theory) of the title compound were obtained.
'H-NMR (400MHZ, DMSO-d6): δ [ppm]= 1.33 - 1.45 (m, 10H), 1.52 - 1.70 (m, 6H), 1.70 - 1.92 (m, 5H), 2.22 - 2.38 (m, 2H), 3.00 - 3.28 (m, 6H), 3.67 (br. s, 1H). 'H-NMR (400MHz, DMSO-d 6): δ [ppm] = 1:33 to 1:45 (m, 10H), 1:52 - 1.70 (m, 6H), 1.70 - 1.92 (m, 5H), 2:22 to 2:38 (m , 2H), 3.00 - 3.28 (m, 6H), 3.67 (brs s, 1H).
Drehwert: [a] = - 26,7 ° (c = 1.0, CHC13). Rotation: [a] = - 26.7 ° (c = 1.0, CHC1 3 ).
Intermediat 14-26Intermediate 14-26
utyl)sulfonyl]propyl}pyrrolidin-l-carboxylat utyl) sulfonyl] propyl} pyrrolidin-l-carboxylate
5.66 g (17.15 mmol) tert-Butyl-(2S)-2- {3-[(3,3-dimethylbutyl)sulfanyl]propyl}pyrrolidin-l-carboxylat wurden entsprechend der allgemeinen Vorschrift 15 mit 9.48 g meta-Chlorperbenzoesäure umgesetzt. Man erhielt nach säulenchromatographischer Reinigung an Kieselgel (Hexan/Ethylacetat) 6.81 g (104 % d. Th.) der Titelverbindung. 5.66 g (17.15 mmol) of tert-butyl (2S) -2- {3 - [(3,3-dimethylbutyl) sulfanyl] propyl} pyrrolidine-1-carboxylate were reacted in accordance with general procedure 15 with 9.48 g of meta-chloroperbenzoic acid. After purification by column chromatography on silica gel (hexane / ethyl acetate), 6.81 g (104% of theory) of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.89 (s, 9H), 1.33 - 1.47 (m, 10H), 1.51 - 1.96 (m, 9H), 2.96 - 3.04 (m, 2H), 3.07 - 3.31 (m, 4H), 3.68 (br. s, 1H). 'H NMR (400MHZ, DMSO-de): δ [ppm] = 0.89 (s, 9H), 1.33-1.47 (m, 10H), 1.51-1.96 (m, 9H), 2.96-3.04 (m, 2H) , 3.07 - 3.31 (m, 4H), 3.68 (brs s, 1H).
Drehwert: [a] = - 30,6 0 (c = 1.0, CHCI3). Rotation: [a] = - 30.6 0 (c = 1.0, CHCI3).
Intermediat 1-27 Intermediate 1-27
(2R,4R)-4-Fluor-2-{3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin (2R, 4R) -4-fluoro-2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin
F F F F
0.77 g (1 .90 mmol) tert-Butyl-(2R,4R)-4-fluor-2- {3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-l- carboxylat in 5.0 ml Dichlormethan wurden mit 1.5 ml TFA versetzt und die Lösung wurde über Nacht bei RT gerührt. Man goss auf gesättigte Natriumhydrogencarbonatlösung, rührte 3 h, extrahierte dreimal mit Dichlormethan, engte die vereinigten organischen Phasen ein und trocknete im Vakuum. Es wurden 450 mg der Titelverbindung erhalten. 0.77 g (1.90 mmol) of tert-butyl (2R, 4R) -4-fluoro-2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidine-1-carboxylate in 5.0 ml of dichloromethane were added with 1.5 ml of TFA and the solution was stirred at RT overnight. It was poured onto saturated sodium bicarbonate solution, stirred for 3 h, extracted three times with dichloromethane, the combined organic phases were concentrated and dried in vacuo. 450 mg of the title compound were obtained.
'H-NMR (300MHZ, CHLOROFORM-di): δ [ppm]= 1.42 (ddd), 1.49 - 1.69 (m), 1.83 - 2.06 (m, 2H), 2.06 - 2.41 (m, 7H), 2.97 - 3.23 (m, 6H), 3.32 - 3.46 (m, 1H), 5.06 - 5.32 (m, 1H). 'H-NMR (300MHZ, CHLOROFORM-di): δ [ppm] = 1.42 (ddd), 1.49 - 1.69 (m), 1.83 - 2.06 (m, 2H), 2.06 - 2.41 (m, 7H), 2.97 - 3.23 (m, 6H), 3.32 - 3.46 (m, 1H), 5.06 - 5.32 (m, 1H).
Intermediat 2-27
(2R)-4,4-Difluor-2-{3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin Intermediate 2-27 (2R) -4,4-difluoro-2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin
293 mg (0.69 mmol) tert-Butyl-(2R)-4,4-difluor-2- {3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin- 1-carboxylat wurden in 5 ml Dichlormethan vorgelegt, 533 Microliter TFA wurden zugegeben und die Mischung wurde 7.5 h bei RT gerührt. Man engte ein, addierte dreimal Toluol und engte jeweils ein und trocknete. Man erhielt 336 mg eines Rohprodukts, welches ohne weitere Aufreinigung eingesetzt wurde. 293 mg (0.69 mmol) of tert-butyl (2R) -4,4-difluoro-2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidine-1-carboxylate were initially charged in 5 ml of dichloromethane , 533 microliters of TFA were added and the mixture was stirred at RT for 7.5 h. It was concentrated, three times toluene added and concentrated each one and dried. 336 mg of a crude product were obtained, which was used without further purification.
'H-NMR (400MHZ, DMSO-de, ausgewählte Signale): δ [ppm]= 1.64 - 1.93 (m, 6H), 2.12 - 2.29 (m, 1H), 2.65 - 2.80 (m, 1H), 3.06 - 3.27 (m, 4H), 3.58 - 3.87 (m, 3H). 'H-NMR (400MHZ, DMSO-de, selected signals): δ [ppm] = 1.64-1.93 (m, 6H), 2.12-2.29 (m, 1H), 2.65-2.80 (m, 1H), 3.06-3.27 (m, 4H), 3.58 - 3.87 (m, 3H).
Intermediat 3-27 Intermediate 3-27
(3R,5R)-5-{3-[(4,4,4-Trifluorbutyl)sulfonyl]propyl}pyrrolidin-3-ol (3R, 5R) -5- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin-3-ol
Analog zu Intermediat 2-27 wurden 110 mg (0.27 mmol) tert-Butyl-(2R,4R)-4-hydroxy-2- {3-[(4,4,4- trifluorbutyl)sulfonyl]propyl}pyrrolidin-l-carboxylat mit 210 Microlitern Trifluoressigsäure in Dichlormethan umgesetzt. Man engte ein, addierte dreimal Toluol und engte jeweils ein und trocknete. Man erhielt 144 mg eines Rohproduktes, welches weitere ohne Aufreinigung eingesetzt wurde. Analogously to Intermediate 2-27, 110 mg (0.27 mmol) of tert-butyl (2R, 4R) -4-hydroxy-2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidine-1 Carboxylate reacted with 210 microliters of trifluoroacetic acid in dichloromethane. It was concentrated, three times toluene added and concentrated each one and dried. 144 mg of a crude product were obtained, which was used further without purification.
C11H20F3NO3S, MS (CI+) gefundene Masse: 304+. Intermediat 4-27C11H20F3NO3S, MS (CI +) found mass: 304 + . Intermediate 4-27
tafluorpentyl)sulfonyl]ethyl}morpholin tafluorpentyl) sulfonyl] ethyl} morpholine
1.20 g (2.73 mmol mmol) tert-Butyl-(3R)-3- {2-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]ethyl}morpholin- 4-carboxylat in 5 ml Dichlormethan wurden mit 5 ml TFA versetzt und die Mischung wurde 4 h bei RT gerührt. Man tropfte vorsichtig gesättigte Natriumhydrogencarbonatlösung zu, trennte die organische Phase ab und extrahierte zweimal mit Dichlormethan. Die vereinigten organischen Phasen
wurden zweimal mit gesättigter Natriumhydrogencarbonatlösung und mit Natriumchloridlösung gewaschen, über Natriumsulfat getrocknet und eingeengt. Nach Trocknen im Vakuum erhielt man 1 .09 g Rohprodukt. 1.20 g (2.73 mmol mmol) of tert-butyl (3R) -3- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} morpholine-4-carboxylate in 5 ml of dichloromethane were treated with 5 TFA was added and the mixture was stirred at RT for 4 h. It was added dropwise to saturated sodium bicarbonate solution, the organic phase was separated off and extracted twice with dichloromethane. The combined organic phases were washed twice with saturated sodium bicarbonate solution and with sodium chloride solution, dried over sodium sulfate and concentrated. After drying in vacuo, 1 .09 g of crude product.
'H-NMR (400MHZ, CHLOROFORM-di): δ [ppm]= 1 .68 - 1 .86 (m, 2H), 1 .86 - 1 .99 (m, 1 H), 2.12 - 2.35 (m, 4H), 2.84 - 3.00 (m, 3H), 3.00 - 3.24 (m, 5H), 3.46 (ddd, 1 H), 3.73 - 3.84 (m, 2H). 'H-NMR (400MHZ, CHLOROFORM-di): δ [ppm] = 1 .68 - 1 .86 (m, 2H), 1 .86 - 1 .99 (m, 1H), 2.12 - 2.35 (m, 4H), 2.84 - 3.00 (m, 3H), 3.00 - 3.24 (m, 5H), 3.46 (ddd, 1H), 3.73 - 3.84 (m, 2H).
Intermediat 5-27 Intermediate 5-27
(2S)-2-{3-[(4,4,4-Trifluorbutyl)sulfonyl]propyl}pyrrolidin (2S) -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin
7.94 g (20.5 mmol) tert-Butyl-(2S)-2- {3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-l -carboxylat in 200 ml Dichlormethan wurden mit 3 1 .59 ml TFA versetzt und die Lösung wurde über Nacht bei RT gerührt. Man goss auf gesättigte Natriumhydrogencarbonatlösung, rührte 3 h, extrahierte dreimal mit Dichlormethan, engte die vereinigten organischen Phasen ein und trocknete im Vakuum. Es wurden 4. 1 8 g der Titelverbindung erhalten. Tert-Butyl (2S) -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidine-1-carboxylate in 7.9 g (20.5 mmol) in 200 ml of dichloromethane was treated with 3 1.59 ml of TFA and the solution was stirred at RT overnight. It was poured onto saturated sodium bicarbonate solution, stirred for 3 h, extracted three times with dichloromethane, the combined organic phases were concentrated and dried in vacuo. There were obtained 4. 1 8 g of the title compound.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 1 .09 - 1 .21 (m, 1 H), 1 .37 - 1 .49 (m, 2H), 1 .50 - 1 .83 (m, 5H), 1 .84 - 1 .96 (m, 2H), 2.35 - 2.48 (m, 2H), 2.69 (dt, 1H), 2.76 - 2.91 (m, 2H), 3.10 - 3.21 (m, 4H). 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 1 .09 - 1 .21 (m, 1H), 1 .37 - 1 .49 (m, 2H), 1 .50 - 1. 83 (m, 5H), 1.84-1.96 (m, 2H), 2.35-2.48 (m, 2H), 2.69 (dt, 1H), 2.76-2.91 (m, 2H), 3.10-3.21 (m , 4H).
Intermediat 6-27 Intermediate 6-27
(2R)-2-{3-[(4,4,4-Trifluorbutyl)sulfonyl]propyl}pyrrolidin (2R) -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin
1.5 g (3.87 mmol) tert-Butyl-(2R)-2- {3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-l -carboxylat in 200 ml Dichlormethan wurden mit 5.96 ml TFA versetzt und die Lösung wurde über Nacht bei RT gerührt. Man goss auf gesättigte Natriumhydrogencarbonatlösung, rührte 3 h, extrahierte dreimal mit Dichlormethan, engte die vereinigten organischen Phasen ein und trocknete im Vakuum. Es wurden 1.18 g der Titelverbindung (Trifluoressigsäuresalz) erhalten. 1.5 g (3.87 mmol) of tert-butyl (2R) -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidine 1-carboxylate in 200 ml of dichloromethane were admixed with 5.96 ml of TFA and the Solution was stirred at RT overnight. It was poured onto saturated sodium bicarbonate solution, stirred for 3 h, extracted three times with dichloromethane, the combined organic phases were concentrated and dried in vacuo. There were obtained 1.18 g of the title compound (trifluoroacetic acid salt).
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 1.09 - 1.21 (m, 1H), 1.37 - 1.49 (m, 2H), 1.50 - 1.83 (m, 5H), 1.84 - 1.96 (m, 2H), 2.35 - 2.48 (m, 2H), 2.69 (dt, 1H), 2.76 - 2.91 (m, 2H), 3.10 - 3.21 (m, 4H). 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 1.09-1.21 (m, 1H), 1.37-1.49 (m, 2H), 1.50-1.83 (m, 5H), 1.84-1.96 (m, 2H), 2.35-2.48 (m, 2H), 2.69 (dt, 1H), 2.76-2.91 (m, 2H), 3.10-3.21 (m, 4H).
Intermediat 7-27 Intermediate 7-27
(2S)-2-{3-[(3,3,4,4,4-Pentafluorbutyl)sulfonyl]propyl}pyrrolidin
(2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidin
4.2 g (9.9 mmol) tert-Butyl-(2S)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- carboxylat in 100 ml Dichlormethan wurden mit 15.28 ml TFA versetzt und die Lösung wurde über Nacht bei RT gerührt. Man goss auf gesättigte Natriumhydrogencarbonatlösung, rührte 3 h, extrahierte dreimal mit Dichlormethan, engte die vereinigten organischen Phasen ein und trocknete im Vakuum. Es wurden 3.08 g der Titelverbindung erhalten. 4.2 g (9.9 mmol) of tert-butyl (2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] -propyl} pyrrolidine-1-carboxylate in 100 ml of dichloromethane were mixed with 15.28 ml TFA was added and the solution was stirred at RT overnight. It was poured onto saturated sodium bicarbonate solution, stirred for 3 h, extracted three times with dichloromethane, the combined organic phases were concentrated and dried in vacuo. There was obtained 3.08 g of the title compound.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 1.09 - 1.21 (m, 1H), 1.38 - 1.48 (m, 2H), 1.52 - 1.86 (m, 5H), 2.58 - 2.74 (m, 3H), 2.75 - 2.93 (m, 2H), 3.23 - 3.28 (m, 2H), 3.39 - 3.45 (m, 2H). Intermediat 8-27 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 1.09-1.21 (m, 1H), 1.38-1.48 (m, 2H), 1.52-1.86 (m, 5H), 2.58-2.74 (m, 3H), 2.75 - 2.93 (m, 2H), 3.23 - 3.28 (m, 2H), 3.39 - 3.45 (m, 2H). Intermediate 8-27
2.1 g (5 mmol) tert-Butyl-(2R)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- carboxylat in 44.3 ml Dichlormethan wurden mit 7.64 ml TFA versetzt und die Lösung wurde über Nacht bei RT gerührt. Man goss auf gesättigte Natriumhydrogencarbonatlösung, rührte 3 h, extrahierte dreimal mit Dichlormethan, engte die vereinigten organischen Phasen ein und trocknete im Vakuum. Es wurden 1.43 g der Titelverbindung erhalten. 2.1 g (5 mmol) of tert-butyl (2R) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidine-1-carboxylate in 44.3 ml of dichloromethane were mixed with 7.64 ml TFA was added and the solution was stirred at RT overnight. It was poured onto saturated sodium bicarbonate solution, stirred for 3 h, extracted three times with dichloromethane, the combined organic phases were concentrated and dried in vacuo. There were obtained 1.43 g of the title compound.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 1.09 - 1.21 (m, 1H), 1.38 - 1.48 (m, 2H), 1.52 - 1.86 (m, 5H), 2.58 - 2.74 (m, 3H), 2.75 - 2.93 (m, 2H), 3.23 - 3.28 (m, 2H), 3.39 - 3.45 (m, 2H). 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 1.09-1.21 (m, 1H), 1.38-1.48 (m, 2H), 1.52-1.86 (m, 5H), 2.58-2.74 (m, 3H), 2.75 - 2.93 (m, 2H), 3.23 - 3.28 (m, 2H), 3.39 - 3.45 (m, 2H).
Intermediat 9-27Intermediate 9-27
4.17 g (13 mmol) tert-Butyl-(2S)-2- {3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- carboxylat in 130 ml Dichlormethan wurden mit 20.57 ml TFA versetzt und die Lösung wurde über Nacht bei RT gerührt. Man goss auf gesättigte Natriumhydrogencarbonatlösung, rührte 3 h, extrahierte dreimal mit Dichlormethan, engte die vereinigten organischen Phasen ein und trocknete im Vakuum. Es wurden 3.11 g der Titelverbindung erhalten. 4.17 g (13 mmol) of tert-butyl (2S) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidine-1-carboxylate in 130 ml of dichloromethane were mixed with 20.57 ml TFA was added and the solution was stirred at RT overnight. It was poured onto saturated sodium bicarbonate solution, stirred for 3 h, extracted three times with dichloromethane, the combined organic phases were concentrated and dried in vacuo. There were obtained 3.11 g of the title compound.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 1.16 (ddt, 1H), 1.40 - 1.49 (m, 2H), 1.53 - 1.84 (m, 5H), 1.88 - 1.98 (m, 2H), 2.31 - 2.48 (m, 2H), 2.69 (ddd, 1H), 2.77 - 2.93 (m, 2H), 3.1 1 - 3.16 (m, 2H), 3.19 - 3.24 (m, 2H).
Intermediat 10-27'H-NMR (400MHZ, DMSO-de): δ [ppm] = 1.16 (ddt, 1H), 1.40-1.49 (m, 2H), 1.53-1.84 (m, 5H), 1.88-1.98 (m, 2H) , 2.31 - 2.48 (m, 2H), 2.69 (ddd, 1H), 2.77 - 2.93 (m, 2H), 3.1 1 - 3.16 (m, 2H), 3.19 - 3.24 (m, 2H). Intermediate 10-27
-2-{3-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]propyl}pyrrolidin
-2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidin
1.5 g (3 mmol) tert-Butyl-(2R)-2- {3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- carboxylat in 32.1 ml Dichlormethan wurden mit 5.28 ml TFA versetzt und die Lösung wurde über Nacht bei RT gerührt. Man goss auf gesättigte Natriumhydrogencarbonatlösung, rührte 3 h, extrahierte dreimal mit Dichlormethan, engte die vereinigten organischen Phasen ein und trocknete im Vakuum. Es wurden 930 mg der Titelverbindung erhalten. 1.5 g (3 mmol) of tert-butyl (2R) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidine-1-carboxylate in 32.1 ml of dichloromethane was mixed with 5.28 ml TFA was added and the solution was stirred at RT overnight. It was poured onto saturated sodium bicarbonate solution, stirred for 3 h, extracted three times with dichloromethane, the combined organic phases were concentrated and dried in vacuo. 930 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 1.16 (ddt, 1H), 1.40 - 1.49 (m, 2H), 1.53 - 1.84 (m, 5H), 1.88 - 1.98 (m, 2H), 2.31 - 2.48 (m, 2H), 2.69 (ddd, 1H), 2.77 - 2.93 (m, 2H), 3.1 1 - 3.16 (m, 2H), 3.19 - 3.24 (m, 2H). 'H NMR (400MHZ, DMSO-de): δ [ppm] = 1.16 (ddt, 1H), 1.40-1.49 (m, 2H), 1.53-1.84 (m, 5H), 1.88-1.98 (m, 2H) , 2.31 - 2.48 (m, 2H), 2.69 (ddd, 1H), 2.77 - 2.93 (m, 2H), 3.1 1 - 3.16 (m, 2H), 3.19 - 3.24 (m, 2H).
Intermediat 11-27Intermediate 11-27
8.25 g (22, 1 mmol) tert-Butyl-(2S)-2- {3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l- carboxylat in 215 ml Dichlormethan wurden mit 34 ml TFA versetzt und die Lösung wurde über Nacht bei RT gerührt. Man goss auf gesättigte Natriumhydrogencarbonatlösung, rührte 3 h, extrahierte dreimal mit Dichlormethan, engte die vereinigten organischen Phasen ein und trocknete im Vakuum. Es wurden 3.31 g der Titelverbindung erhalten. 8.25 g (22.1 mmol) of tert-butyl (2S) -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] -propyl} -pyrrolidine-1-carboxylate in 215 ml of dichloromethane were admixed with 34 ml of TFA and the solution was stirred at RT overnight. It was poured onto saturated sodium bicarbonate solution, stirred for 3 h, extracted three times with dichloromethane, the combined organic phases were concentrated and dried in vacuo. There was obtained 3.31 g of the title compound.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 1.10 - 1.20 (m, 1H), 1.38 - 1.48 (m, 2H), 1.53 - 1.84 (m, 5H), 2.65 - 2.91 (m, 5H), 3.23 (t, 2H), 3.35 - 3.40 (m, 2H). Intermediat 12-27 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 1.10-1.20 (m, 1H), 1.38-1.48 (m, 2H), 1.53-1.84 (m, 5H), 2.65-2.91 (m, 5H), 3.23 (t, 2H), 3.35 - 3.40 (m, 2H). Intermediate 12-27
654 mg (1.75 mmol) tert-Butyl-(2R)-2- {3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l- carboxylat in 18 ml Dichlormethan wurden mit 2.69 ml TFA versetzt und die Lösung wurde über Nacht bei RT gerührt. Man goss auf gesättigte Natriumhydrogencarbonatlösung, rührte 3 h, extrahierte dreimal mit Dichlormethan, engte die vereinigten organischen Phasen ein und trocknete im Vakuum. Es wurden 416 mg der Titelverbindung erhalten.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 1.10 - 1.20 (m, 1H), 1.38 - 1.48 (m, 2H), 1.53 - 1.84 (m, 5H), 2.65 - 2.91 (m, 5H), 3.23 (t, 2H), 3.35 - 3.40 (m, 2H). 654 mg (1.75 mmol) of tert-butyl (2R) -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidine-1-carboxylate in 18 ml of dichloromethane were admixed with 2.69 ml of TFA and the Solution was stirred at RT overnight. It was poured onto saturated sodium bicarbonate solution, stirred for 3 h, extracted three times with dichloromethane, the combined organic phases were concentrated and dried in vacuo. 416 mg of the title compound were obtained. 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 1.10-1.20 (m, 1H), 1.38-1.48 (m, 2H), 1.53-1.84 (m, 5H), 2.65-2.91 (m, 5H), 3.23 (t, 2H), 3.35 - 3.40 (m, 2H).
Intermediat 13-27Intermediate 13-27
2.34 g (5.84 mmol) tert-Butyl-(2S)-2- {3-[(5,5,5-trifluorpentyl)sulfonyl]propyl}pyrrolidin-l -carboxylat in 57 ml Dichlormethan wurden mit 9 ml TFA versetzt und die Lösung wurde über Nacht bei RT gerührt. Man goss auf gesättigte Natriumhydrogencarbonatlösung, rührte 3 h, extrahierte dreimal mit Dichlormethan, engte die vereinigten organischen Phasen ein und trocknete im Vakuum. Es wurden 1.64 g der Titelverbindung erhalten. 2.34 g (5.84 mmol) of tert-butyl (2S) -2- {3 - [(5,5,5-trifluoropentyl) sulfonyl] propyl} pyrrolidine 1-carboxylate in 57 ml of dichloromethane were admixed with 9 ml of TFA and the Solution was stirred at RT overnight. It was poured onto saturated sodium bicarbonate solution, stirred for 3 h, extracted three times with dichloromethane, the combined organic phases were concentrated and dried in vacuo. There were obtained 1.64 g of the title compound.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 1.13 - 1.24 (m, 1H), 1.46 (q, 2H), 1.56 - 1.82 (m, 9H), 2.24 - 2.38 (m, 2H), 2.69 - 2.77 (m, 1 H), 2.81 - 2.88 (m, 1H), 2.88 - 2.96 (m, 1H), 3.08 (t, 2H), 3.10 - 3.15 (m, 2H). 'H NMR (400MHZ, DMSO-de): δ [ppm] = 1.13-1.24 (m, 1H), 1.46 (q, 2H), 1.56-1.82 (m, 9H), 2.24-2.38 (m, 2H) , 2.69-2.7 (m, 1H), 2.81-2.88 (m, 1H), 2.88-2.96 (m, 1H), 3.08 (t, 2H), 3.10-3.15 (m, 2H).
Intermediat 14-27Intermediate 14-27
-2-{3-[(3,3-Dimethylbutyl)sulfonyl]propyl}pyrrolidin
-2- {3 - [(3,3-dimethylbutyl) sulfonyl] propyl} pyrrolidin
6.75 g (18.69 mmol) tert-Butyl-(2S)-2- {3-[(3,3-dimethylbutyl)sulfonyl]propyl}pyrrolidin-l-carboxylat in 182 ml Dichlormethan wurden mit 28.8 ml TFA versetzt und die Lösung wurde über Nacht bei RT gerührt. Man goss auf gesättigte Natriumhydrogencarbonatlösung, rührte 3 h, extrahierte dreimal mit Dichlormethan, engte die vereinigten organischen Phasen ein und trocknete im Vakuum. Es wurden 5 g der Titelverbindung erhalten. 6.75 g (18.69 mmol) of tert-butyl (2S) -2- {3 - [(3,3-dimethylbutyl) sulfonyl] propyl} pyrrolidine-1-carboxylate in 182 ml of dichloromethane were admixed with 28.8 ml of TFA and the solution became stirred overnight at RT. It was poured onto saturated sodium bicarbonate solution, stirred for 3 h, extracted three times with dichloromethane, the combined organic phases were concentrated and dried in vacuo. There was obtained 5 g of the title compound.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.90 (s, 9H), 1.19 - 1.31 (m, 1H), 1.48 - 1.59 (m, 4H), 1.60 - 1.79 (m, 4H), 1.81 - 1.93 (m, 1 H), 2.77 - 2.86 (m, 1H), 2.87 - 2.95 (m, 1H), 2.97 - 3.05 (m, 3H), 3.12 (t, 2H). 'H NMR (400MHZ, DMSO-de): δ [ppm] = 0.90 (s, 9H), 1.19-1.31 (m, 1H), 1.48-1.59 (m, 4H), 1.60-1.79 (m, 4H) , 1.81 - 1.93 (m, 1H), 2.77 - 2.86 (m, 1H), 2.87 - 2.95 (m, 1H), 2.97 - 3.05 (m, 3H), 3.12 (t, 2H).
Beispiele Allgemeine Vorschrift zur Herstellung der Verbindungen der allgemeinen Formel (I) unter Schutzgasatmosphäre und Feuchtigkeitsausschluss:
EXAMPLES General procedure for the preparation of the compounds of the general formula (I) under a protective gas atmosphere and exclusion of moisture:
1 g Bromid der allgemeinen Formel (III) wurde in ca. 30-55 ml DMF gelöst. Es wurden 1.2 - 2.2 Äquivalente Amin der allgemeinen Formel (II) (bezogen auf das Bromid), 0.5 Äquivalente Natriumiodid (bezogen auf das Bromid) und 1.0 Äquivalente Natriumcarbonat (bezogen auf das Bromid) zugegeben. Es wurde 10-24 Stunden bei 80-85 °C Badtemperatur gerührt. Nach dem Abkühlen auf RT wurde die Lösung im Ölpumpenvakuum am Rotationsverdampfer eingeengt. Der Rückstand wurde in Essigsäureethylester oder Dichlormethan aufgenommen, zwei- bis dreimal gewaschen (Wasser, gegebenenfalls gesättigte Natriumchloridlösung), über Magnesiumsulfat getrocknet und eingeengt. Anschließend wurde mittels HPLC gereinigt. 1 g of bromide of the general formula (III) was dissolved in about 30-55 ml of DMF. 1.2 - 2.2 equivalents of amine of general formula (II) (based on the bromide), 0.5 equivalents of sodium iodide (based on the bromide) and 1.0 equivalents of sodium carbonate (based on the bromide) were added. It was stirred for 10-24 hours at 80-85 ° C bath temperature. After cooling to RT, the solution was concentrated in an oil pump vacuum on a rotary evaporator. The residue was taken up in ethyl acetate or dichloromethane, washed two to three times (water, optionally saturated sodium chloride solution), dried over magnesium sulfate and concentrated. It was then purified by HPLC.
Beispiel 1 example 1
2-Fluor-8-(4-fluor-3-hydroxyphenyl)-9-{6-[(2R)-2-{4-[(4,4,5,5,5- ntafluorpentyl)sulfonyl]butyl}pyrrolidin-l-yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 2-Fluoro-8- (4-fluoro-3-hydroxyphenyl) -9- {6 - [(2R) -2- {4 - [(4,4,5,5,5-n-pentafluoropentyl) sulfonyl] butyl} pyrrolidine -l-yl] hexyl} -6,7-dihydro-5H-benzo [7] annulene-3-ol
130 mg (0.29 mmol) 9-(6-Bromhexyl)-2-fluor-8-(4-fluor-3-hydroxyphenyl)-6,7-dihydro-5H- benzo[7]annulen-3-ol wurden mit 121.4 mg (0.35 mmol) (2R)-2- {4-[(4,4,5,5,5- Pentafluorpentyl)sulfonyl]butyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Es wurden 63 mg (30% d. Th.) Produkt isoliert. 130 mg (0.29 mmol) of 9- (6-bromohexyl) -2-fluoro-8- (4-fluoro-3-hydroxyphenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were obtained with 121.4 mg (0.35 mmol) of (2R) -2- {4 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] butyl} pyrrolidine according to the general procedure. It was purified by preparative HPLC. 63 mg (30% of theory) of product were isolated.
'H-NMR (300 MHz, Chloroform-di): δ = 0.99-1.27 (m, 6H), 1.47-1.67 (m, 3H), 1.69-1.88 (m, 3H), 1.88-2.57 (m, 19H), 2.73 (m, 1H), 2.84-3.20 (m, 6H), 3.77 (m, 1H), 6.54 (ddd, 1H), 6.80 (d, 1H), 6.89- 7.04 (m, 3H).
Beispiel 2 'H-NMR (300 MHz, chloroform-di): δ = 0.99-1.27 (m, 6H), 1.47-1.67 (m, 3H), 1.69-1.88 (m, 3H), 1.88-2.57 (m, 19H) , 2.73 (m, 1H), 2.84-3.20 (m, 6H), 3.77 (m, 1H), 6.54 (ddd, 1H), 6.80 (d, 1H), 6.89-7.04 (m, 3H). Example 2
8-(3-Fluorphenyl)-9-{6-[(2S)-2-{3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- -dihydro-5H-benzo [7] annulen-3-ol 8- (3-fluorophenyl) -9- {6 - [(2S) -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -dihydro-5H benzo [7] annulen-3-ol
400 mg (0.91 mmol) 9-(6-Bromhexyl)-8-(3-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 392.9 mg (1.37 mmol) (2S)-2- {3-[(3,3,3-Trifluorpropyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Der Rücksatnd wurde in 30 ml Essigsäureethylester aufgenommen, einmal mit 25%iger wässriger Ammoniaklösung und zweimal mit Wasser gewaschen, über Magnesiumsulfat getrocknet und eingeengt. Es fielen 270 mg (49% d. Th.) Produkt an. 400 mg (0.91 mmol) of 9- (6-bromohexyl) -8- (3-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were mixed with 392.9 mg (1.37 mmol) (2S). -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. It was purified by preparative HPLC. The Rücksatnd was taken up in 30 ml of ethyl acetate, washed once with 25% aqueous ammonia solution and twice with water, dried over magnesium sulfate and concentrated. 270 mg (49% of theory) of product were obtained.
'H-NMR (300 MHz, Chloroform-di): δ = 1.02-1.52 (m, 10H), 1.62-2.27 (m, 13H), 2.36 (t, 2H), 2.54- 2.77 (m, 5H), 3.00-3.22 (m, 5H), 6.67-6.75 (m, 2H), 6.90-6.98 (m, 2H), 7.01 (d, 1H), 7.16 (d, 1H), 7.30 (m, 1H). 'H-NMR (300 MHz, chloroform-di): δ = 1.02-1.52 (m, 10H), 1.62-2.27 (m, 13H), 2.36 (t, 2H), 2.54-2.7 (m, 5H), 3.00 -3.22 (m, 5H), 6.67-6.75 (m, 2H), 6.90-6.98 (m, 2H), 7.01 (d, 1H), 7.16 (d, 1H), 7.30 (m, 1H).
Beispiel 3 Example 3
8-(4-Fluorphenyl)-9-{6-[(2R)-2-{2-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]ethyl}pyrrolidin-l- ulen-3-ol 8- (4-fluorophenyl) -9- {6 - [(2R) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidin-1 -ulen-3-ol
130 mg (0.31 mmol) 9-(6-Bromhexyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 120.9 mg (0.37 mmol) (2R)-2- {2-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]ethyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Es wurden 77.1 mg (38% d. Th.) Produkt isoliert.
'H-NMR (400 MHz, Chloroform-di): δ = 0.97-1.28 (m, 6H), 1.36-1.70 (m, 6H), 1.80 (mc, 1H), 1.92- 2.45 (m, 11H), 2.49-2.77 (m, 4H), 2.97 (mc, 1H), 3.11-3.26 (m, 3H), 3.28-3.38 (m, 1H), 3.56 (mc, 1H), 3.82 (mc, 1H), 6.78-6.83 (m, 2H), 7.05 (tt, 2H), 7.15-7.22 (m, 3H). 130 mg (0.31 mmol) of 9- (6-bromohexyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 120.9 mg (0.37 mmol) (2R). -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidine reacted according to the general procedure. It was purified by preparative HPLC. 77.1 mg (38% of theory) of product were isolated. 'H-NMR (400 MHz, chloroform-di): δ = 0.97-1.28 (m, 6H), 1.36-1.70 (m, 6H), 1.80 (mc, 1H), 1.92-2.45 (m, 11H), 2.49 -2.77 (m, 4H), 2.97 (mc, 1H), 3.11-3.26 (m, 3H), 3.28-3.38 (m, 1H), 3.56 (mc, 1H), 3.82 (mc, 1H), 6.78-6.83 (m, 2H), 7.05 (tt, 2H), 7.15-7.22 (m, 3H).
Beispiel 4 Example 4
8-(4-Fluorphenyl)-9-{6-[(2R)-2-{2-[(3,3,3-trifluorpropyl)sulfonyl]ethyl}pyrrolidin-l-yl]hexyl}- -dihydro-5H-benzo [7] annulen-3-ol 8- (4-fluorophenyl) -9- {6 - [(2R) -2- {2 - [(3,3,3-trifluoropropyl) sulfonyl] ethyl} pyrrolidin-1-yl] hexyl} - dihydro-5H benzo [7] annulen-3-ol
130 mg (0.31 mmol) 9-(6-Bromhexyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 96.9 mg (0.37 mmol) (2R)-2- {2-[(3,3,3-Trifluorpropyl)sulfonyl]ethyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Es wurden 92.4 mg (50% d. Th.) Produkt isoliert. 130 mg (0.31 mmol) of 9- (6-bromohexyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 96.9 mg (0.37 mmol) (2R). -2- {2 - [(3,3,3-trifluoropropyl) sulfonyl] ethyl} pyrrolidine reacted according to the general procedure. It was purified by preparative HPLC. 92.4 mg (50% of theory) of product were isolated.
'H-NMR (400 MHz, Chloroform-di): δ = 1.02-1.24 (m, 6H), 1.36 (mc, 2H), 1.57 (mc, 1H), 1.73-1.90 (m, 2H), 1.95-2.23 (m, 8H), 2.28 (q, 1H), 2.35 (t, 2H), 2.57-2-79 (m, 6H), 3.04 (ddd, 1H), 3.13-3.24 (m, 3H), 3.28 (mc, 1H), 6.71-6.78 (m, 2H), 7.04 (tt, 2H), 7.13-7.23 (m, 3H). 'H-NMR (400 MHz, chloroform-di): δ = 1.02-1.24 (m, 6H), 1.36 (mc, 2H), 1.57 (mc, 1H), 1.73-1.90 (m, 2H), 1.95-2.23 (m, 8H), 2.28 (q, 1H), 2.35 (t, 2H), 2.57-2-79 (m, 6H), 3.04 (ddd, 1H), 3.13-3.24 (m, 3H), 3.28 (mc , 1H), 6.71-6.78 (m, 2H), 7.04 (tt, 2H), 7.13-7.23 (m, 3H).
Beispiel 5 Example 5
8-(4-Fluorphenyl)-9-{6-[(2S)-2-{2-[(4,4,4-trifluorbutyl)sulfonyl]ethyl}pyrrolidin-l-yl]hexyl}-6,7- ihydro-5H-benzo [7] annulen-3-ol 8- (4-fluorophenyl) -9- {6 - [(2S) -2- {2 - [(4,4,4-trifluorobutyl) sulfonyl] ethyl} pyrrolidin-l-yl] hexyl} -6,7- ihydro-5H-benzo [7] annulen-3-ol
130 mg (0.31 mmol) 9-(6-Bromhexyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 102.1 mg (0.37 mmol) (2S)-2- {2-[(4,4,4-Trifluorbutyl)sulfonyl]ethyl}pyrrolidin
entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Es wurden 75 mg (39% d. Th.) Produkt isoliert. 130 mg (0.31 mmol) of 9- (6-bromohexyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were mixed with 102.1 mg (0.37 mmol) (2S). -2- {2 - [(4,4,4-trifluorobutyl) sulfonyl] ethyl} pyrrolidine implemented in accordance with the general rule. It was purified by preparative HPLC. 75 mg (39% of theory) of product were isolated.
'H-NMR (300 MHz, Chloroform-di): δ = 1.00-1.26 (m, 6H), 1.28-1.43 (m, 2H), 1.51-1.65 (m, 1H), 1.72-2.40 (m, 17H), 2.55-2-81 (m, 4H), 2.92-3.19 (m, 4H), 3.30 (ddd, 1H), 6.71-6.78 (m, 2H), 7.03 (tt, 2H), 7.12-7.23 (m, 3H). 'H-NMR (300 MHz, chloroform-di): δ = 1.00-1.26 (m, 6H), 1.28-1.43 (m, 2H), 1.51-1.65 (m, 1H), 1.72-2.40 (m, 17H) , 2.55-2-81 (m, 4H), 2.92-3.19 (m, 4H), 3.30 (ddd, 1H), 6.71-6.78 (m, 2H), 7.03 (tt, 2H), 7.12-7.23 (m, 3H).
Beispiel 6 Example 6
8-(4-Fluorphenyl)-9-{6-[(2R)-2-{2-[(4,4,4-trifluorbutyl)sulfonyl]ethyl}pyrrolidin-l-yl]hexyl}-6,7- dihydro-5H-benzo [7] annulen-3-ol 8- (4-fluorophenyl) -9- {6 - [(2R) -2- {2 - [(4,4,4-trifluorobutyl) sulfonyl] ethyl} pyrrolidin-l-yl] hexyl} -6,7- dihydro-5H-benzo [7] annulen-3-ol
130 mg (0.31 mmol) 9-(6-Bromhexyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 102.2 mg (0.37 mmol) (2R)-2- {2-[(4,4,4-Trifluorbutyl)sulfonyl]ethyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Es wurden 57 mg (30% d. Th.) Produkt isoliert. 130 mg (0.31 mmol) of 9- (6-bromohexyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were mixed with 102.2 mg (0.37 mmol) (2R). -2- {2 - [(4,4,4-trifluorobutyl) sulfonyl] ethyl} pyrrolidine reacted according to the general procedure. It was purified by preparative HPLC. 57 mg (30% of theory) of product were isolated.
'H-NMR (300 MHz, Chloroform-di): δ = 1.00-1.40 (m, 8H), 1.54 (mc, 1H), 1.70-1.87 (m, 2H), 1.90- 2.41 (m, 15H), 2.55-2.73 (m, 4H), 2.91-3.17 (m, 4H), 3.25 (mc, 1H), 6.70-6.78 (m, 2H), 7.04 (tt, 2H), 7.12-7.23 (m, 3H). 'H-NMR (300 MHz, chloroform-di): δ = 1.00-1.40 (m, 8H), 1.54 (mc, 1H), 1.70-1.87 (m, 2H), 1.90-2.41 (m, 15H), 2.55 -2.73 (m, 4H), 2.91-3.17 (m, 4H), 3.25 (mc, 1H), 6.70-6.78 (m, 2H), 7.04 (t, 2H), 7.12-7.23 (m, 3H).
Beispiel 7 Example 7
8-(4-Fluorphenyl)-9-{6-[(2R)-2-{2-[(3,3,3-trifluorpropyl)sulfonyl]ethyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo [7] annulen-3-ol
8- (4-fluorophenyl) -9- {6 - [(2R) -2- {2 - [(3,3,3-trifluoropropyl) sulfonyl] ethyl} pyrrolidin-1-yl] hexyl} - 6,7- dihydro-5H-benzo [7] annulen-3-ol
400 mg (0.96 mmol) 9-(6-Bromhexyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 298.2 mg (1.15 mmol) (2R)-2- {2-[(3,3,3-Trifluorpropyl)sulfonyl]ethyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Die Fraktionen wurden in Dichlormethan gelöst, einmal mit gesättigter Natnumhydrogencarbonatlösung und dreimal mit Wasser gewaschen, über Magnesiumsulfat getrocknet und eingeengt. Der Rückstand wurde zweimal mit Diethylether und zweimal mit Pentan versetzt und zur Trockene eingeengt. Es wurde mit Pentan versetzt, abgesaugt und bei 40 °C im Trockenschrank getrocknet. Es wurden 274.1 mg (48% d. Th.) Produkt isoliert. 400 mg (0.96 mmol) of 9- (6-bromohexyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were mixed with 298.2 mg (1.15 mmol) (2R). -2- {2 - [(3,3,3-trifluoropropyl) sulfonyl] ethyl} pyrrolidine reacted according to the general procedure. It was purified by preparative HPLC. The fractions were dissolved in dichloromethane, washed once with saturated Natnumhydrogencarbonatlösung and three times with water, dried over magnesium sulfate and concentrated. The residue was treated twice with diethyl ether and twice with pentane and concentrated to dryness. It was mixed with pentane, filtered off and dried at 40 ° C in a drying oven. 274.1 mg (48% of theory) of product were isolated.
'H-NMR (400 MHz, Chloroform-di): δ = 1.01-1.47 (m, 9H), 1.64-1.76 (m, 2H), 1.81-2.15 (m, 9H), 2.35 (mc, 2H), 2.44 (mc, 1H), 2.54 (mc, 1H), 2.59-2.74 (m, 4H), 2.98 (mc, 1H), 3.03-3.21 (m, 4H), 6.71 (d, 1H), 6.74 (dd, 1H), 7.04 (tt, 2H), 7.15-7.23 (m, 3H). 'H-NMR (400 MHz, chloroform-di): δ = 1.01-1.47 (m, 9H), 1.64-1.76 (m, 2H), 1.81-2.15 (m, 9H), 2.35 (mc, 2H), 2.44 (mc, 1H), 2.54 (mc, 1H), 2.59-2.74 (m, 4H), 2.98 (mc, 1H), 3.03-3.21 (m, 4H), 6.71 (d, 1H), 6.74 (dd, 1H ), 7.04 (tt, 2H), 7.15-7.23 (m, 3H).
Beispiel 8 Example 8
8-(4-Fluorphenyl)-9-{6-[(2S)-2-{2-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]ethyl}pyrrolidin-l- l] hexyl}-6,7-dihydro-5H-benzo [7] annulen-3-ol 8- (4-fluorophenyl) -9- {6 - [(2S) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidin-1-hexyl} - 6,7-dihydro-5H-benzo [7] annulen-3-ol
130 mg (0.31 mmol) 9-(6-Bromhexyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 120.9 mg (0.37 mmol) (2S)-2- {2-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]ethyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Es wurden 56.4 mg (27% d. Th.) Produkt isoliert.
'H-NMR (300 MHz, Chloroform-di): δ = 0.98-1.29 (m, 6H), 1.35-1.53 (m, 1H), 1.61-1.78 (m, 1 1.82-2.68 (m, 20H), 2.83-2.95 (m, 1H), 3.08-3.23 (m, 3H), 3.24-3.44 (m, 2H), 3.66 (mc, 1H), 6. 6.83 (m, 2H), 7.05 (tt, 2H), 7.14-7.23 (m, 3H). 130 mg (0.31 mmol) of 9- (6-bromohexyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 120.9 mg (0.37 mmol) (2S). -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidine reacted according to the general procedure. It was purified by preparative HPLC. 56.4 mg (27% of theory) of product were isolated. 'H-NMR (300 MHz, chloroform-di): δ = 0.98-1.29 (m, 6H), 1.35-1.53 (m, 1H), 1.61-1.78 (m, 1.82-2.68 (m, 20H), 2.83 -2.95 (m, 1H), 3.08-3.23 (m, 3H), 3.24-3.44 (m, 2H), 3.66 (mc, 1H), 6. 6.83 (m, 2H), 7.05 (tt, 2H), 7.14 -7.23 (m, 3H).
Beispiel 9 Example 9
2-Fluor-8-(4-fluorphenyl)-9-{6-[(2S)-2-{2-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]ethyl}pyrrolidin- 1- l] hexyl}-6,7-dihydro-5H-benzo [7] annulen-3-ol 2-fluoro-8- (4-fluorophenyl) -9- {6 - [(2S) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidin-1-l ] hexyl} -6,7-dihydro-5H-benzo [7] annulen-3-ol
130 mg (0.30 mmol) 9-(6-Bromhexyl)-2-fluor-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3- ol wurden mit 115.9 mg (0.36 mmol) (2S)-2- {2-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]ethyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Es wurden 99.2 mg (49% d. Th.) Produkt isoliert. 130 mg (0.30 mmol) of 9- (6-bromohexyl) -2-fluoro-8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 115.9 mg (0.36 mmol ) (2S) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidine according to the general procedure. It was purified by preparative HPLC. 99.2 mg (49% of theory) of product were isolated.
'H-NMR (300 MHz, Chloroform-di): δ = 1.00-1.26 (m, 6H), 1.36 (mc, 2H), 1.47-1.61 (m, 1H), 1.70- 1.88 (m, 2H), 1.91-2.37 (m, 15H), 2.57 (mc, 2H), 2.62-2.75 (m, 2H), 2.92-3.19 (m, 4H), 3.25 (mc, 1H), 6.84 (d, 1H), 6.96-7.09 (m, 3H), 7.14-7.23 (m, 2H). 'H-NMR (300 MHz, chloroform-di): δ = 1.00-1.26 (m, 6H), 1.36 (mc, 2H), 1.47-1.61 (m, 1H), 1.70- 1.88 (m, 2H), 1.91 -2.37 (m, 15H), 2.57 (mc, 2H), 2.62-2.75 (m, 2H), 2.92-3.19 (m, 4H), 3.25 (mc, 1H), 6.84 (d, 1H), 6.96-7.09 (m, 3H), 7.14-7.23 (m, 2H).
Beispiel 10 Example 10
2-Fluor-8-(4-fluorphenyl)-9-{6-[(2R)-2-{2-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]ethyl}pyrrolidin- -yl] hexyl}-6,7-dihydro-5H-benzo [7] annulen-3-ol 2-fluoro-8- (4-fluorophenyl) -9- {6 - [(2R) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidinyl] hexyl} -6,7-dihydro-5H-benzo [7] annulen-3-ol
130 mg (0.30 mmol) 9-(6-Bromhexyl)-2-fluor-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3- ol wurden mit 115.9 mg (0.36 mmol) (2R)-2- {2-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]ethyl}pyrrolidin
entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Es wurden 40.0 mg (20% d. Th.) Produkt isoliert. 130 mg (0.30 mmol) of 9- (6-bromohexyl) -2-fluoro-8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 115.9 mg (0.36 mmol ) (2R) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidine implemented in accordance with the general rule. It was purified by preparative HPLC. 40.0 mg (20% of theory) of product were isolated.
'H-NMR (300 MHz, Chloroform-di): δ = 1.00-1.25 (m, 6H), 1.34 (mc, 2H), 1.44-1.58 (m, 1H), 1.70- 1.84 (m, 2H), 1.88-2.41 (m, 15H), 2.52-2.71 (m, 4H), 2.90-3.25 (m, 5H), 6.85 (d, 1H), 6.97-7.09 (m, 3H), 7.14-7.22 (m, 2H). 'H-NMR (300 MHz, chloroform-di): δ = 1.00-1.25 (m, 6H), 1.34 (mc, 2H), 1.44-1.58 (m, 1H), 1.70-1.84 (m, 2H), 1.88 -2.41 (m, 15H), 2.52-2.71 (m, 4H), 2.90-3.25 (m, 5H), 6.85 (d, 1H), 6.97-7.09 (m, 3H), 7.14-7.22 (m, 2H) ,
Beispiel 11 Example 11
2-Fluor-8-(4-fluorphenyl)-9-{6-[(2R)-2-{2-[(4,4,4-trifluorbutyl)sulfonyl]ethyl}pyrrolidin-l- nulen-3-ol 2-Fluoro-8- (4-fluorophenyl) -9- {6 - [(2R) -2- {2 - [(4,4,4-trifluorobutyl) sulfonyl] ethyl} pyrrolidin-1-nulen-3-ol
130 mg (0.30 mmol) 9-(6-Bromhexyl)-2-fluor-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3- ol wurden mit 97.9 mg (0.36 mmol) (2R)-2- {2-[(4,4,4-Trifluorbutyl)sulfonyl]ethyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Es wurden 49.7 mg (25% d. Th.) Produkt isoliert. 130 mg (0.30 mmol) of 9- (6-bromohexyl) -2-fluoro-8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 97.9 mg (0.36 mmol ) (2R) -2- {2 - [(4,4,4-trifluorobutyl) sulfonyl] ethyl} pyrrolidine according to the general procedure. It was purified by preparative HPLC. 49.7 mg (25% of theory) of product were isolated.
'H-NMR (400 MHz, Chloroform-di): δ = 1.01-1.24 (m, 6H), 1.36 (mc, 2H), 1.49-1.60 (m, 1H), 1.71- 1.89 (m, 2H), 1.93-2.03 (m, 2H), 2.04-2.38 (m, 13H), 2.57 (mc, 2H), 2.63-2.74 (m, 2H), 2.98 (ddd, 1H), 3.03-3.17 (m, 3H), 3.25 (mc, 1H), 6.84 (d, 1H), 6.97-7.08 (m, 3H), 7.15-7.21 (m, 2H). 'H-NMR (400 MHz, chloroform-di): δ = 1.01-1.24 (m, 6H), 1.36 (mc, 2H), 1.49-1.60 (m, 1H), 1.71- 1.89 (m, 2H), 1.93 -2.03 (m, 2H), 2.04-2.38 (m, 13H), 2.57 (mc, 2H), 2.63-2.74 (m, 2H), 2.98 (ddd, 1H), 3.03-3.17 (m, 3H), 3.25 (mc, 1H), 6.84 (d, 1H), 6.97-7.08 (m, 3H), 7.15-7.21 (m, 2H).
Beispiel 12 Example 12
2-Fluor-8-(4-fluorphenyl)-9-{6-[(2S)-2-{2-[(4,4,4-trifluorbutyl)sulfonyl]ethyl}pyrrolidin-l- nulen-3-ol 2-Fluoro-8- (4-fluorophenyl) -9- {6 - [(2S) -2- {2 - [(4,4,4-trifluorobutyl) sulfonyl] ethyl} pyrrolidin-1-nulen-3-ol
130 mg (0.30 mmol) 9-(6-Bromhexyl)-2-fluor-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3- ol wurden mit 97.9 mg (0.36 mmol) (2S)-2- {2-[(4,4,4-Trifluorbutyl)sulfonyl]ethyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Es wurden 58.8 mg (31% d. Th.) Produkt isoliert. 130 mg (0.30 mmol) of 9- (6-bromohexyl) -2-fluoro-8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 97.9 mg (0.36 mmol ) (2S) -2- {2 - [(4,4,4-trifluorobutyl) sulfonyl] ethyl} pyrrolidine according to the general procedure. It was purified by preparative HPLC. 58.8 mg (31% of theory) of product were isolated.
'H-NMR (400 MHz, Chloroform-di): δ = 1.02-1.25 (m, 6H), 1.36 (mc, 2H), 1.48-1.59 (m, 1H), 1.70- 1.88 (m, 2H), 1.91-2.03 (m, 2H), 2.04-2.41 (m, 13H), 2.57 (mc, 2H), 2.62-2.74 (m, 2H), 2.97 (ddd, 1H), 3.03-3.17 (m, 3H), 3.23 (mc, 1H), 6.84 (d, 1H), 6.97-7.09 (m, 3H), 7.15-7.22 (m, 2H). 'H-NMR (400 MHz, chloroform-di): δ = 1.02-1.25 (m, 6H), 1.36 (mc, 2H), 1.48-1.59 (m, 1H), 1.70- 1.88 (m, 2H), 1.91 -2.03 (m, 2H), 2.04-2.41 (m, 13H), 2.57 (mc, 2H), 2.62-2.74 (m, 2H), 2.97 (ddd, 1H), 3.03-3.17 (m, 3H), 3.23 (mc, 1H), 6.84 (d, 1H), 6.97-7.09 (m, 3H), 7.15-7.22 (m, 2H).
Beispiel 13 Example 13
2-Fluor-8-(4-fluorphenyl)-9-{6-[(2S)-2-{2-[(3,3,3-trifluorpropyl)sulfonyl]ethyl}pyrrolidin-l- ] annulen-3-ol 2-Fluoro-8- (4-fluorophenyl) -9- {6 - [(2S) -2- {2 - [(3,3,3-trifluoropropyl) sulfonyl] ethyl} pyrrolidin-1-yl-3-olene oil
130 mg (0.30 mmol) 9-(6-Bromhexyl)-2-fluor-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3- ol wurden mit 92.9 mg (0.36 mmol) (2S)-2- {2-[(3,3,3-Trifluorpropyl)sulfonyl]ethyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Es wurden 50.0 mg (27% d. Th.) Produkt isoliert. 130 mg (0.30 mmol) of 9- (6-bromohexyl) -2-fluoro-8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 92.9 mg (0.36 mmol ) (2S) -2- {2 - [(3,3,3-trifluoropropyl) sulfonyl] ethyl} pyrrolidine according to the general procedure. It was purified by preparative HPLC. 50.0 mg (27% of theory) of product were isolated.
'H-NMR (400 MHz, Chloroform-di): δ = 1.03-1.25 (m, 6H), 1.34 (mc, 2H), 1.42-1.53 (m, 1H), 1.70- 1.79 (m, 2H), 1.88-1.99 (m, 2H), 2.02-2.19 (m, 7H), 2.30 (mc, 2H), 2.51-2.74 (m, 6H), 3.00 (ddd, 1H), 3.11-3.22 (m, 4H), 6.85 (d, 1H), 6.99-7.08 (m, 3H), 7.15-7.21 (m, 2H). 'H NMR (400 MHz, chloroform-di): δ = 1.03-1.25 (m, 6H), 1.34 (mc, 2H), 1.42-1.53 (m, 1H), 1.70-1.79 (m, 2H), 1.88 -1.99 (m, 2H), 2.02-2.19 (m, 7H), 2.30 (mc, 2H), 2.51-2.74 (m, 6H), 3.00 (ddd, 1H), 3.11-3.22 (m, 4H), 6.85 (d, 1H), 6.99-7.08 (m, 3H), 7.15-7.21 (m, 2H).
Beispiel 14 Example 14
2-Fluor-8-(4-fluorphenyl)-9-{6-[(2R)-2-{2-[(3,3,3-trifluorpropyl)sulfonyl]ethyl}pyrrolidin-l- yl] hexyl}-6,7-dihydro-5H-benzo [7] annulen-3-ol
2-Fluoro-8- (4-fluorophenyl) -9- {6 - [(2R) -2- {2 - [(3,3,3-trifluoropropyl) sulfonyl] ethyl} pyrrolidin-1-yl] hexyl} - 6,7-dihydro-5H-benzo [7] annulen-3-ol
130 mg (0.30 mmol) 9-(6-Bromhexyl)-2-fluor-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3- ol wurden mit 92.9 mg (0.36 mmol) (2R)-2- {2-[(3,3,3-Trifluorpropyl)sulfonyl]ethyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Es wurden 30.7 mg (17% d. Th.) Produkt isoliert. 130 mg (0.30 mmol) of 9- (6-bromohexyl) -2-fluoro-8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 92.9 mg (0.36 mmol ) (2R) -2- {2 - [(3,3,3-trifluoropropyl) sulfonyl] ethyl} pyrrolidine according to the general procedure. It was purified by preparative HPLC. 30.7 mg (17% of theory) of product were isolated.
'H-NMR (400 MHz, Chloroform-di): δ = 1.02-1.25 (m, 6H), 1.35 (mc, 2H), 1.44-1.55 (m, 1H), 1.71- 1.81 (m, 2H), 1.89-2.02 (m, 2H), 2.03-2.22 (m, 7H), 2.30 (mc, 2H), 2.54-2.74 (m, 6H), 3.01 (ddd, 1H), 3.11-3.23 (m, 4H), 6.84 (d, 1H), 6.98-7.08 (m, 3H), 7.15-7.21 (m, 2H). 'H-NMR (400 MHz, chloroform-di): δ = 1.02-1.25 (m, 6H), 1.35 (mc, 2H), 1.44-1.55 (m, 1H), 1.71-1.81 (m, 2H), 1.89 -2.02 (m, 2H), 2.03-2.22 (m, 7H), 2.30 (mc, 2H), 2.54-2.74 (m, 6H), 3.01 (ddd, 1H), 3.11-3.23 (m, 4H), 6.84 (d, 1H), 6.98-7.08 (m, 3H), 7.15-7.21 (m, 2H).
Beispiel 15 Example 15
4-Fluor-8-(4-fluorphenyl)-9-{6-[(2R)-2-{4-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]butyl}pyrrolidin- l- l]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 4-fluoro-8- (4-fluorophenyl) -9- {6 - [(2R) -2- {4 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] -butyl} -pyrrolidin-1-l ] hexyl} -6,7-dihydro-5H-benzo [7] annulene-3-ol
130 mg (0.30 mmol) 9-(6-Bromhexyl)-4-fluor-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3- ol wurden mit 125.9 mg (0.36 mmol) (2R)-2- {4-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]butyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Es wurden 101.9 mg (48% d. Th.) Produkt isoliert. 130 mg (0.30 mmol) of 9- (6-bromohexyl) -4-fluoro-8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulene-3-ol were mixed with 125.9 mg (0.36 mmol ) (2R) -2- {4 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] butyl} pyrrolidine according to the general procedure. It was purified by preparative HPLC. 101.9 mg (48% of theory) of product were isolated.
'H-NMR (400 MHz, Chloroform-di): δ = 1.04-1.24 (m, 6H), 1.31-1.61 (m, 6H), 1.66-2.37 (m, 18H), 2.41 (mc, 1H), 2.67-2.79 (m, 3H), 2.97-3.10 (m, 4H), 3.33 (mc, 1H), 6.88 (t, 1H), 6.96 (d, 1H), 7.04 (tt, 2H), 7.19 (mc, 2H). 'H-NMR (400 MHz, chloroform-di): δ = 1.04-1.24 (m, 6H), 1.31-1.61 (m, 6H), 1.66-2.37 (m, 18H), 2.41 (mc, 1H), 2.67 -2.79 (m, 3H), 2.97-3.10 (m, 4H), 3.33 (mc, 1H), 6.88 (t, 1H), 6.96 (d, 1H), 7.04 (tt, 2H), 7.19 (mc, 2H ).
Beispiel 16
4-Fluor-8-(4-fluorphenyl)-9-{6-[(2S)-2-{3-[(4,4,5,5,5- din-l-yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol Example 16 4-fluoro-8- (4-fluorophenyl) -9- {6 - [(2S) -2- {3 - [(4,4,5,5,5-din-1-yl) hexyl} -6, 7-dihydro-5H-benzo [7] annulene-3-ol
130 mg (0.30 mmol) 9-(6-Bromhexyl)-4-fluor-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3- ol wurden mit 120.9 mg (0.36 mmol) (2S)-2- {3-[(4,4,5,5,5- Pentafluorpentyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Es wurden 76.4 mg (37% d. Th.) Produkt isoliert. 130 mg (0.30 mmol) of 9- (6-bromohexyl) -4-fluoro-8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were mixed with 120.9 mg (0.36 mmol ) (2S) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidine according to the general procedure. It was purified by preparative HPLC. 76.4 mg (37% of theory) of product were isolated.
'H-NMR (300 MHz, Chloroform-di): δ = 1.01-1.24 (m, 6H), 1.39 (mc, 2H), 1.51-1.67 (m, 2H), 1.71- 2.38 (m, 18H), 2.49 (mc, 1H), 2.66-2.78 (m, 3H), 2.99-3.10 (m, 4H), 3.32 (mc, 1H), 6.87 (t, 1H), 6.95 (d, 1H), 7.04 (tt, 2H), 7.19 (m, 2H). 'H-NMR (300 MHz, chloroform-di): δ = 1.01-1.24 (m, 6H), 1.39 (mc, 2H), 1.51-1.67 (m, 2H), 1.71-2.38 (m, 18H), 2.49 (mc, 1H), 2.66-2.78 (m, 3H), 2.99-3.10 (m, 4H), 3.32 (mc, 1H), 6.87 (t, 1H), 6.95 (d, 1H), 7.04 (tt, 2H ), 7.19 (m, 2H).
Beispiel 17 Example 17
4-Fluor-8-(4-fluorphenyl)-9-{6-[(2S)-2-{3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin- -yl] hexyl}-6,7-dihydro-5H-benzo [7] annulen-3-ol 4-fluoro-8- (4-fluorophenyl) -9- {6 - [(2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidin-yl] hexyl} -6,7-dihydro-5H-benzo [7] annulen-3-ol
130 mg (0.30 mmol) 9-(6-Bromhexyl)-4-fluor-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3- ol wurden mit 115.9 mg (0.36 mmol) (2S)-2- {3-[(3,3,4,4,4-Pentafluorbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Es wurden 83.2 mg (41% d. Th.) Produkt isoliert. 130 mg (0.30 mmol) of 9- (6-bromohexyl) -4-fluoro-8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulene-3-ol were treated with 115.9 mg (0.36 mmol ) (2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidine according to the general procedure. It was purified by preparative HPLC. 83.2 mg (41% of theory) of product were isolated.
'H-NMR (300 MHz, Chloroform-di): δ = 1.01-1.24 (m, 6H), 1.39 (mc, 2H), 1.52-1.67 (m, 2H), 1.71- 2.21 (m, 11H), 2.23-2.38 (m, 3H), 2.44-2.79 (m, 6H), 3.10 (mc, 2H), 3.22 (mc, 2H), 3.33 (mc, 1H), 6.88 (t, 1H), 6.96 (d, 1H), 7.04 (tt, 2H), 7.19 (m, 2H).
Beispiel 18 'H-NMR (300 MHz, chloroform-di): δ = 1.01-1.24 (m, 6H), 1.39 (mc, 2H), 1.52-1.67 (m, 2H), 1.71-2.21 (m, 11H), 2.23 -2.38 (m, 3H), 2.44-2.79 (m, 6H), 3.10 (mc, 2H), 3.22 (mc, 2H), 3.33 (mc, 1H), 6.88 (t, 1H), 6.96 (d, 1H ), 7.04 (tt, 2H), 7.19 (m, 2H). Example 18
8-(3,4-Difluorphenyl)-9-{6-[(2S)-2-{3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- l] hexyl}-6,7-dihydro-5H-benzo [7] annulen-3-ol 8- (3,4-Difluorophenyl) -9- {6 - [(2S) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidin-1-hexyl] } -6,7-dihydro-5H-benzo [7] annulen-3-ol
130 mg (0.30 mmol) 9-(6-Bromhexyl)-8-(3,4-difluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 120.9 mg (0.36 mmol) (2S)-2- {3-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Es wurden 91.2 mg (44% d. Th.) Produkt isoliert. 130 mg (0.30 mmol) of 9- (6-bromohexyl) -8- (3,4-difluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 120.9 mg (0.36 mmol) ( 2S) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidine according to the general procedure implemented. It was purified by preparative HPLC. 91.2 mg (44% of theory) of product were isolated.
'H-NMR (300 MHz, Chloroform-di): δ = 1.00-1.26 (m, 6H), 1.47 (mc, 1H), 1.67 (mc, 1H), 1.79-2.40 (m, 18H), 2.48 (mc, 1H), 2.60 (mc, 2H), 2.69 (mc, 1H), 2.91 (mc, 1H), 3.00-3.19 (m, 5H), 3.69 (mc, 1H), 6.78 (d, 1H), 6.82 (dd, 1H), 6.90-6.97 (m, 1H), 7.03 (ddd, 1H), 7.09-7.20 (m, 2H). 'H-NMR (300 MHz, chloroform-di): δ = 1.00-1.26 (m, 6H), 1.47 (mc, 1H), 1.67 (mc, 1H), 1.79-2.40 (m, 18H), 2.48 (mc , 1H), 2.60 (mc, 2H), 2.69 (mc, 1H), 2.91 (mc, 1H), 3.00-3.19 (m, 5H), 3.69 (mc, 1H), 6.78 (d, 1H), 6.82 ( dd, 1H), 6.90-6.97 (m, 1H), 7.03 (ddd, 1H), 7.09-7.20 (m, 2H).
Beispiel 19 Example 19
8-(3,4-Difluorphenyl)-9-{6-[(2S)-2-{3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- l] hexyl}-6,7-dihydro-5H-benzo [7] annulen-3-ol 8- (3,4-Difluorophenyl) -9- {6 - [(2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidin-1-hexyl] } -6,7-dihydro-5H-benzo [7] annulen-3-ol
130 mg (0.30 mmol) 9-(6-Bromhexyl)-8-(3,4-difluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 115.9 mg (0.36 mmol) (2S)-2- {3-[(3,3,4,4,4-Pentafluorbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Es wurden 117.7 mg (58% d. Th.) Produkt isoliert.
'H-NMR (300 MHz, Chloroform-di): δ = 1.00-1.26 (m, 6H), 1.47 (mc, 1H), 1.67 (mc, 1H), 1.82-2.27 (m, 12H), 2.35 (t, 2H), 2.41-2.76 (m, 6H), 2.92 (mc, 1H), 3.07 (mc, 1H), 3.15 (t, 2H), 3.27 (mc, 2H), 3.70 (mc, 1H), 6.79 (d, 1H), 6.82 (dd, 1H), 6.90-6.97 (m, 1H), 7.03 (ddd, 1H), 7.09-7.20 (m, 2H). Beispiel 20 130 mg (0.30 mmol) of 9- (6-bromohexyl) -8- (3,4-difluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 115.9 mg (0.36 mmol) ( 2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidine according to the general procedure implemented. It was purified by preparative HPLC. 117.7 mg (58% of theory) of product were isolated. 'H-NMR (300 MHz, chloroform-di): δ = 1.00-1.26 (m, 6H), 1.47 (mc, 1H), 1.67 (mc, 1H), 1.82-2.27 (m, 12H), 2.35 (t , 2H), 2.41-2.76 (m, 6H), 2.92 (mc, 1H), 3.07 (mc, 1H), 3.15 (t, 2H), 3.27 (mc, 2H), 3.70 (mc, 1H), 6.79 ( d, 1H), 6.82 (dd, 1H), 6.90-6.97 (m, 1H), 7.03 (ddd, 1H), 7.09-7.20 (m, 2H). Example 20
8-(3,4-Difluorphenyl)-9-{6-[(2R)-2-{2-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]ethyl}pyrrolidin-l- ulen-3-ol 8- (3,4-Difluorophenyl) -9- {6 - [(2R) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidin-1-olene-3 -oil
130 mg (0.30 mmol) 9-(6-Bromhexyl)-8-(3,4-difluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 115.9 mg (0.36 mmol) (2R)-2- {2-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]ethyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Es wurden 87.5 mg (43% d. Th.) Produkt isoliert. 130 mg (0.30 mmol) of 9- (6-bromohexyl) -8- (3,4-difluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 115.9 mg (0.36 mmol) ( 2R) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidine according to the general procedure implemented. It was purified by preparative HPLC. 87.5 mg (43% of theory) of product were isolated.
'H-NMR (400 MHz, Chloroform-di): δ = 1.02-1.24 (m, 6H),1.36 (m, 2H), 1.52-1.62 (m, 1H), 1.73- 1.91 (m, 2H), 1.92-2.38 (m, 15H), 2.60 (t, 2H), 2.64-2.78 (m, 2H), 3.00 (ddd, 1H), 3.05-3.18 (m, 3H), 3.29 (mc, 1H), 6.72 (d, 1H), 6.75 (dd, 1H), 6.92-6.97 (m, 1H), 7.04 (ddd, 1H), 7.09-7.17 (m, 2H). 'H-NMR (400 MHz, chloroform-di): δ = 1.02-1.24 (m, 6H), 1.36 (m, 2H), 1.52-1.62 (m, 1H), 1.73-1.91 (m, 2H), 1.92 -2.38 (m, 15H), 2.60 (t, 2H), 2.64-2.78 (m, 2H), 3.00 (ddd, 1H), 3.05-3.18 (m, 3H), 3.29 (mc, 1H), 6.72 (i.e. , 1H), 6.75 (dd, 1H), 6.92-6.97 (m, 1H), 7.04 (ddd, 1H), 7.09-7.17 (m, 2H).
Beispiel 21 Example 21
8-(3,4-Difluorphenyl)-9-{6-[(2S)-2-{3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l- l] hexyl}-6,7-dihydro-5H-benzo [7] annulen-3-ol 8- (3,4-Difluorophenyl) -9- {6 - [(2S) -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidin-1-hexyl} -6, 7-dihydro-5H-benzo [7] annulen-3-ol
350 mg (0.76 mmol) 9-(6-Bromhexyl)-8-(3,4-difluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 263.7 mg (0.92 mmol) (2S)-2- {3-[(3,3,3-Trifluorpropyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Der Rückstand wurde in Essigsäureethylester
aufgenommen und einmal mit gesättigter Natriumhydrogencarbonatlösung und zweimal mit Wasser gewaschen, über Magnesiumsulalfat getrocknet und eingeengt. Das Produkt wurde mit Diethylether und Pentan versetzt, verrührt, abgesaugt und bei 45 °C im Trockenschrank getrocknet. Es wurden 160 mg (33% d. Th.) Produkt isoliert. 350 mg (0.76 mmol) of 9- (6-bromohexyl) -8- (3,4-difluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 263.7 mg (0.92 mmol) ( 2S) -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidine according to the general procedure implemented. The residue was in ethyl acetate taken and washed once with saturated sodium bicarbonate solution and twice with water, dried over Magnesiumsulalfat and concentrated. The product was treated with diethyl ether and pentane, stirred, filtered off with suction and dried at 45 ° C in a drying oven. 160 mg (33% of theory) of product were isolated.
'H-NMR (300 MHz, Chloroform-di): δ = 1.03-1.53 (m, 10H), 1.63-2.16 (m, 12H), 2.18-2.29 (m, 1H), 2.35 (t, 2H), 2.54-2.77 (m, 5H), 3.01-3.22 (m, 5H), 6.68-6.76 (m, 2H), 6.90-6.98 (m, 1H), 7.04 (ddd, 1H), 7.08-7.19 (m, 2H). 'H-NMR (300 MHz, chloroform-di): δ = 1.03-1.53 (m, 10H), 1.63-2.16 (m, 12H), 2.18-2.29 (m, 1H), 2.35 (t, 2H), 2.54 -2.77 (m, 5H), 3.01-3.22 (m, 5H), 6.68-6.76 (m, 2H), 6.90-6.98 (m, 1H), 7.04 (ddd, 1H), 7.08-7.19 (m, 2H) ,
Beispiel 22 Example 22
8-(3,5-Difluorphenyl)-9-{6-[(2R)-2-{4-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]butyl}pyrrolidin-l- l] hexyl}-6,7-dihydro-5H-benzo [7] annulen-3-ol 8- (3,5-Difluorophenyl) -9- {6 - [(2R) -2- {4 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] butyl} pyrrolidin-1-hexyl] } -6,7-dihydro-5H-benzo [7] annulen-3-ol
103.3 mg (0.24 mmol) 9-(6-Bromhexyl)-8-(3,5-difluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 100 mg (0.28 mmol) (2R)-2- {4-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]butyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Es wurden 102.3 mg (60% d. Th.) Produkt isoliert. 103.3 mg (0.24 mmol) of 9- (6-bromohexyl) -8- (3,5-difluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 100 mg (0.28 mmol) ( 2R) -2- {4 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] butyl} pyrrolidine reacted according to the general procedure. It was purified by preparative HPLC. 102.3 mg (60% of theory) of product were isolated.
'H-NMR (600 MHz, Chloroform-di): δ = 1.02-2.14 (m, 22H), 2.17-2.34 (m, 5H), 2.38 (mc, 2H), 2.49 (mc, 1H), 2.60 (t, 2H), 2.70 (mc, 1H), 2.80 (mc, 1H), 2.97-3.11 (m, 4H), 3.57 (mc, 1H), 6.70 (tt, 1H), 6.73-6.79 (m, 4H), 7.13 (d, 1H). 'H-NMR (600 MHz, chloroform-di): δ = 1.02-2.14 (m, 22H), 2.17-2.34 (m, 5H), 2.38 (mc, 2H), 2.49 (mc, 1H), 2.60 (t , 2H), 2.70 (mc, 1H), 2.80 (mc, 1H), 2.97-3.11 (m, 4H), 3.57 (mc, 1H), 6.70 (tt, 1H), 6.73-6.79 (m, 4H), 7.13 (d, 1H).
Beispiel 23 Example 23
8-(3,5-Difluorphenyl)-9-{6-[(2R)-2-{2-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]ethyl}pyrrolidin-l- yl] hexyl}-6,7-dihydro-5H-benzo [7] annulen-3-ol
8- (3,5-Difluorophenyl) -9- {6 - [(2R) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidin-1-yl] hexyl } -6,7-dihydro-5H-benzo [7] annulen-3-ol
130 mg (0.30 mmol) 9-(6-Bromhexyl)-8-(3,5-difluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 115.9 mg (0.36 mmol) (2R)-2- {2-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]ethyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Es wurden 104.2 mg (51 % d. Th.) Produkt isoliert. 130 mg (0.30 mmol) of 9- (6-bromohexyl) -8- (3,5-difluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 115.9 mg (0.36 mmol) ( 2R) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidine according to the general procedure implemented. It was purified by preparative HPLC. 104.2 mg (51% of theory) of product were isolated.
'H-NMR (300 MHz, Chloroform-di): δ = 1.01-1.49 (m, 10H), 1.63-1.76 (m, 2H), 1.78-2.48 (m, 15H), 2.49-2.66 (m, 3H), 2.87-3.15 (m, 5H), 6.64-6.81 (m, 5H), 7.16 (d, 1H). 'H-NMR (300 MHz, chloroform-di): δ = 1.01-1.49 (m, 10H), 1.63-1.76 (m, 2H), 1.78-2.48 (m, 15H), 2.49-2.66 (m, 3H) , 2.87-3.15 (m, 5H), 6.64-6.81 (m, 5H), 7.16 (d, 1H).
Beispiel 24 Example 24
8-(2,4-Difluorphenyl)-9-{6-[(2S)-2-{2-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]ethyl}pyrrolidin-l- ulen-3-ol 8- (2,4-Difluorophenyl) -9- {6 - [(2S) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidin-1-olene-3 -oil
130 mg (0.30 mmol) 9-(6-Bromhexyl)-8-(2,4-difluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 115.9 mg (0.36 mmol) (2S)-2- {2-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]ethyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Es wurden 96.4 mg (48% d. Th.) Produkt isoliert. 130 mg (0.30 mmol) of 9- (6-bromohexyl) -8- (2,4-difluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 115.9 mg (0.36 mmol) ( 2S) -2- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} pyrrolidine according to the general procedure implemented. It was purified by preparative HPLC. 96.4 mg (48% of theory) of product were isolated.
'H-NMR (300 MHz, Chloroform-di): δ = 0.99-1.24 (m, 6H), 1.26-1.40 (m, 2H), 1.47-1.61 (m, 1H), 1.71-1.87 (m, 2H), 1.92-2.37 (m, 15H), 2.56-2.74 (m, 4H), 2.92-3.18 (m, 4H), 3.25 (mc, 1H), 6.71- 6.78 (m, 2H), 6.80-6.92 (m, 2H), 7.10-7.20 (m, 2H). 'H-NMR (300 MHz, chloroform-di): δ = 0.99-1.24 (m, 6H), 1.26-1.40 (m, 2H), 1.47-1.61 (m, 1H), 1.71-1.87 (m, 2H) , 1.92-2.37 (m, 15H), 2.56-2.74 (m, 4H), 2.92-3.18 (m, 4H), 3.25 (mc, 1H), 6.71-6.78 (m, 2H), 6.80-6.92 (m, 2H), 7.10-7.20 (m, 2H).
Beispiel 25 Example 25
8-(2,4-Difluorphenyl)-9-{6-[(2S)-2-{2-[(4,4,4-trifluorbutyl)sulfonyl]ethyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo [7] annulen-3-ol
8- (2,4-Difluorophenyl) -9- {6 - [(2S) -2- {2 - [(4,4,4-trifluorobutyl) sulfonyl] ethyl} pyrrolidin-1-yl] hexyl} - 6, 7-dihydro-5H-benzo [7] annulen-3-ol
130 mg (0.30 mmol) 9-(6-Bromhexyl)-8-(2,4-difluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 97.9 mg (0.36 mmol) (2S)-2- {2-[(4,4,4-Trifluorbutyl)sulfonyl]ethyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Es wurden 74.5 mg (40% d. Th.) Produkt isoliert. 130 mg (0.30 mmol) of 9- (6-bromohexyl) -8- (2,4-difluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 97.9 mg (0.36 mmol) ( 2S) -2- {2 - [(4,4,4-trifluorobutyl) sulfonyl] ethyl} pyrrolidine according to the general procedure implemented. It was purified by preparative HPLC. 74.5 mg (40% of theory) of product were isolated.
'H-NMR (300 MHz, Chloroform-di): δ = 0.98-1.24 (m, 6H), 1.35 (mc, 2H), 1.50-1.64 (m, 1H), 1.72- 1.91 (m, 2H), 1.93-2.41 (m, 15H), 2.56-2.81 (m, 4H), 2.92-3.18 (m, 4H), 3.29 (mc, 1H), 6.70-6.78 (m, 2H), 6.80-6.92 (m, 2H), 7.10-7.20 (m, 2H). 'H NMR (300 MHz, chloroform-di): δ = 0.98-1.24 (m, 6H), 1.35 (mc, 2H), 1.50-1.64 (m, 1H), 1.72-1.91 (m, 2H), 1.93 -2.41 (m, 15H), 2.56-2.81 (m, 4H), 2.92-3.18 (m, 4H), 3.29 (mc, 1H), 6.70-6.78 (m, 2H), 6.80-6.92 (m, 2H) , 7.10-7.20 (m, 2H).
Beispiel 26 Example 26
8-(2,4-Difluorphenyl)-9-{6-[(2S)-2-{2-[(3,3,3-trifluorpropyl)sulfonyl]ethyl}pyrrolidin-l-yl]hexyl}- -dihydro-5H-benzo [7] annulen-3-ol 8- (2,4-Difluorophenyl) -9- {6 - [(2S) -2- {2 - [(3,3,3-trifluoropropyl) sulfonyl] ethyl} pyrrolidin-1-yl] hexyl} -dihydro 5H-benzo [7] annulen-3-ol
130 mg (0.30 mmol) 9-(6-Bromhexyl)-8-(2,4-difluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 92.9 mg (0.36 mmol) (2S)-2- {2-[(3,3,3-Trifluorpropyl)sulfonyl]ethyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Es wurden 106.2 mg (58% d. Th.) Produkt isoliert. 130 mg (0.30 mmol) of 9- (6-bromohexyl) -8- (2,4-difluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 92.9 mg (0.36 mmol) ( 2S) -2- {2 - [(3,3,3-trifluoropropyl) sulfonyl] ethyl} pyrrolidine according to the general procedure implemented. It was purified by preparative HPLC. 106.2 mg (58% of theory) of product were isolated.
'H-NMR (300 MHz, Chloroform-di): δ = 0.99-1.24 (m, 6H), 1.34 (mc, 2H), 1.51-1.65 (m, 1H), 1.74- 1.92 (m, 2H), 1.95-2.36 (m, 11H), 2.58-2.83 (m, 6H), 3.05 (ddd, 1H), 3.12-3.25 (m, 3H), 3.30 (mc, 1H), 6.71-6.79 (m, 2H), 6.81-6.92 (m, 2H), 7.09-7.20 (m, 2H). 'H-NMR (300 MHz, chloroform-di): δ = 0.99-1.24 (m, 6H), 1.34 (mc, 2H), 1.51-1.65 (m, 1H), 1.74-1.92 (m, 2H), 1.95 -2.36 (m, 11H), 2.58-2.83 (m, 6H), 3.05 (ddd, 1H), 3.12-3.25 (m, 3H), 3.30 (mc, 1H), 6.71-6.79 (m, 2H), 6.81 -6.92 (m, 2H), 7.09-7.20 (m, 2H).
Beispiel 27
8-(2,4-Difluorphenyl)-9-{6-[(2S)-2-{3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l- l] hexyl}-6,7-dihydro-5H-benzo [7] annulen-3-ol Example 27 8- (2,4-Difluorophenyl) -9- {6 - [(2S) -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidin-1-hexyl} -6, 7-dihydro-5H-benzo [7] annulen-3-ol
400 mg (0.87 mmol) 9-(6-Bromhexyl)-8-(2,4-difluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 301.3 mg (1.05 mmol) (2S)-2- {3-[(3,3,3-Trifluorpropyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Der Rückstand wurde in 30 ml Essigsäureethylester aufgenommen, einmal mit 25 %iger wässriger Ammoniaklösung und zweimal mit Wasser gewaschen, über Magnesiumsulfat getrocknet und eingeengt. Es fielen 253 mg (46% d. Th.) Produkt an. 400 mg (0.87 mmol) of 9- (6-bromohexyl) -8- (2,4-difluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were mixed with 301.3 mg (1.05 mmol) ( 2S) -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidine according to the general procedure implemented. The residue was taken up in 30 ml of ethyl acetate, washed once with 25% aqueous ammonia solution and twice with water, dried over magnesium sulfate and concentrated. 253 mg (46% of theory) of product were obtained.
'H-NMR (300 MHz, Chloroform-di): δ = 1.01-1.51 (m, 10H), 1.63-2.32 (m, 15), 2.52-2.77 (m, 5H), 3.00-3.22 (m, 5H), 6.68-6.76 (m, 2H), 6.79-6.92 (m, 2H), 7.10-7.21 (m, 2H). 'H-NMR (300 MHz, chloroform-di): δ = 1.01-1.51 (m, 10H), 1.63-2.32 (m, 15), 2.52-2.77 (m, 5H), 3.00-3.22 (m, 5H) , 6.68-6.76 (m, 2H), 6.79-6.92 (m, 2H), 7.10-7.21 (m, 2H).
Beispiel 28 Example 28
8-(3,4-Difluorphenyl)-9-{6-[(2R)-2-{4-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]butyl}pyrrolidin-l- l] hexyl}-6,7-dihydro-5H-benzo [7] annulen-3-ol 8- (3,4-Difluorophenyl) -9- {6 - [(2R) -2- {4 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] butyl} pyrrolidin-1-hexyl] } -6,7-dihydro-5H-benzo [7] annulen-3-ol
103.3 mg (0.24 mmol) 9-(6-Bromhexyl)-8-(3,4-difluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 100 mg (0.28 mmol) (2R)-2- {4-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]butyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Es wurde mittels präparativer HPLC gereinigt. Es wurden 109 mg (64% d. Th.) Produkt isoliert. 103.3 mg (0.24 mmol) of 9- (6-bromohexyl) -8- (3,4-difluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were mixed with 100 mg (0.28 mmol) ( 2R) -2- {4 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] butyl} pyrrolidine reacted according to the general procedure. It was purified by preparative HPLC. 109 mg (64% of theory) of product were isolated.
'H-NMR (300 MHz, Chloroform-di): δ = 0.99-1.26 (m, 6H), 1.29-1.71 (m, 7H), 1.73-2.48 (m, 17H), 2.50-2.70 (m, 3H), 2.83 (mc, 1H), 2.93-3.12 (m, 4H), 3.45 (mc, 1H), 6.69-6.78 (m, 2H), 6.89-6.97 (m, 1H), 7.03 (ddd, 1H), 7.08-7.18 (m, 2H).
Beispiel 29 'H-NMR (300 MHz, chloroform-di): δ = 0.99-1.26 (m, 6H), 1.29-1.71 (m, 7H), 1.73-2.48 (m, 17H), 2.50-2.70 (m, 3H) , 2.83 (mc, 1H), 2.93-3.12 (m, 4H), 3.45 (mc, 1H), 6.69-6.78 (m, 2H), 6.89-6.97 (m, 1H), 7.03 (ddd, 1H), 7.08 -7.18 (m, 2H). Example 29
9-{6-[(3R)-3-{2-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]ethyl}morpholin-4-yl]hexyl}-8-phenyl-6,7- 9- {6 - [(3R) -3- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} morpholin-4-yl] hexyl} -8-phenyl-6,7-
200 mg (0.50 mmol) 9-(6-Bromhexyl)-8-phenyl-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 170 mg (0.50 mmol) (3R)-3- {2-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]ethyl}morpholin entsprechend der allgemeinen Vorschrift umgesetzt. Anschließend wurde mittels präparativer HPLC und Chiralpak IB, 5μ, 250 x 20 mm, 25 ml/min, Laufmittel: Hexan mit 0.1% Diethylamin-Hexan 80:20 gereinigt. Es fielen 45 mg ( 14% d. Th.) Produkt an. 200 mg (0.50 mmol) of 9- (6-bromohexyl) -8-phenyl-6,7-dihydro-5H-benzo [7] annulene-3-ol were mixed with 170 mg (0.50 mmol) of (3R) -3- { 2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} morpholine according to the general procedure implemented. The mixture was then purified by preparative HPLC and Chiralpak IB, 5μ, 250 x 20 mm, 25 ml / min, eluent: hexane with 0.1% diethylamine-hexane 80:20. There was 45 mg (14% of theory) of product.
'H-NMR (600 MHz, Cloroform-di): δ = 1.02-1.15 (m, 4H), 1.17-1.32 (m, 4H), 1.90 (mc, 1H), 2.06- 2.22 (m, 8H), 2.22-2.32 (m, 3H), 2.38 (t, 2H), 2.46-2.53 (m, 2H), 2.64 (t, 2H), 2.70 (mc, 1H), 2.91 (mc, 1H), 3.01-3.10 (m, 3H), 3.34 (dd, 1H), 3.56 (mc, 1H), 3.67 (dd, 1H), 3.73 (dt, 1H), 6.72 (d, 1H), 6.75 (dd, 1H), 7.18 (d, 1H), 7.23-7.27 (m, 3H), 7.35 (t, 2H). 'H NMR (600 MHz, chloroform-di): δ = 1.02-1.15 (m, 4H), 1.17-1.32 (m, 4H), 1.90 (mc, 1H), 2.06-2.22 (m, 8H), 2.22 -2.32 (m, 3H), 2.38 (t, 2H), 2.46-2.53 (m, 2H), 2.64 (t, 2H), 2.70 (mc, 1H), 2.91 (mc, 1H), 3.01-3.10 (m , 3H), 3.34 (dd, 1H), 3.56 (mc, 1H), 3.67 (dd, 1H), 3.73 (dt, 1H), 6.72 (d, 1H), 6.75 (dd, 1H), 7.18 (d, 1H), 7.23-7.27 (m, 3H), 7.35 (t, 2H).
Beispiel 30 Example 30
8-(4-Fluorphenyl)-9-{6-[(2R)-2-{4-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]butyl}pyrrolidin-l- yl] hexyl}-6,7-dihydro-5H-benzo [7] annulen-3-ol 8- (4-fluorophenyl) -9- {6 - [(2R) -2- {4 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] butyl} pyrrolidin-1-yl] hexyl} - 6,7-dihydro-5H-benzo [7] annulen-3-ol
120 mg (0.31 mmol) 9-(6-Bromhexyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 121 mg (0.37 mmol) (2R)-2- {4-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]butyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC erhielt man 70 mg der Titelverbindung. 120 mg (0.31 mmol) of 9- (6-bromohexyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were mixed with 121 mg (0.37 mmol) (2R). -2- {4 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] butyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 70 mg of the title compound were obtained.
'H-NMR (300MHZ, DMSO-de): δ [ppm]= 0.96 - 2.10 (m), 2.19 - 2.44 (m, 4H), 2.49 - 2.60 (m, 3H), 2.84 - 2.93 (m, 1H), 3.07 (t, 2H), 3.17 (t, 2H), 6.55 - 6.69 (m, 2H), 7.06 - 7.27 (m, 5H), 9.27 (s, 1H). 'H NMR (300MHZ, DMSO-de): δ [ppm] = 0.96-2.10 (m), 2.19-2.44 (m, 4H), 2.49-2.60 (m, 3H), 2.84-2.93 (m, 1H) , 3.07 (t, 2H), 3.17 (t, 2H), 6.55-6.69 (m, 2H), 7.06 - 7.27 (m, 5H), 9.27 (s, 1H).
Beispiel 31 Example 31
8-(4-Fluorphenyl)-9-{6-[(2R,4R)-4-fluor-2-{3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl] hexyl}-6,7-dihydro-5H-benzo [7] annulen-3-ol 8- (4-fluorophenyl) -9- {6 - [(2R, 4R) -4-fluoro-2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl } -6,7-dihydro-5H-benzo [7] annulen-3-ol
120 mg (0.29 mmol) 9-(6-Bromhexyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 105 mg (0.35 mmol) (2R,4R)-4-Fluor-2- {3-[(4,4,4- trifluorbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 116 mg der Titelverbindung erhalten. 120 mg (0.29 mmol) of 9- (6-bromohexyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 105 mg (0.35 mmol) (2R, 4R) -4-Fluoro-2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidine according to the general procedure implemented. After preparative HPLC, 116 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.95 - 1.24 (m), 1.44 - 1.68 (m, 4H), 1.79 - 2.06 (m, 8H), 2.16 - 2.45 (m, 5H), 2.48 - 2.59 (m, verdeckt durch DMSO-Lösemittel), 3.02 - 3.19 (m, 4H), 3.22 - 3.38 (m, verdeckt durch Wassersignal), 4.97 - 5.17 (m, 1H), 6.57 - 6.66 (m, 2H), 7.07 - 7.26 (m, 5H), 9.29 (br. s, 1H). 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.95-1.24 (m), 1.44-1.68 (m, 4H), 1.79-2.06 (m, 8H), 2.16-2.45 (m, 5H) , 2.48 - 2.59 (m, masked by DMSO solvent), 3.02 - 3.19 (m, 4H), 3.22 - 3.38 (m, obscured by water signal), 4.97 - 5.17 (m, 1H), 6.57 - 6.66 (m, 2H ), 7.07 - 7.26 (m, 5H), 9.29 (brs s, 1H).
Beispiel 32 Example 32
9-{6-[(2R)-4,4-Difluor-2-{3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-8-(4- fluorphenyl)-6,7-dihydro-5H-benzo [7] annulen-3-ol
9- {6 - [(2R) -4,4-Difluoro-2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -8- (4-fluorophenyl ) -6,7-dihydro-5H-benzo [7] annulen-3-ol
trifluorbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 9 mg der Titelverbindung erhalten. trifluorobutyl) sulfonyl] propyl} pyrrolidine according to the general procedure implemented. After preparative HPLC, 9 mg of the title compound were obtained.
LCMS (Waters Aqcuity UPLC-MS: Binary Solvent Manager, Sample Manager/Organizer, Column Manager, PDA, ELSD, SQD 3001 ; Aqcuity BEH C18 1.7 50x2.1mm; A = Wasser + 0.2% Ammoniak; B = Acetonitril; 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; 0.8 ml/min; 60°C; 1.0 mg/ml EtOH/MeOH 1 : 1 ; 2.0 μΐ; DAD scan ränge 210-400 nm; MS ESI+, ESI-, scan ränge 160-1000 m/z) Rt = 1.60 min; m/z = 659+. LCMS (Waters Aqcuity UPLC-MS: Binary Solvent Manager, Sample Manager / Organizer, Column Manager, PDA, ELSD, SQD 3001; Aqcuity BEH C18 1.7 50x2.1mm; A = water + 0.2% ammonia; B = acetonitrile; 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; 0.8 ml / min; 60 ° C; 1.0 mg / ml EtOH / MeOH 1: 1; 2.0 μΐ; DAD scan ranges 210-400 nm; MS ESI +, ESI - scan ranges 160-1000 m / z) R t = 1.60 min; m / z = 659 + .
Beispiel 33 Example 33
(3R,5R)-l-{6-[8-(4-Fluorphenyl)-3-hydroxy-6,7-dihydro-5H-benzo[7]annulen-9-yl]hexyl}-5-{3- [(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-3-ol (3R, 5R) -l- {6- [8- (4-fluorophenyl) -3-hydroxy-6,7-dihydro-5H-benzo [7] annulene-9-yl] hexyl} -5- {3- [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin-3-ol
129 mg (0.31 mmol) 9-(6-Bromhexyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 131 mg (0.43 mmol) (3R,5R)-5- {3-[(4,4,4-Trifluorbutyl)sulfonyl]propyl}pyrrolidin-3-ol entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 90 mg der Titelverbindung erhalten. 129 mg (0.31 mmol) of 9- (6-bromohexyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were mixed with 131 mg (0.43 mmol) (3R, 5R) -5- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin-3-ol was reacted according to the general procedure. After preparative HPLC, 90 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.87 - 1.28 (m, 9H), 1.44 - 1.71 (m, 5H), 1.80 - 1.90 (m, 2H), 1.90 - 2.05 (m, 6H), 2.21 - 2.31 (m, 2H), 2.31 - 2.44 (m, 2H), 2.48 - 2.60 (m, 3H), 3.01 - 3.10 (m,
2H), 3.10 - 3.22 (m, 4H), 4.02 - 4.10 (m, 1H), 6.55 - 6.67 (m, 2H), 6.57 - 6.66 (m, 1H), 7.07 - 7.25 (m,'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.87-1.28 (m, 9H), 1.44-1.71 (m, 5H), 1.80-1.90 (m, 2H), 1.90-2.05 (m, 6H), 2.21 - 2.31 (m, 2H), 2.31 - 2.44 (m, 2H), 2.48 - 2.60 (m, 3H), 3.01 - 3.10 (m, 2H), 3.10-3.22 (m, 4H), 4.02-4.10 (m, 1H), 6.55-6.67 (m, 2H), 6.57-6.66 (m, 1H), 7.07-7.25 (m,
5H), 9.2 (br. s, 1H). 5H), 9.2 (brs s, 1H).
MS ES+ (gefundene Masse) 639.30+. MS ES + (found mass) 639.30 + .
Beispiel 34 Example 34
8-(3-Hydroxyphenyl)-9-{6-[(2S)-2-{3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- [7] annulen-3-ol 8- (3-Hydroxyphenyl) -9- {6 - [(2S) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidin-1- [7] -annulene- 3-ol
90 mg (0.21 mmol) 9-(6-Bromhexyl)-8-(3-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 95 mg (0.28 mmol) (2S)-2- {3-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 85 mg der Titelverbindung erhalten. 90 mg (0.21 mmol) of 9- (6-bromohexyl) -8- (3-hydroxyphenyl) -6,7-dihydro-5H-benzo [7] annulene-3-ol were treated with 95 mg (0.28 mmol) (2S). -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 85 mg of the title compound were obtained.
1H-NMR (400MHz, DMSO-d6): δ [ppm]= 0.97 - 1.18 (m, 6H), 1.21 - 1.43 (m, 4H), 1.54 - 1.72 (m, 5H), 1.81 - 2.11 (m, 9H), 2.26 - 2.47 (m, 5H), 2.52 - 2.56 (m, 2H), 2.58 - 2.68 (m, 1H), 2.98 - 3.06 (m, 1H), 3.10 - 3.15 (m, 2H), 3.18 - 3.23 (m, 2H), 6.58 - 6.69 (m, 5H), 7.07 - 7.18 (m, 2H), 9.41 (br., 2H). MS (CI+) [M+H]+ = 672+. 1H NMR (400MHz, DMSO-d6): δ [ppm] = 0.97-1.18 (m, 6H), 1.21-1.43 (m, 4H), 1.54-1.72 (m, 5H), 1.81-2.11 (m, 9H ), 2.26 - 2.47 (m, 5H), 2.52 - 2.56 (m, 2H), 2.58 - 2.68 (m, 1H), 2.98 - 3.06 (m, 1H), 3.10 - 3.15 (m, 2H), 3.18 - 3.23 (m, 2H), 6.58-6.69 (m, 5H), 7.07-7.18 (m, 2H), 9.41 (br., 2H). MS (CI +) [M + H] + = 672+.
Drehwert: [a] = - 45,5 ° (c = 1.0, CHC13). Rotation: [a] = - 45.5 ° (c = 1.0, CHC13).
Beispiel 35 Example 35
8-(4-Fluorphenyl)-9-{6-[(2S)-2-{3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- yl] hexyl}-6,7-dihydro-5H-benzo [7] annulen-3-ol
8- (4-fluorophenyl) -9- {6 - [(2S) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6,7-dihydro-5H-benzo [7] annulen-3-ol
90 mg (0.21 mmol) 9-(6-Bromohexyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 95 mg (0.28 mmol) (2S)-2- {3-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 92 mg der Titelverbindung erhalten. 90 mg (0.21 mmol) of 9- (6-bromohexyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 95 mg (0.28 mmol) (2S). -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 92 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.95 - 1.17 (m, 6H), 1.18 - 1.40 (m, 4H), 1.52 - 1.74 (m, 5H), 1.76 - 2.09 (m, 9H), 2.14 - 2.23 (m, 1H), 2.26 - 2.48 (m, 4H), 2.52 - 2.60 (m, 3H), 2.92 - 2.99 (m, 1H), 3.08 - 3.15 (m, 2H), 3.18 - 3.23 (m, 2H), 6.62 - 6.69 (m, 2H), 7.13 (d, 1H), 7.15 - 7.22 (m, 3H), 7.23 - 7.30 (m, 3H), 9.33 (br. s, 1H). 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.95-1.17 (m, 6H), 1.18-1.40 (m, 4H), 1.52-1.74 (m, 5H), 1.76-2.09 (m, 9H), 2.14 - 2.23 (m, 1H), 2.26 - 2.48 (m, 4H), 2.52 - 2.60 (m, 3H), 2.92 - 2.99 (m, 1H), 3.08 - 3.15 (m, 2H), 3.18 - 3.23 (m, 2H), 6.62-6.69 (m, 2H), 7.13 (d, 1H), 7.15 - 7.22 (m, 3H), 7.23 - 7.30 (m, 3H), 9.33 (br, s, 1H).
MS (CI+) [M+H]+ = 674+. MS (CI + ) [M + H] + = 674 + .
Drehwert: [a] = - 29,2 ° (c = 1.0, CHC13). Rotation: [a] = - 29.2 ° (c = 1.0, CHC1 3 ).
Beispiel 36 Example 36
8-(3-Fluorphenyl)-9-{6-[(2S)-2-{3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- [7] annulen-3-ol 8- (3-fluorophenyl) -9- {6 - [(2S) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidin-1- [7] -annulene- 3-ol
90 mg (0.21 mmol) 9-(6-Bromhexyl)-8-(3-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 94.5 mg (0.28 mmol) (2S)-2- {3-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 88 mg der Titelverbindung erhalten.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.97 - 1.18 (m, 6H), 1.19 - 1.40 (m, 4H), 1.52 - 1.72 (m, 5H), 1.77 - 1.87 (m, 1H), 1.87 - 2.08 (m, 8H), 2.1 8 - 2.27 (m, 1 H), 2.29 - 2.47 (m, 4H), 2.52 - 2.64 (m, 3H), 2.94 - 3.01 (m, 1H), 3.09 - 3.14 (m, 2H), 3.18 - 3.23 (m, 2H), 6.63 - 6.69 (m, 2H), 7.00 - 7.16 (m, 4H), 7.41 (td, 1H), 9.54 (br. s, 1H). 90 mg (0.21 mmol) of 9- (6-bromohexyl) -8- (3-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 94.5 mg (0.28 mmol) (2S). -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 88 mg of the title compound were obtained. 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.97-1.18 (m, 6H), 1.19-1.40 (m, 4H), 1.52-1.72 (m, 5H), 1.77-1.87 (m, 1H), 1.87 - 2.08 (m, 8H), 2.1 8 - 2.27 (m, 1H), 2.29 - 2.47 (m, 4H), 2.52 - 2.64 (m, 3H), 2.94 - 3.01 (m, 1H), 3.09-3.14 (m, 2H), 3.18-3.23 (m, 2H), 6.63-6.69 (m, 2H), 7.00-7.16 (m, 4H), 7.41 (td, 1H), 9.54 (brs s, 1H ).
MS (CI+) [M+H]+ = 674+. MS (CI + ) [M + H] + = 674 + .
Drehwert: [a] = - 24,3 ° (c = 1.0, CHC13). Rotation: [a] = - 24.3 ° (c = 1.0, CHC1 3 ).
Beispiel 37 Example 37
8-(3,5-Difluorphenyl)-9-{6-[(2S)-2-{3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- [7] annulen-3-ol 8- (3,5-Difluorophenyl) -9- {6 - [(2S) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidine-1- [7] annulene-3-ol
90 mg (0.21 mmol) 9-(6-Bromhexyl)-8-(3,5-difluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 90 mg (0.27 mmol) (2S)-2- {3-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 64 mg der Titelverbindung erhalten. 90 mg (0.21 mmol) of 9- (6-bromohexyl) -8- (3,5-difluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 90 mg (0.27 mmol) ( 2S) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidine according to the general procedure implemented. After preparative HPLC, 64 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.99 - 1.19 (m, 6H), 1.20 - 1.40 (m, 4H), 1.53 - 1.71 (m, 5H), 1.78 - 2.08 (m, 9H), 2.16 - 2.26 (m, 1H), 2.29 - 2.47 (m, 4H), 2.52 - 2.64 (m, 3H), 2.94 - 3.00 (m, 1H), 3.08 - 3.14 (m, 2H), 3.18 - 3.23 (m, 2H), 6.63 - 6.69 (m, 2H), 6.90 - 6.98 (m, 2H), 7.09 - 7.17 (m, 2H), 9.44 (br. s, 1H). 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.99-1.19 (m, 6H), 1.20-1.40 (m, 4H), 1.53-1.71 (m, 5H), 1.78-0.208 (m, 9H), 2.16 - 2.26 (m, 1H), 2.29 - 2.47 (m, 4H), 2.52 - 2.64 (m, 3H), 2.94 - 3.00 (m, 1H), 3.08 - 3.14 (m, 2H), 3.18 - 3.23 (m, 2H), 6.63-6.69 (m, 2H), 6.90-6.98 (m, 2H), 7.09-7.17 (m, 2H), 9.44 (br, s, 1H).
MS (CI+) [M+H]+ = 692+. MS (CI + ) [M + H] + = 692 + .
Drehwert: [a] = - 25,6 0 (c = 1.0, CHCI3). Rotation: [a] = - 25.6 0 (c = 1.0, CHCI3).
Beispiel 38 Example 38
8-(3-Hydroxyphenyl)-9-{6-[(2S)-2-{3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl] hexyl}-6,7-dihydro-5H-benzo [7] annulen-3-ol
8- (3-Hydroxyphenyl) -9- {6 - [(2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6,7-dihydro-5H-benzo [7] annulen-3-ol
90 mg (0.21 mmol) 9-(6-Bromhexyl)-8-(3-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol- wurden mit 91 mg (0.28 mmol) (2S)-2- {3-[(3,3,4,4,4-Pentafluorbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 97 mg der Titelverbindung erhalten. 90 mg (0.21 mmol) of 9- (6-bromohexyl) -8- (3-hydroxyphenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 91 mg (0.28 mmol) (2S ) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidine according to the general procedure implemented. After preparative HPLC, 97 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.98 - 1.18 (m, 6H), 1.21 - 1.43 (m, 4H), 1.57 - 1.74 (m, 5H), 1.83 - 2.13 (m, 7H), 2.29 - 2.38 (m, 3H), 2.52 - 2.56 (m 2H), 2.58 - 2.73 (m, 3H), 3.00 - 3.07 (m, 1H), 3.22 - 3.28 (m, 2H), 3.39 - 3.44 (m, 2H), 6.60 - 6.69 (m, 5H), 7.08 - 7.17 (m, 2H), 9.62 (br. s, 2H). 'H NMR (400MHZ, DMSO-de): δ [ppm] = 0.98-1.18 (m, 6H), 1.21-1.43 (m, 4H), 1.57-1.74 (m, 5H), 1.83-2.13 (m, 7H), 2.29 - 2.38 (m, 3H), 2.52 - 2.56 (m 2H), 2.58 - 2.73 (m, 3H), 3.00 - 3.07 (m, 1H), 3.22 - 3.28 (m, 2H), 3.39 - 3.44 (m, 2H), 6.60-6.69 (m, 5H), 7.08-7.17 (m, 2H), 9.62 (br, s, 2H).
MS (CI+) [M+H]+ = 658+. MS (CI + ) [M + H] + = 658 + .
Drehwert: [a] = - 46,8 ° (c = 1.0, CHC13). Rotation: [a] = - 46.8 ° (c = 1.0, CHC1 3 ).
Beispiel 39 Example 39
8-(4-Fluorphenyl)-9-{6-[(2S)-2-{3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- nzo [7] annulen-3-ol 8- (4-fluorophenyl) -9- {6 - [(2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidin-1-nzo [7] annulene -3-ol
90 mg (0.21 mmol) 9-(6-Bromohexyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 90 mg (0.28 mmol) (2S)-2- {3-[(3,3,4,4,4-Pentafluorbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 109 mg der Titelverbindung erhalten.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.96 - 1.18 (m, 6H), 1.18 - 1.42 (m, 4H), 1.54 - 1.75 (m, 5H), 1.78 - 1.89 (m, 1H), 1.90 - 2.09 (m, 6H), 2.19 - 2.27 (m, 1 H), 2.27 - 2.36 (m, 2H), 2.52 - 2.73 (m, 5H), 2.95 - 3.02 (m, 1H), 3.22 - 3.28 (m, 3H), 3.38 - 3.44 (m, 3H), 6.62 - 6.69 (m, 2H), 7.13 (d, 1H), 7.15 - 7.22 (m, 2H), 7.23 - 7.29 (m, 2H), 9.21 (br. s, 1H). 90 mg (0.21 mmol) of 9- (6-bromohexyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were mixed with 90 mg (0.28 mmol) (2S). -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 109 mg of the title compound were obtained. 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.96-1.18 (m, 6H), 1.18-1.42 (m, 4H), 1.54-1.75 (m, 5H), 1.78-1.89 (m, 1H), 1.90 - 2.09 (m, 6H), 2.19 - 2.27 (m, 1H), 2.27 - 2.36 (m, 2H), 2.52 - 2.73 (m, 5H), 2.95 - 3.02 (m, 1H), 3.22 - 3.28 (m, 3H), 3.38 - 3.44 (m, 3H), 6.62 - 6.69 (m, 2H), 7.13 (d, 1H), 7.15 - 7.22 (m, 2H), 7.23 - 7.29 (m, 2H) , 9.21 (brs s, 1H).
MS (CI+) [M+H]+ = 660+. MS (CI + ) [M + H] + = 660 + .
Drehwert: [a] = - 25,5 ° (c = 1.0, CHC13). Rotation: [a] = - 25.5 ° (c = 1.0, CHC1 3 ).
Beispiel 40 Example 40
8-(3,5-Difluorphenyl)-9-{6-[(2S)-2-{3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- [7] annulen-3-ol 8- (3,5-Difluorophenyl) -9- {6 - [(2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidine-1- [7] annulene-3-ol
90 mg (0.21 mmol) 9-(6-Bromhexyl)-8-(3,5-difluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 86 mg (0.27 mmol) (2S)-2- {3-[(3,3,4,4,4-Pentafluorbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 70 mg der Titelverbindung erhalten. 90 mg (0.21 mmol) of 9- (6-bromohexyl) -8- (3,5-difluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 86 mg (0.27 mmol) ( 2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidine according to the general procedure implemented. After preparative HPLC, 70 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.97 - 1.19 (m, 6H), 1.19 - 1.40 (m, 4H), 1.53 - 1.74 (m, 5H), 1.78 - 1.89 (m, 1H), 1.90 - 2.10 (m, 6H), 2.16 - 2.26 (m, 1H), 2.28 - 2.36 (m, 2H), 2.52 - 2.72 (m, 5H), 2.94 - 3.00 (m, 1H), 3.22 - 3.28 (m, 2H), 3.38 - 3.43 (m, 2H), 6.63 - 6.69 (m, 2H), 6.89 - 6.99 (m, 2H), 7.09 - 7.17 (m, 2H), 9.36 (br. s, 1H). 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.97-1.19 (m, 6H), 1.19-1.40 (m, 4H), 1.53-1.74 (m, 5H), 1.78-1.89 (m, 1H), 1.90 - 2.10 (m, 6H), 2.16 - 2.26 (m, 1H), 2.28 - 2.36 (m, 2H), 2.52 - 2.72 (m, 5H), 2.94 - 3.00 (m, 1H), 3.22 - 3.28 (m, 2H), 3.38-3.43 (m, 2H), 6.63-6.69 (m, 2H), 6.89-6.99 (m, 2H), 7.09-7.17 (m, 2H), 9.36 (br. S, 1H ).
MS (CI+) [M+H]+ = 678+. MS (CI + ) [M + H] + = 678 + .
Drehwert: [a] = - 29 0 (c = 1.0, CHCI3). Rotation: [a] = - 29 0 (c = 1.0, CHCI3).
Beispiel 41 Example 41
8-(2-Fluorphenyl)-9-{6-[(2S)-2-{3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl] hexyl}-6,7-dihydro-5H-benzo [7] annulen-3-ol
8- (2-fluorophenyl) -9- {6 - [(2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6,7-dihydro-5H-benzo [7] annulen-3-ol
90 mg (0.21 mmol) 9-(6-Bromhexyl)-8-(2-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 90 mg (0.28 mmol) (2S)-2- {3-[(3,3,4,4,4-Pentafluorbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 94 mg der Titelverbindung erhalten. 90 mg (0.21 mmol) of 9- (6-bromohexyl) -8- (2-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 90 mg (0.28 mmol) (2S). -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 94 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.91 - 1.16 (m, 6H), 1.16 - 1.41 (m, 4H), 1.53 - 1.75 (m, 5H), 1.77 - 1.99 (m, 5H), 2.00 - 2.1 1 (m, 2H), 2.15 - 2.28 (m, 3H), 2.53 - 2.73 (m, 5H), 2.93 - 3.00 (m, 1H), 3.25 (m, 2H), 3.38 - 3.44 (m, 2H), 6.63 - 6.70 (m, 2H), 7.14 (d, 1H), 7.17 - 7.29 (m, 3H), 7.30 - 7.38 (m, 1H), 9.39 (br. s, 1H). 'H NMR (400MHZ, DMSO-de): δ [ppm] = 0.91-1.16 (m, 6H), 1.16-1.41 (m, 4H), 1.53-1.75 (m, 5H), 1.77-1.99 (m, 5H), 2.00 - 2.1 1 (m, 2H), 2.15 - 2.28 (m, 3H), 2.53 - 2.73 (m, 5H), 2.93 - 3.00 (m, 1H), 3.25 (m, 2H), 3.38 - 3.44 (m, 2H), 6.63-6.70 (m, 2H), 7.14 (d, 1H), 7.17-2.29 (m, 3H), 7.30-7.38 (m, 1H), 9.39 (br, s, 1H).
MS (CI+) [M+H]+ = 660+. MS (CI + ) [M + H] + = 660 + .
Drehwert: [a] = - 28,2 ° (c = 1.0, CHC13). Rotation: [a] = - 28.2 ° (c = 1.0, CHC1 3 ).
Beispiel 42 Example 42
8-(2-Fluorphenyl)-9-{6-[(2R)-2-{3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- [7] annulen-3-ol 8- (2-fluorophenyl) -9- {6 - [(2R) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidin-1- [7] -annulene- 3-ol
90 mg (0.21 mmol) 9-(6-Bromhexyl)-8-(2-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 94 mg (0.28 mmol) (2R)-2- {3-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 1 13 mg der Titelverbindung erhalten.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.93 - 1.16 (m, 6H), 1.17 - 1.41 (m, 4H), 1.52 - 1.72 (m, 5H), 1.77 - 1.87 (m, 1H), 1.87 - 2.00 (m, 6H), 2.00 - 2.1 1 (m, 2H), 2.16 - 2.29 (m, 3H), 2.31 - 2.48 (m, 2H), 2.53 - 2.62 (m, 3H), 2.94 - 3.00 (m, 1H), 3.09 - 3.14 (m, 2H), 3.18 - 3.23 (m, 2H), 6.64 - 6.69 (m, 2H), 7.14 (d, 1H), 7.17 - 7.29 (m, 3H), 7.29 - 7.37 (m, 1H), 9.49 (br. s, 1H). 90 mg (0.21 mmol) of 9- (6-bromohexyl) -8- (2-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 94 mg (0.28 mmol) (2R). -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 1 13 mg of the title compound were obtained. 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.93-1.16 (m, 6H), 1.17-1.41 (m, 4H), 1.52-1.72 (m, 5H), 1.77-1.87 (m, 1H), 1.87 - 2.00 (m, 6H), 2.00 - 2.1 1 (m, 2H), 2.16 - 2.29 (m, 3H), 2.31 - 2.48 (m, 2H), 2.53 - 2.62 (m, 3H), 2.94 - 3.00 (m, 1H), 3.09 - 3.14 (m, 2H), 3.18 - 3.23 (m, 2H), 6.64 - 6.69 (m, 2H), 7.14 (d, 1H), 7.17 - 7.29 (m, 3H) , 7.29 - 7.37 (m, 1H), 9.49 (brs s, 1H).
MS (CI+) [M+H]+ = 674+. MS (CI + ) [M + H] + = 674 + .
Drehwert: [a] = 20 ° (c = 1.0, CHC13). Rotation: [a] = 20 ° (c = 1.0, CHC1 3 ).
Beispiel 43 Example 43
8-(4-Fluorphenyl)-9-{6-[(2R)-2-{3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- [7] annulen-3-ol 8- (4-fluorophenyl) -9- {6 - [(2R) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidin-l- [7] annulene 3-ol
90 mg (0.21 mmol) 9-(6-Bromhexyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 94 mg (0.28 mmol) (2R)-2- {3-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 103 mg der Titelverbindung erhalten. 90 mg (0.21 mmol) of 9- (6-bromohexyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 94 mg (0.28 mmol) (2R). -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 103 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.96 - 1.17 (m, 6H), 1.18 - 1.41 (m, 4H), 1.53 - 1.71 (m, 'H NMR (400MHZ, DMSO-de): δ [ppm] = 0.96-1.17 (m, 6H), 1.18-1.41 (m, 4H), 1.53-1.71 (m,
5H), 1.77 - 2.08 (m, 9H), 2.15 - 2.25 (m, 1H), 2.26 - 2.47 (m, 4H), 2.51 - 2.62 (m, 3H), 2.93 - 3.00 (m,5H), 1.77 - 2.08 (m, 9H), 2.15 - 2.25 (m, 1H), 2.26 - 2.47 (m, 4H), 2.51 - 2.62 (m, 3H), 2.93 - 3.00 (m,
1H), 3.08 - 3.14 (m, 2H), 3.18 - 3.23 (m, 2H), 6.63 - 6.68 (m, 2H), 7.09 - 7.22 (m, 3H), 7.22 - 7.29 (m,1H), 3.08 - 3.14 (m, 2H), 3.18 - 3.23 (m, 2H), 6.63 - 6.68 (m, 2H), 7.09 - 7.22 (m, 3H), 7.22 - 7.29 (m,
2H), 9.36 (br. s, 1H). 2H), 9.36 (brs s, 1H).
MS (CI+) [M+H]+ = 674+. MS (CI + ) [M + H] + = 674 + .
Drehwert: [a] = 24,5 0 (c = 1.0, CHCI3). Rotation: [a] = 24.5 0 (c = 1.0, CHCI3).
Beispiel 44 Example 44
8-(3-Fluorphenyl)-9-{6-[(2R)-2-{3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- yl] hexyl}-6,7-dihydro-5H-benzo [7] annulen-3-ol
8- (3-fluorophenyl) -9- {6 - [(2R) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6,7-dihydro-5H-benzo [7] annulen-3-ol
90 mg (0.21 mmol) 9-(6-Bromohexyl)-8-(3-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 94 mg (0.28 mmol) (2R)-2- {3-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 108 mg der Titelverbindung erhalten. 90 mg (0.21 mmol) of 9- (6-bromohexyl) -8- (3-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 94 mg (0.28 mmol) (2R). -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 108 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.97 - 1.18 (m, 6H), 1.18 - 1.40 (m, 4H), 1.52 - 1.72 (m, 5H), 1.77 - 1.86 (m, 1H), 1.86 - 2.10 (m, 8H), 2.15 - 2.24 (m, 1 H), 2.28 - 2.47 (m, 4H), 2.52 - 2.62 (m, 3H), 2.93 - 2.99 (m, 1H), 3.09 - 3.14 (m, 2H), 3.18 - 3.22 (m, 2H), 6.63 - 6.69 (m, 2H), 7.00 - 7.17 (m, 4H), 7.36 - 7.45 (m, 1H), 9.18 (br. s, 1H). 'H NMR (400MHZ, DMSO-de): δ [ppm] = 0.97-1.18 (m, 6H), 1.18-1.40 (m, 4H), 1.52-1.72 (m, 5H), 1.77-1.86 (m, 1H), 1.86 - 2.10 (m, 8H), 2.15 - 2.24 (m, 1H), 2.28 - 2.47 (m, 4H), 2.52 - 2.62 (m, 3H), 2.93 - 2.99 (m, 1H), 3.09 - 3.14 (m, 2H), 3.18 - 3.22 (m, 2H), 6.63 - 6.69 (m, 2H), 7.00 - 7.17 (m, 4H), 7.36 - 7.45 (m, 1H), 9.18 (br. S, 1H).
MS (CI+) [M+H]+ = 674+. MS (CI + ) [M + H] + = 674 + .
Drehwert: [a] = 21 ,2 ° (c = 1.0, CHC13). Rotation: [a] = 21, 2 ° (c = 1.0, CHC1 3 ).
Beispiel 45 Example 45
8-(3-Hydroxyphenyl)-9-{6-[(2R)-2-{3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- [7] annulen-3-ol 8- (3-Hydroxyphenyl) -9- {6 - [(2R) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidin-1- [7] -annulene- 3-ol
90 mg (0.21 mmol) 9-(6-Bromhexyl)-8-(3-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 95 mg (0.28 mmol) (2R)-2- {3-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 108 mg der Titelverbindung erhalten.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.98 - 1.17 (m, 6H), 1.22 - 1.46 (m, 4H), 1.54 - 1.75 (m, 5H), 1.86 - 2.06 (m, 7H), 2.08 - 2.47 (m, 7H), 2.52 - 2.55 (m, 1 H), 2.65 - 2.76 (m, 1H), 3.05 - 3.15 (m, 3H), 3.16 - 3.23 (m, 2H), 6.60 - 6.67 (m, 5H), 7.09 - 7.17 (m, 2H), 9.30 (br. s, 1H). 90 mg (0.21 mmol) of 9- (6-bromo-hexyl) -8- (3-hydroxyphenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were mixed with 95 mg (0.28 mmol) (2R). -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 108 mg of the title compound were obtained. 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.98-1.17 (m, 6H), 1.22- 1.46 (m, 4H), 1.54-1.75 (m, 5H), 1.86-2.06 (m, 7H), 2.08 - 2.47 (m, 7H), 2.52 - 2.55 (m, 1H), 2.65 - 2.76 (m, 1H), 3.05 - 3.15 (m, 3H), 3.16 - 3.23 (m, 2H), 6.60 - 6.67 (m, 5H), 7.09 - 7.17 (m, 2H), 9.30 (br, s, 1H).
MS (CI+) [M+H]+ = 672+. MS (CI + ) [M + H] + = 672 + .
Drehwert: [a] = 38,5 ° (c = 1.0, CHC13). Rotation: [a] = 38.5 ° (c = 1.0, CHC1 3 ).
Beispiel 46 Example 46
8-(4-Fluorphenyl)-9-{6-[(2R)-2-{3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- nzo [7] annulen-3-ol 8- (4-fluorophenyl) -9- {6 - [(2R) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidin-1-nzo [7] annulene -3-ol
90 mg (0.21 mmol) 9-(6-Bromohexyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 90 mg (0.28 mmol) (2R)-2- {3-[(3,3,4,4,4-Pentafluorbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 107 mg der Titelverbindung erhalten. 90 mg (0.21 mmol) of 9- (6-bromohexyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 90 mg (0.28 mmol) (2R). -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 107 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.95 - 1.17 (m, 6H), 1.17 - 1.40 (m, 4H), 1.54 - 1.75 (m, 5H), 1.79 - 1.89 (m, 1H), 1.90 - 2.09 (m, 6H), 2.19 - 2.26 (m, 1H), 2.27 - 2.34 (m, 2H), 2.52 - 2.73 (m, 5H), 2.94 - 3.01 (m, 1H), 3.20 - 3.28 (m, 2H), 3.33 - 3.42 (m, 2H), 6.63 - 6.68 (m, 2H), 7.10 - 7.21 (m, 3H), 7.22 - 7.28 (m, 2H), 9.35 (br. s, 1H). 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.95-1.17 (m, 6H), 1.17-1.40 (m, 4H), 1.54-1.75 (m, 5H), 1.79-1.89 (m, 1H), 1.90 - 2.09 (m, 6H), 2.19 - 2.26 (m, 1H), 2.27 - 2.34 (m, 2H), 2.52 - 2.73 (m, 5H), 2.94 - 3.01 (m, 1H), 3.20 - 3.28 (m, 2H), 3.33 - 3.42 (m, 2H), 6.63 - 6.68 (m, 2H), 7.10 - 7.21 (m, 3H), 7.22 - 7.28 (m, 2H), 9.35 (br, s, 1H ).
MS (CI+) [M+H]+ = 660+. MS (CI + ) [M + H] + = 660 + .
Drehwert: [a] = 26,9 0 (c = 1.0, CHCI3). Rotation: [a] = 26.9 0 (c = 1.0, CHCl 3).
Beispiel 47 Example 47
8-(3-Fluorphenyl)-9-{6-[(2R)-2-{3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol
8- (3-fluorophenyl) -9- {6 - [(2R) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6,7-dihydro-5H-benzo [7] annulene-3-ol
90 mg (0.21 mmol) 9-(6-Bromhexyl)-8-(3-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 91 mg (0.28 mmol) (2R)-2- {3-[(3,3,4,4,4-Pentafluorbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 73 mg der Titelverbindung erhalten. 90 mg (0.21 mmol) of 9- (6-bromohexyl) -8- (3-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 91 mg (0.28 mmol) (2R). -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 73 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.96 - 1.18 (m, 6H), 1.20 - 1.41 (m, 4H), 1.53 - 1.75 (m, 5H), 1.78 - 1.88 (m, 1H), 1.88 - 2.10 (m, 6H), 2.18 - 2.27 (m, 1H), 2.28 - 2.35 (m, 2H), 2.52 - 2.73 (m, 5H), 2.94 - 3.01 (m, 1H), 3.25 (mc, 2H), 3.38 - 3.44 (m, 2H), 6.63 - 6.69 (m, 2H), 6.99 - 7.16 (m, 4H), 7.40 (td, 1H), 9.46 (br. s, 1H). 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.96-1.18 (m, 6H), 1.20-1.41 (m, 4H), 1.53-1.75 (m, 5H), 1.78-1.88 (m, 1H), 1.88 - 2.10 (m, 6H), 2.18 - 2.27 (m, 1H), 2.28 - 2.35 (m, 2H), 2.52 - 2.73 (m, 5H), 2.94 - 3.01 (m, 1H), 3.25 ( mc, 2H), 3.38-3.44 (m, 2H), 6.63-6.69 (m, 2H), 6.99-7.16 (m, 4H), 7.40 (td, 1H), 9.46 (br, s, 1H).
MS (CI+) [M+H]+ = 660+. MS (CI + ) [M + H] + = 660 + .
Drehwert: [a] = 21,4 ° (c = 1.0, CHC13). Rotation: [a] = 21.4 ° (c = 1.0, CHC1 3 ).
Beispiel 48 Example 48
8-(3-Fluorphenyl)-9-{6-[(2S)-2-{3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- [7] annulen-3-ol 8- (3-fluorophenyl) -9- {6 - [(2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidin-1- [7] -annulene- 3-ol
90 mg (0.21 mmol) 9-(6-Bromhexyl)-8-(3-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 90 mg (0.28 mmol) (2S)-2- {3-[(3,3,4,4,4-Pentafluorbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 86 mg der Titelverbindung erhalten.
'H-NMR (400MHz, DMSO-de): δ [ppm]= 0.93 - 1.15 (m, 6H), 1.16 - 1.39 (m, 4H), 1.52 - 1.74 (m,90 mg (0.21 mmol) of 9- (6-bromohexyl) -8- (3-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulene-3-ol were treated with 90 mg (0.28 mmol) (2S). -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 86 mg of the title compound were obtained. 'H-NMR (400MHz, DMSO-de): δ [ppm] = 0.93 - 1.15 (m, 6H), 1.16 - 1.39 (m, 4H), 1.52 - 1.74 (m,
5H), 1.76 - 1.88 (m, 1H), 1.89 - 2.05 (m, 6H), 2.19 - 2.32 (m, 3H), 2.48 - 2.69 (m, 5H), 2.92 - 2.99 (m,5H), 1.76 - 1.88 (m, 1H), 1.89 - 2.05 (m, 6H), 2.19 - 2.32 (m, 3H), 2.48 - 2.69 (m, 5H), 2.92 - 2.99 (m,
1H), 3.19 - 3.25 (m, 2H), 3.34 - 3.40 (m, 2H), 6.59 - 6.66 (m, 2H), 6.97 - 7.12 (m, 4H), 7.33 - 7.42 (m,1H), 3.19-3.25 (m, 2H), 3.34-3.40 (m, 2H), 6.59-6.66 (m, 2H), 6.97-7.12 (m, 4H), 7.33-7.42 (m,
1H), 9.35 (br. s, 1H). 1H), 9.35 (brs s, 1H).
MS (CI+) [M+H]+ = 660+. MS (CI + ) [M + H] + = 660 + .
Drehwert: [a] = - 21,7 ° (c = 1.0, CHC13). Rotation: [a] = - 21.7 ° (c = 1.0, CHC1 3 ).
Beispiel 49 Example 49
8-(4-Fluorphenyl)-9-{6-[(2R)-2-{3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- ulen-3-ol 8- (4-fluorophenyl) -9- {6 - [(2R) -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -ulen-3- oil
90 mg (0.21 mmol) 9-(6-Bromhexyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 80 mg (0.28 mmol) (2R)-2- {3-[(4,4,4-Trifluorbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 96 mg der Titelverbindung erhalten. 90 mg (0.21 mmol) of 9- (6-bromohexyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulene-3-ol were treated with 80 mg (0.28 mmol) (2R). -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 96 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.95 - 1.18 (m, 6H), 1.18 - 1.40 (m, 4H), 1.53 - 1.74 (m, 5H), 1.77 - 2.09 (m, 9H), 2.16 - 2.26 (m, 1H), 2.26 - 2.34 (m, 2H), 2.35 - 2.48 (m, 2H), 2.52 - 2.63 (m, 3H), 2.97 (br. s, 1H), 3.08 - 3.14 (m, 2H), 3.14 - 3.19 (m, 2H), 6.62 - 6.69 (m, 2H), 7.10 - 7.22 (m, 3H), 7.23 - 7.30 (m, 2H), 9.35 (br. s, 1H). 'H NMR (400MHZ, DMSO-de): δ [ppm] = 0.95-1.18 (m, 6H), 1.18-1.40 (m, 4H), 1.53-1.74 (m, 5H), 1.77-2.09 (m, 9H), 2.16 - 2.26 (m, 1H), 2.26 - 2.34 (m, 2H), 2.35 - 2.48 (m, 2H), 2.52 - 2.63 (m, 3H), 2.97 (br, s, 1H), 3.08 - 3.14 (m, 2H), 3.14-3.19 (m, 2H), 6.62-6.69 (m, 2H), 7.10-2.22 (m, 3H), 7.23-7.30 (m, 2H), 9.35 (br. S, 1H ).
MS (CI+) [M+H]+ = 624+. MS (CI + ) [M + H] + = 624 + .
Drehwert: [a] = 26,3 0 (c = 1.0, CHCI3). Rotation: [a] = 26.3 0 (c = 1.0, CHCl 3).
Beispiel 50 Example 50
8-(3-Fluorphenyl)-9-{6-[(2R)-2-{3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo [7] annulen-3-ol
8- (3-fluorophenyl) -9- {6 - [(2R) -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6,7- dihydro-5H-benzo [7] annulen-3-ol
90 mg (0.21 mmol) 9-(6-Bromhexyl)-8-(3-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 80 mg (0.28 mmol) (2R)-2- {3-[(4,4,4-Trifluorbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 93 mg der Titelverbindung erhalten. 90 mg (0.21 mmol) of 9- (6-bromohexyl) -8- (3-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulene-3-ol were mixed with 80 mg (0.28 mmol) (2R). -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 93 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.95 - 1.18 (m, 6H), 1.19 - 1.41 (m, 4H), 1.50 - 1.73 (m, 5H), 1.77 - 2.10 (m, 9H), 2.16 - 2.26 (m, 1H), 2.28 - 2.37 (m, 2H), 2.37 - 2.48 (m, 2H), 2.52 - 2.63 (m, 3H), 2.93 - 3.01 (m, 1H), 3.09 - 3.14 (m, 2H), 3.14 - 3.19 (m, 2H), 6.63 - 6.69 (m, 2H), 7.00 - 7.16 (m, 4H), 7.37 - 7.45 (m, 1H), 9.35 (br. s, 1H). 'H NMR (400MHZ, DMSO-de): δ [ppm] = 0.95-1.18 (m, 6H), 1.19-1.41 (m, 4H), 1.50-1.73 (m, 5H), 1.77-2.10 (m, 9H), 2.16-2.26 (m, 1H), 2.28-2.37 (m, 2H), 2.37-2.48 (m, 2H), 2.52-2.63 (m, 3H), 2.93-3.01 (m, 1H), 3.09 3.14 (m, 2H), 3.14-3.19 (m, 2H), 6.63-6.69 (m, 2H), 7.00-7.16 (m, 4H), 7.37-7.45 (m, 1H), 9.35 (br. S, 1H ).
MS(CI+) [M+H]+ = 624+. MS (CI + ) [M + H] + = 624 + .
Drehwert: [a] = 24,3 ° (c = 1.0, CHC13). Rotation: [a] = 24.3 ° (c = 1.0, CHC1 3 ).
Beispiel 51 Example 51
8-(4-Fluorphenyl)-9-{6-[(2R)-2-{3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- annulen-3-ol 8- (4-fluorophenyl) -9- {6 - [(2R) -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -annulene-3 oil
100 mg (0.23 mmol) 9-(6-Bromhexyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 103 mg (0.34 mmol) (2R)-2- {3-[(3,3,3-Trifluorpropyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 77 mg der Titelverbindung erhalten. 100 mg (0.23 mmol) of 9- (6-bromohexyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were mixed with 103 mg (0.34 mmol) (2R). -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 77 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.95 - 1.18 (m, 6H), 1.18 - 1.41 (m, 4H), 1.54 - 1.77 (m, 5H), 1.78 - 1.87 (m, 1H), 1.87 - 2.08 (m, 6H), 2.17 - 2.26 (m, 1 H), 2.27 - 2.35 (m, 2H), 2.52 - 2.62 (m,
3H), 2.66 - 2.80 (m, 2H), 2.93 - 3.00 (m, 1H), 3.17 - 3.24 (m, 2H), 3.34 - 3.39 (m, 2H), 6.62 - 6.68 (m,'H NMR (400MHZ, DMSO-de): δ [ppm] = 0.95-1.18 (m, 6H), 1.18-1.41 (m, 4H), 1.54-1.7 (m, 5H), 1.78-1.87 (m, 1H), 1.87 - 2.08 (m, 6H), 2.17 - 2.26 (m, 1H), 2.27 - 2.35 (m, 2H), 2.52 - 2.62 (m, 3H), 2.66 - 2.80 (m, 2H), 2.93 - 3.00 (m, 1H), 3.17 - 3.24 (m, 2H), 3.34 - 3.39 (m, 2H), 6.62 - 6.68 (m,
2H), 7.10 - 7.22 (m, 3H), 7.23 - 7.30 (m, 2H), 9.35 (br. s, 1H). 2H), 7.10 - 7.22 (m, 3H), 7.23 - 7.30 (m, 2H), 9.35 (br, s, 1H).
MS (CI+) [M+H]+ = 610+. MS (CI + ) [M + H] + = 610 + .
Drehwert: [a] = 29,1 ° (c = 1.0, CHC13). Rotation: [a] = 29.1 ° (c = 1.0, CHC1 3 ).
Beispiel 52 Example 52
8-(3-Fluorphenyl)-9-{6-[(2R)-2-{3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- len-3-ol 8- (3-fluorophenyl) -9- {6 - [(2R) -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -len-3 oil
106 mg (0.25 mmol) 9-(6-Bromhexyl)-8-(3-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 100 mg (0.33 mmol) (2R)-2- {3-[(3,3,3-Trifluorpropyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 95 mg der Titelverbindung erhalten. 106 mg (0.25 mmol) of 9- (6-bromohexyl) -8- (3-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 100 mg (0.33 mmol) (2R). -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 95 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.97 - 1.19 (m, 6H), 1.20 - 1.42 (m, 4H), 1.54 - 1.76 (m, 5H), 1.81 - 1.91 (m, 1H), 1.94 - 2.1 1 (m, 6H), 2.24 - 2.36 (m, 3H), 2.52 - 2.66 (m, 3H), 2.66 - 2.80 (m, 2H), 2.97 - 3.04 (m, 1H), 3.18 - 3.24 (m, 2H), 3.35 - 3.39 (m, 2H), 6.63 - 6.69 (m, 2H), 7.00 - 7.16 (m, 4H), 7.37 - 7.44 (m, 1H), 9.35 (br. s, 1H). 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.97-1.19 (m, 6H), 1.20-1.42 (m, 4H), 1.54-1.76 (m, 5H), 1.81-1.91 (m, 1H), 1.94 - 2.1 1 (m, 6H), 2.24 - 2.36 (m, 3H), 2.52 - 2.66 (m, 3H), 2.66 - 2.80 (m, 2H), 2.97 - 3.04 (m, 1H), 3.18 - 3.24 (m, 2H), 3.35 - 3.39 (m, 2H), 6.63 - 6.69 (m, 2H), 7.00 - 7.16 (m, 4H), 7.37 - 7.44 (m, 1H), 9.35 (br. S, 1H).
MS (CI+) [M+H]+ = 610+. MS (CI + ) [M + H] + = 610 + .
Drehwert: [a] = 26,2 0 (c = 1.0, CHCI3). Rotation: [a] = 26.2 0 (c = 1.0, CHCI3).
Beispiel 53 Example 53
8-(3,5-Difluorphenyl)-9-{6-[(2R)-2-{3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l- yl] hexyl}-6,7-dihydro-5H-benzo [7] annulen-3-ol
8- (3,5-difluorophenyl) -9- {6 - [(2R) -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -6, 7-dihydro-5H-benzo [7] annulen-3-ol
83 mg (0.19 mmol) 9-(6-Bromhexyl)-8-(3,5-difluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 75 mg (0.24 mmol) (2R)-2- {3-[(3,3,3-Trifluorpropyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 73 mg der Titelverbindung erhalten. 83 mg (0.19 mmol) of 9- (6-bromohexyl) -8- (3,5-difluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 75 mg (0.24 mmol) ( 2R) -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidine according to the general procedure implemented. After preparative HPLC, 73 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.98 - 1.20 (m, 6H), 1.21 - 1.41 (m, 4H), 1.56 - 1.74 (m, 5H), 1.79 - 1.91 (m, 1H), 1.91 - 2.1 1 (m, 6H), 2.20 - 2.29 (m, 1H), 2.29 - 2.36 (m, 2H), 2.53 (d, 3H), 2.66 - 2.79 (m, 2H), 2.95 - 3.02 (m, 1H), 3.21 (td, 2H), 3.35 - 3.39 (m, 2H), 6.63 - 6.69 (m, 2H), 6.90 - 6.98 (m, 2H), 7.09 - 7.17 (m, 2H), 9.40 (br. s, 1H). 'H NMR (400MHZ, DMSO-de): δ [ppm] = 0.98-1.20 (m, 6H), 1.21-1.41 (m, 4H), 1.56-1.74 (m, 5H), 1.79-1.91 (m, 1H), 1.91 - 2.1 1 (m, 6H), 2.20 - 2.29 (m, 1H), 2.29 - 2.36 (m, 2H), 2.53 (d, 3H), 2.66 - 2.79 (m, 2H), 2.95 - 3.02 (m, 1H), 3.21 (td, 2H), 3.35-3.39 (m, 2H), 6.63-6.69 (m, 2H), 6.90-6.98 (m, 2H), 7.09-7.17 (m, 2H), 9.40 (brs s, 1H).
MS (CI+) [M+H]+ = 628+. MS (CI + ) [M + H] + = 628 + .
Drehwert: [a] = 26 ° (c = 1.0, CHC13). Rotation: [a] = 26 ° (c = 1.0, CHC1 3 ).
Beispiel 54 Example 54
8-(4-Fluorphenyl)-9-{6-[(2S)-2-{3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- ulen-3-ol 8- (4-fluorophenyl) -9- {6 - [(2S) -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -ulen-3-yl oil
100 mg (0.24 mmol) 9-(6-bromohexyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 99 mg (0.31 mmol) (2S)-2- {3-[(4,4,4-Trifluorbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 95 mg der Titelverbindung erhalten. 100 mg (0.24 mmol) of 9- (6-bromohexyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 99 mg (0.31 mmol) (2S). -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 95 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.95 - 1.18 (m, 6H), 1.18 - 1.43 (m, 4H), 1.53 - 1.72 (m, 5H), 1.80 - 1.94 (m, 3H), 1.94 - 2.10 (m, 6H), 2.25 - 2.35 (m, 3H), 2.36 - 2.47 (m, 2H), 2.52 - 2.69 (m,
3H), 2.97 - 3.04 (m, 1H), 3.10 - 3.19 (m, 4H), 6.62 - 6.69 (m, 2H), 7.10 - 7.22 (m, 3H), 7.23 - 7.30 (m,'H NMR (400MHZ, DMSO-de): δ [ppm] = 0.95-1.18 (m, 6H), 1.18-1.43 (m, 4H), 1.53-1.72 (m, 5H), 1.80-1.94 (m, 3H), 1.94 - 2.10 (m, 6H), 2.25 - 2.35 (m, 3H), 2.36 - 2.47 (m, 2H), 2.52 - 2.69 (m, 3H), 2.97-3.04 (m, 1H), 3.10-3.19 (m, 4H), 6.62-6.69 (m, 2H), 7.10-2.22 (m, 3H), 7.23-7.30 (m,
2H), 9.34 (br. s, 1H). 2H), 9.34 (brs s, 1H).
MS (CI+) [M+H]+ = 624+. MS (CI + ) [M + H] + = 624 + .
Drehwert: [a] = - 25,4 ° (c = 1.08, CHC13). Rotation: [a] = - 25.4 ° (c = 1.08, CHC1 3 ).
Beispiel 55 Example 55
8-(4-Fluorphenyl)-9-{6-[(2S)-2-{3-[(5,5,5-trifluorpentyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo [7] annulen-3-ol 8- (4-fluorophenyl) -9- {6 - [(2S) -2- {3 - [(5,5,5-trifluoropentyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6,7- dihydro-5H-benzo [7] annulen-3-ol
100 mg (0.24 mmol) 9-(6-Bromhexyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 104 mg (0.31 mmol) (2S)-2- {3-[(5,5,5-Trifluorpentyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 85 mg der Titelverbindung erhalten. 100 mg (0.24 mmol) of 9- (6-bromohexyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were mixed with 104 mg (0.31 mmol) (2S). -2- {3 - [(5,5,5-trifluoropentyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 85 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.96 - 1.17 (m, 6H), 1.20 - 1.42 (m, 4H), 1.53 - 1.79 (m, 10H), 1.80 - 1.91 (m, 1H), 2.00 (dd, 6H), 2.23 - 2.37 (m, 5H), 2.52 - 2.66 (m, 3H), 2.97 - 3.02 (m, 1H), 3.03 - 3.08 (m, 2H), 3.09 - 3.14 (m, 2H), 6.62 - 6.68 (m, 2H), 7.13 (d, 1H), 7.15 - 7.22 (m, 2H), 7.23 - 7.30 (m, 2H), 9.36 (br. s, 1H). 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.96-1.17 (m, 6H), 1.20-1.42 (m, 4H), 1.53-1.79 (m, 10H), 1.80-1.91 (m, 1H), 2.00 (dd, 6H), 2.23 - 2.37 (m, 5H), 2.52 - 2.66 (m, 3H), 2.97 - 3.02 (m, 1H), 3.03 - 3.08 (m, 2H), 3.09 - 3.14 ( m, 2H), 6.62 - 6.68 (m, 2H), 7.13 (d, 1H), 7.15 - 7.22 (m, 2H), 7.23 - 7.30 (m, 2H), 9.36 (br, s, 1H).
MS (CI+) [M+H]+ = 638+. MS (CI + ) [M + H] + = 638 + .
Drehwert: [a] = - 28,8 0 (c = 1.0, CHCI3). Rotation: [a] = - 28.8 0 (c = 1.0, CHCI3).
Beispiel 56 Example 56
9-{6-[(2S)-2-{3-[(3,3-Dimethylbutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-8-(4-fluorphenyl)-6,7- dihydro-5H-benzo [7] annulen-3-ol
9- {6 - [(2S) -2- {3 - [(3,3-dimethylbutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -8- (4-fluorophenyl) -6,7-dihydro- 5H-benzo [7] annulen-3-ol
100 mg (0.24 mmol) 9-(6-Bromhexyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 90 mg (0.31 mmol) (2S)-2- {3-[(3,3-Dimethylbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 55 mg der Titelverbindung erhalten. 100 mg (0.24 mmol) of 9- (6-bromohexyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were mixed with 90 mg (0.31 mmol) (2S). -2- {3 - [(3,3-dimethylbutyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 55 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.88 (s, 9H), 0.97 - 1.17 (m, 6H), 1.18 - 1.40 (m, 4H), 1.50 - 1.71 (m, 7H), 1.77 - 1.87 (m, 1 H), 1.87 - 2.08 (m, 6H), 2.16 - 2.26 (m, 1H), 2.27 - 2.35 (m, 2H), 2.53 (d, 3H), 2.95 - 3.03 (m, 3H), 3.08 (t, 2H), 6.62 - 6.68 (m, 2H), 7.13 (d, 1H), 7.15 - 7.22 (m, 2H), 7.23 - 7.29 (m, 2H), 9.34 (br. s, 1H). 'H NMR (400MHZ, DMSO-de): δ [ppm] = 0.88 (s, 9H), 0.97-1.17 (m, 6H), 1.18-1.40 (m, 4H), 1.50-1.71 (m, 7H) , 1.77 - 1.87 (m, 1H), 1.87 - 2.08 (m, 6H), 2.16 - 2.26 (m, 1H), 2.27 - 2.35 (m, 2H), 2.53 (d, 3H), 2.95 - 3.03 (m , 3H), 3.08 (t, 2H), 6.62 - 6.68 (m, 2H), 7.13 (d, 1H), 7.15 - 7.22 (m, 2H), 7.23 - 7.29 (m, 2H), 9.34 (see p , 1H).
MS (CI+) [M+H]+ = 598+. MS (CI + ) [M + H] + = 598 + .
Drehwert: [a] = - 31,7 ° (c = 1.0, CHC13). Rotation: [a] = - 31.7 ° (c = 1.0, CHC1 3 ).
Beispiel 57 Example 57
8-(4-Fluorphenyl)-9-{6-[(2S)-2-{3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- annulen-3-ol 8- (4-fluorophenyl) -9- {6 - [(2S) -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -annulene-3 oil
100 mg (0.21 mmol) 9-(6-Bromhexyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 94 mg (0.28 mmol) (2S)-2- {3-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 94 mg der Titelverbindung erhalten. 100 mg (0.21 mmol) of 9- (6-bromohexyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulene-3-ol were treated with 94 mg (0.28 mmol) (2S). -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 94 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.96 - 1.18 (m, 6H), 1.19 - 1.42 (m, 4H), 1.54 - 1.75 (m, 5H), 1.80 - 1.91 (m, 1H), 1.92 - 2.09 (m, 6H), 2.22 - 2.35 (m, 3H), 2.52 - 2.64 (m, 3H), 2.67 - 2.80 (m,
2H), 2.96 - 3.03 (m, 1H), 3.18 - 3.25 (m, 2H), 3.35 - 3.39 (m, 2H), 6.62 - 6.68 (m, 2H), 7.13 (d, 1H),'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.96-1.18 (m, 6H), 1.19-1.42 (m, 4H), 1.54-1.75 (m, 5H), 1.80-1.91 (m, 1H), 1.92 - 2.09 (m, 6H), 2.22 - 2.35 (m, 3H), 2.52 - 2.64 (m, 3H), 2.67 - 2.80 (m, 2H), 2.96 - 3.03 (m, 1H), 3.18 - 3.25 (m, 2H), 3.35 - 3.39 (m, 2H), 6.62 - 6.68 (m, 2H), 7.13 (d, 1H),
7.15 - 7.22 (m, 2H), 7.23 - 7.29 (m, 2H), 9.35 (br. s, 1H). 7.15 - 7.22 (m, 2H), 7.23 - 7.29 (m, 2H), 9.35 (br, s, 1H).
MS (CI+) [M+H]+ = 610+. MS (CI + ) [M + H] + = 610 + .
Drehwert: [a] = - 27,2 ° (c = 1.0, CHC13). Rotation: [a] = - 27.2 ° (c = 1.0, CHC1 3 ).
Beispiel 58 Example 58
8-(3-Fluorphenyl)-9-{6-[(2S)-2-{3-[(5,5,5-trifluorpentyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo [7] annulen-3-ol 8- (3-fluorophenyl) -9- {6 - [(2S) -2- {3 - [(5,5,5-trifluoropentyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6,7- dihydro-5H-benzo [7] annulen-3-ol
90 mg (0.24 mmol) 9-(6-Bromhexyl)-8-(3-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 95 mg (0.31 mmol) (2S)-2- {3-[(3,3,3-Trifluorpropyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 85 mg der Titelverbindung erhalten. 90 mg (0.24 mmol) of 9- (6-bromohexyl) -8- (3-hydroxyphenyl) -6,7-dihydro-5H-benzo [7] annulene-3-ol were treated with 95 mg (0.31 mmol) (2S). -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 85 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.97 - 1.19 (m, 6H), 1.19 - 1.43 (m, 4H), 1.52 - 1.69 (m, 7H), 1.69 - 1.89 (m, 3H), 1.90 - 2.10 (m, 6H), 2.19 - 2.38 (m, 5H), 2.53 - 2.64 (m, 3H), 2.95 - 3.02 (m, 1H), 3.02 - 3.08 (m, 2H), 3.09 - 3.14 (m, 2H), 6.62 - 6.71 (m, 2H), 6.98 - 7.17 (m, 4H), 7.35 - 7.45 (m, 1H), 9.41 (br. s, 1H). 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.97-1.19 (m, 6H), 1.19-1.43 (m, 4H), 1.52-1.69 (m, 7H), 1.69-1.89 (m, 3H), 1.90 - 2.10 (m, 6H), 2.19 - 2.38 (m, 5H), 2.53 - 2.64 (m, 3H), 2.95 - 3.02 (m, 1H), 3.02 - 3.08 (m, 2H), 3.09 - 3.14 (m, 2H), 6.62-6.71 (m, 2H), 6.98-7.17 (m, 4H), 7.35-7.45 (m, 1H), 9.41 (br, s, 1H).
MS (CI+) [M+H]+ = 638+. MS (CI + ) [M + H] + = 638 + .
Drehwert: [a] = - 23,6 0 (c = 1.0, CHCI3). Rotation: [a] = - 23.6 0 (c = 1.0, CHCI3).
Beispiel 59 Example 59
9-{6-[(2S)-2-{3-[(3,3-Dimethylbutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-8-(3-fluorphenyl)-6,7- dihydro-5H-benzo [7] annulen-3-ol
9- {6 - [(2S) -2- {3 - [(3,3-dimethylbutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -8- (3-fluorophenyl) -6,7-dihydro- 5H-benzo [7] annulen-3-ol
100 mg (0.24 mmol) 9-(6-Bromhexyl)-8-(3-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 153 mg (0.52 mmol) (2S)-2- {3-[(3,3-Dimethylbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 77 mg der Titelverbindung erhalten. 100 mg (0.24 mmol) of 9- (6-bromohexyl) -8- (3-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 153 mg (0.52 mmol) (2S). -2- {3 - [(3,3-dimethylbutyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 77 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.88 (s, 9H), 1.09 (d, 6H), 1.18 - 1.39 (m, 4H), 1.50 - 1.68 (m, 7H), 1.77 - 2.06 (m, 7H), 2.19 (d, 1 H), 2.27 - 2.36 (m, 2H), 2.52 - 2.61 (m, 3H), 2.95 - 3.02 (m, 3H), 3.05 - 3.1 1 (m, 2H), 6.62 - 6.70 (m, 2H), 7.00 - 7.17 (m, 4H), 7.35 - 7.47 (m, 1H), 9.38 (br. s, 1H). 'H NMR (400MHZ, DMSO-de): δ [ppm] = 0.88 (s, 9H), 1.09 (d, 6H), 1.18-1.39 (m, 4H), 1.50- 1.68 (m, 7H), 1.77 - 2.06 (m, 7H), 2.19 (d, 1H), 2.27 - 2.36 (m, 2H), 2.52 - 2.61 (m, 3H), 2.95 - 3.02 (m, 3H), 3.05 - 3.1 1 (m, 2H), 6.62-6.70 (m, 2H), 7.00-7.17 (m, 4H), 7.35-7.47 (m, 1H), 9.38 (br, s, 1H).
MS (CI+) [M+H]+ = 598+. MS (CI + ) [M + H] + = 598 + .
Drehwert: [a] = - 28,8 ° (c = 1.0, CHC13). Rotation: [a] = - 28.8 ° (c = 1.0, CHC1 3 ).
Beispiel 60 Example 60
8-(2,4-Difluorphenyl)-9-{6-[(2S)-2-{3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- [7] annulen-3-ol 8- (2,4-Difluorophenyl) -9- {6 - [(2S) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidine-1- [7] annulene-3-ol
100 mg (0.21 mmol) 9-(6-Bromhexyl)-8-(2,4-difluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 116 mg (0.32 mmol) (2S)-2- {3-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 96 mg der Titelverbindung erhalten. 100 mg (0.21 mmol) of 9- (6-bromohexyl) -8- (2,4-difluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 116 mg (0.32 mmol) ( 2S) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidine according to the general procedure implemented. After preparative HPLC, 96 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 1.05 (br. s, 6H), 1.16 - 1.42 (m, 4H), 1.50 - 1.74 (m, 5H), 1.76 - 2.10 (m, 9H), 2.21 (d, 3H), 2.31 - 2.45 (m, 2H), 2.56 (t, 3H), 2.93 - 3.00 (m, 1H), 3.09 - 3.14
(m, 2H), 3.17 - 3.23 (m, 2H), 6.61 - 6.71 (m, 2H), 7.05 - 7.18 (m, 2H), 7.20 - 7.36 (m, 2H), 9.40 (br. s, 1H). 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 1.05 (br, s, 6H), 1.16 - 1.42 (m, 4H), 1.50 - 1.74 (m, 5H), 1.76 - 2.10 (m, 9H), 2.21 (d, 3H), 2.31-2.45 (m, 2H), 2.56 (t, 3H), 2.93-3.00 (m, 1H), 3.09-3.14 (m, 2H), 3.17-3.23 (m, 2H), 6.61-6.71 (m, 2H), 7.05-7.18 (m, 2H), 7.20-7.36 (m, 2H), 9.40 (br s, 1H) ,
MS (CI+) [M+H]+ = 692+. MS (CI + ) [M + H] + = 692 + .
Drehwert: [a] = - 25,4 ° (c = 1.0, CHC13). Rotation: [a] = - 25.4 ° (c = 1.0, CHC1 3 ).
Beispiel 61 Example 61
8-(2,4-Difluorphenyl)-9-{6-[(2S)-2-{3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- nzo [7] annulen-3-ol 8- (2,4-Difluorophenyl) -9- {6 - [(2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidinolino [7 ] annulen-3-ol
100 mg (0.21 mmol) 9-(6-Bromhexyl)-8-(2,4-difluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 111 mg (0.32 mmol) (2S)-2- {3-[(3,3,4,4,4-Pentafluorbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 86 mg der Titelverbindung erhalten. 100 mg (0.21 mmol) of 9- (6-bromohexyl) -8- (2,4-difluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were mixed with 111 mg (0.32 mmol) ( 2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidine according to the general procedure implemented. After preparative HPLC, 86 mg of the title compound were obtained.
'H-NMR (400MHz, DMSO-de): δ [ppm]= 0.95 - 1.16 (m, 6H), 1.18 - 1.42 (m, 4H), 1.56 - 1.75 (m, 5H), 1.77 - 2.12 (m, 8H), 2.15 - 2.30 (m, 3H), 2.54 - 2.70 (m, 4H), 2.94 - 3.02 (m, 1H), 3.22 - 3.27 (m, 2H), 3.38 - 3.43 (m, 2H), 6.63 - 6.72 (m, 2H), 7.05 - 7.18 (m, 2H), 7.20 - 7.34 (m, 2H), 9.42 (br. s, 1H). 'H NMR (400MHz, DMSO-de): δ [ppm] = 0.95-1.16 (m, 6H), 1.18-1.42 (m, 4H), 1.56-1.75 (m, 5H), 1.77-2.12 (m, 8H), 2.15 - 2.30 (m, 3H), 2.54 - 2.70 (m, 4H), 2.94 - 3.02 (m, 1H), 3.22 - 3.27 (m, 2H), 3.38 - 3.43 (m, 2H), 6.63 - 6.72 (m, 2H), 7.05-7.18 (m, 2H), 7.20-7.34 (m, 2H), 9.42 (br, s, 1H).
MS (CI+) [M+H]+ = 678+. MS (CI + ) [M + H] + = 678 + .
Drehwert: [a] = - 23,4 0 (c = 1.0, CHCI3). Rotation: [a] = - 23,4 0 (c = 1.0, CHCI3).
Beispiel 62 Example 62
8-(2,4-Difluorphenyl)-9-{6-[(2S)-2-{3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl] hexyl}-6,7-dihydro-5H-benzo [7] annulen-3-ol
8- (2,4-Difluorophenyl) -9- {6 - [(2S) -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -6, 7-dihydro-5H-benzo [7] annulen-3-ol
100 mg (0.21 mmol) 9-(6-Bromhexyl)-8-(2,4-difluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 99 mg (0.32 mmol) (2S)-2- {3-[(4,4,4-Trifluorbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 91 mg der Titelverbindung erhalten. 100 mg (0.21 mmol) of 9- (6-bromo-hexyl) -8- (2,4-difluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 99 mg (0.32 mmol) ( 2S) -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidine according to the general procedure implemented. After preparative HPLC, 91 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.94 - 1.15 (m, 6H), 1.18 - 1.41 (m, 4H), 1.53 - 1.72 (m, 5H), 1.79 - 1.97 (m, 6H), 1.97 - 2.10 (m, 3H), 2.17 - 2.28 (m, 3H), 2.37 - 2.47 (m, 2H), 2.54 - 2.61 (m, 3H), 2.94 - 3.01 (m, 1H), 3.09 - 3.14 (m, 2H), 3.15 - 3.19 (m, 2H), 6.63 - 6.69 (m, 2H), 7.05 - 7.17 (m, 2H), 7.21 - 7.36 (m, 2H), 9.49 (br. s, 1H). 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.94-1.15 (m, 6H), 1.18-1.41 (m, 4H), 1.53-1.72 (m, 5H), 1.79-1.97 (m, 6H), 1.97 - 2.10 (m, 3H), 2.17 - 2.28 (m, 3H), 2.37 - 2.47 (m, 2H), 2.54 - 2.61 (m, 3H), 2.94 - 3.01 (m, 1H), 3.09 - 3.14 (m, 2H), 3.15-3.19 (m, 2H), 6.63-6.69 (m, 2H), 7.05-7.17 (m, 2H), 7.21-7.36 (m, 2H), 9.49 (br. S, 1H ).
MS (CI+) [M+H]+ = 642+. MS (CI +) [M + H] + = 642 +.
Drehwert: [a] = - 24,8 ° (c = 1.0, CHC13). Rotation: [a] = - 24.8 ° (c = 1.0, CHC1 3).
Beispiel 63 Example 63
8-(2,4-Difluorphenyl)-9-{6-[(2S)-2-{3-[(5,5,5-trifluorpentyl)sulfonyl]propyl}pyrrolidin-l- yl] hexyl}-6,7-dihydro-5H-benzo [7] annulen-3-ol 8- (2,4-Difluorophenyl) -9- {6 - [(2S) -2- {3 - [(5,5,5-trifluoropentyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -6, 7-dihydro-5H-benzo [7] annulen-3-ol
100 mg (0.22 mmol) 9-(6-Bromhexyl)-8-(2,4-difluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 109 mg (0.32 mmol) (2S)-2- {3-[(5,5,5-Trifluorpentyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 100 mg der Titelverbindung erhalten. 100 mg (0.22 mmol) of 9- (6-bromohexyl) -8- (2,4-difluorophenyl) -6,7-dihydro-5H-benzo [7] annulene-3-ol were mixed with 109 mg (0.32 mmol) ( 2S) -2- {3 - [(5,5,5-trifluoropentyl) sulfonyl] propyl} pyrrolidine according to the general procedure implemented. After preparative HPLC, 100 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.94 - 1.15 (m, 6H), 1.17 - 1.41 (m, 4H), 1.54 - 1.88 (m, 10H), 1.89 - 2.09 (m, 6H), 2.17 - 2.35 (m, 5H), 2.54 - 2.63 (m, 3H), 2.95 - 3.01 (m, 1H), 3.03 - 3.08
(m, 2H), 3.09 - 3.14 (m, 2H), 6.63 - 6.70 (m, 2H), 7.05 - 7.17 (m, 2H), 7.21 - 7.35 (m, 2H), 9.45 (br. s, 1H). 'H NMR (400MHZ, DMSO-de): δ [ppm] = 0.94-1.15 (m, 6H), 1.17-1.41 (m, 4H), 1.54-1.88 (m, 10H), 1.89-2.09 (m, 6H), 2.17-2.35 (m, 5H), 2.54-2.63 (m, 3H), 2.95-3.01 (m, 1H), 3.03- 3.08 (m, 2H), 3.09-3.14 (m, 2H), 6.63-6.70 (m, 2H), 7.05-7.17 (m, 2H), 7.21-7.35 (m, 2H), 9.45 (br, s, 1H) ,
MS (CI+) [M+H]+ = 656+. MS (CI + ) [M + H] + = 656 + .
Drehwert: [a] = - 25,6 ° (c = 1.0, CHC13). Rotation: [a] = - 25.6 ° (c = 1.0, CHC1 3 ).
Beispiel 64 Example 64
8-(3-Fluorphenyl)-9-{6-[(2S)-2-{3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- -dihydro-5H-benzo [7] annulen-3-ol 8- (3-fluorophenyl) -9- {6 - [(2S) -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -dihydro-5H benzo [7] annulen-3-ol
100 mg (0.24 mmol) 9-(6-Bromhexyl)-8-(3-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 1 14 mg (0.36 mmol) (2S)-2- {3-[(4,4,4-Trifluorbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 92 mg der Titelverbindung erhalten. 100 mg (0.24 mmol) of 9- (6-bromohexyl) -8- (3-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 14 mg (0.36 mmol) (2S ) -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidine according to the general procedure implemented. After preparative HPLC, 92 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.96 - 1.18 (m, 6H), 1.19 - 1.42 (m, 4H), 1.53 - 1.72 (m, 5H), 1.81 - 2.08 (m, 9H), 2.24 (d, 1H), 2.28 - 2.35 (m, 2H), 2.38 - 2.47 (m, 2H), 2.53 - 2.64 (m, 3H), 2.95 - 3.02 (m, 1H), 3.08 - 3.14 (m, 2H), 3.14 - 3.20 (m, 2H), 6.62 - 6.69 (m, 2H), 6.99 - 7.17 (m, 4H), 7.36 - 7.45 (m, 1H), 9.30 (br. s, 1H). 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.96-1.18 (m, 6H), 1.19-1.42 (m, 4H), 1.53-1.72 (m, 5H), 1.81-0.208 (m, 9H), 2.24 (d, 1H), 2.28 - 2.35 (m, 2H), 2.38 - 2.47 (m, 2H), 2.53 - 2.64 (m, 3H), 2.95 - 3.02 (m, 1H), 3.08 - 3.14 ( m, 2H), 3.14-3.20 (m, 2H), 6.62-6.69 (m, 2H), 6.99-7.17 (m, 4H), 7.36-7.45 (m, 1H), 9.30 (br, s, 1H).
MS (CI+) [M+H]+ = 624+. MS (CI + ) [M + H] + = 624 + .
Drehwert: [a] = - 25,9 0 (c = 1.0, CHCI3). Rotation: [a] = - 25.9 0 (c = 1.0, CHCI3).
Beispiel 65 Example 65
8-(2-Fluorphenyl)-9-{6-[(2S)-2-{3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo [7] annulen-3-ol
8- (2-fluorophenyl) -9- {6 - [(2S) -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - 6,7- dihydro-5H-benzo [7] annulen-3-ol
80 mg (0.18 mmol) 9-(6-Bromhexyl)-8-(2-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 78 mg (0.27 mmol) (2S)-2- {3-[(3,3,3-Trifluorpropyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 73 mg der Titelverbindung erhalten. 80 mg (0.18 mmol) of 9- (6-bromohexyl) -8- (2-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 78 mg (0.27 mmol) (2S). -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 73 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.92 - 1.16 (m, 6H), 1.17 - 1.41 (m, 4H), 1.53 - 1.74 (m, 5H), 1.78 - 1.88 (m, 1H), 1.88 - 2.00 (m, 4H), 2.00 - 2.10 (m, 1 H), 2.17 - 2.28 (m, 2H), 2.53 - 2.62 (m, 3H), 2.66 - 2.80 (m, 2H), 2.94 - 2.99 (m, 1H), 3.18 - 3.24 (m, 2H), 3.34 - 3.39 (m, 2H), 6.62 - 6.70 (m, 2H), 7.14 (d, 1H), 7.17 - 7.29 (m, 3H), 7.29 - 7.37 (m, 1H), 9.36 (br. s, 1H). 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.92-1.16 (m, 6H), 1.17-1.41 (m, 4H), 1.53-1.74 (m, 5H), 1.78-1.88 (m, 1H), 1.88 - 2.00 (m, 4H), 2.00 - 2.10 (m, 1H), 2.17 - 2.28 (m, 2H), 2.53 - 2.62 (m, 3H), 2.66 - 2.80 (m, 2H), 2.94 - 2.99 (m, 1H), 3.18 - 3.24 (m, 2H), 3.34 - 3.39 (m, 2H), 6.62 - 6.70 (m, 2H), 7.14 (d, 1H), 7.17 - 7.29 (m, 3H) , 7.29 - 7.37 (m, 1H), 9.36 (br, s, 1H).
MS (CI+) [M+H]+ = 610+. MS (CI + ) [M + H] + = 610 + .
Drehwert: [a] = - 26,8 ° (c = 1.0, CHC13). Rotation: [a] = - 26.8 ° (c = 1.0, CHC1 3 ).
Beispiel 66 Example 66
8-(2,4-Difluorphenyl)-9-{6-[(2R)-2-{3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- [7] annulen-3-ol 8- (2,4-Difluorophenyl) -9- {6 - [(2R) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidine-1- [7] annulene-3-ol
100 mg (0.23 mmol) 9-(6-Bromhexyl)-8-(2,4-difluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 116 mg (0.33 mmol) (2R)-2- {3-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 99 mg der Titelverbindung erhalten. 100 mg (0.23 mmol) of 9- (6-bromohexyl) -8- (2,4-difluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 116 mg (0.33 mmol) ( 2R) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidine according to the general procedure implemented. After preparative HPLC, 99 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.93 - 1.15 (m, 6H), 1.16 - 1.41 (m, 4H), 1.52 - 1.73 (m, 5H), 1.77 - 1.86 (m, 1H), 1.87 - 1.99 (m, 6H), 1.99 - 2.1 1 (m, 2H), 2.21 (d, 3H), 2.32 - 2.47 (m, 2H),
2.56 (t, 3H), 2.93 - 3.00 (m, 1H), 3.09 - 3.14 (m, 2H), 3.17 - 3.23 (m, 2H), 6.62 - 6.70 (m, 2H), 7.05 -'H NMR (400MHZ, DMSO-de): δ [ppm] = 0.93-1.15 (m, 6H), 1.16-1.41 (m, 4H), 1.52-1.73 (m, 5H), 1.77-1.86 (m, 1H), 1.87 - 1.99 (m, 6H), 1.99 - 2.1 1 (m, 2H), 2.21 (d, 3H), 2.32 - 2.47 (m, 2H), 2.56 (t, 3H), 2.93 - 3.00 (m, 1H), 3.09 - 3.14 (m, 2H), 3.17 - 3.23 (m, 2H), 6.62 - 6.70 (m, 2H), 7.05 -
7.17 (m, 2H), 7.21 - 7.35 (m, 2H), 9.42 (br. s, 1H). 7.17 (m, 2H), 7.21-7.35 (m, 2H), 9.42 (br, s, 1H).
MS (CI+) [M+H]+ = 692+. MS (CI + ) [M + H] + = 692 + .
Drehwert: [a] = 25,2 ° (c = 1.0, CHC13). Rotation: [a] = 25.2 ° (c = 1.0, CHC1 3 ).
Beispiel 67 Example 67
8-(2,4-Difluorphenyl)-9-{6-[(2R)-2-{3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- nzo [7] annulen-3-ol 8- (2,4-Difluorophenyl) -9- {6 - [(2R) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidinolino [7 ] annulen-3-ol
90 mg (0.21 mmol) 9-(6-Bromhexyl)-8-(2,4-difluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 105.8 mg (0.33 mmol) (2R)-2- {3-[(3,3,4,4,4-Pentafluorbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 73 mg der Titelverbindung erhalten. 90 mg (0.21 mmol) of 9- (6-bromohexyl) -8- (2,4-difluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 105.8 mg (0.33 mmol) ( 2R) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidine according to the general procedure implemented. After preparative HPLC, 73 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.94 - 1.15 (m, 6H), 1.16 - 1.40 (m, 4H), 1.53 - 1.76 (m, 5H), 1.77 - 1.98 (m, 5H), 1.99 - 2.10 (m, 2H), 2.15 - 2.28 (m, 3H), 2.53 - 2.74 (m, 5H), 2.93 - 2.99 (m, 1H), 3.22 - 3.27 (m, 2H), 3.37 - 3.44 (m, 2H), 6.62 - 6.70 (m, 2H), 7.05 - 7.16 (m, 2H), 7.22 - 7.35 (m, 2H), 9.42 (br. s, 1H). 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.94-1.15 (m, 6H), 1.16-1.40 (m, 4H), 1.53-1.76 (m, 5H), 1.77-1.98 (m, 5H), 1.99 - 2.10 (m, 2H), 2.15 - 2.28 (m, 3H), 2.53 - 2.74 (m, 5H), 2.93 - 2.99 (m, 1H), 3.22 - 3.27 (m, 2H), 3.37 - 3.44 (m, 2H), 6.62-6.70 (m, 2H), 7.05-7.16 (m, 2H), 7.22-7.35 (m, 2H), 9.42 (br, s, 1H).
MS (CI+) [M+H]+ = 678+. MS (CI + ) [M + H] + = 678 + .
Drehwert: [a] = 24,9 0 (c = 1.0, CHCI3). Rotation: [a] = 24.9 0 (c = 1.0, CHCI3).
Beispiel 68 Example 68
8-(2,4-Difluorphenyl)-9-{6-[(2R)-2-{3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l- yl] hexyl}-6,7-dihydro-5H-benzo [7] annulen-3-ol
8- (2,4-Difluorophenyl) -9- {6 - [(2R) -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} -6, 7-dihydro-5H-benzo [7] annulen-3-ol
100 mg (0.23 mmol) 9-(6-Bromhexyl)-8-(2,4-difluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 99 mg (0.32 mmol) (2R)-2- {3-[(3,3,3-Trifluorpropyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 87 mg der Titelverbindung erhalten. 100 mg (0.23 mmol) of 9- (6-bromohexyl) -8- (2,4-difluorophenyl) -6,7-dihydro-5H-benzo [7] annulene-3-ol were treated with 99 mg (0.32 mmol) ( 2R) -2- {3 - [(3,3,3-trifluoropropyl) sulfonyl] propyl} pyrrolidine according to the general procedure implemented. After preparative HPLC, 87 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.94 - 1.16 (m, 6H), 1.18 - 1.40 (m, 4H), 1.53 - 1.74 (m, 5H), 1.79 - 1.87 (m, 1H), 1.88 - 2.10 (m, 6H), 2.17 - 2.28 (m, 3H), 2.54 - 2.62 (m, 3H), 2.66 - 2.80 (m, 2H), 2.94 - 3.00 (m, 1H), 3.18 - 3.24 (m, 2H), 3.34 - 3.40 (m, 2H), 6.63 - 6.70 (m, 2H), 7.05 - 7.17 (m, 2H), 7.21 - 7.35 (m, 2H), 9.52 (br. s, 1H). 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.94-1.16 (m, 6H), 1.18-1.40 (m, 4H), 1.53-1.74 (m, 5H), 1.79-1.87 (m, 1H), 1.88 - 2.10 (m, 6H), 2.17 - 2.28 (m, 3H), 2.54 - 2.62 (m, 3H), 2.66 - 2.80 (m, 2H), 2.94 - 3.00 (m, 1H), 3.18 - 3.24 (m, 2H), 3.34-3.40 (m, 2H), 6.63-6.70 (m, 2H), 7.05-7.17 (m, 2H), 7.21-7.35 (m, 2H), 9.52 (br. S, 1H ).
MS (CI+) [M+H]+ = 628+. MS (CI + ) [M + H] + = 628 + .
Drehwert: [a] = 26,5 ° (c = 1.0, CHC13). Rotation: [a] = 26.5 ° (c = 1.0, CHC1 3 ).
Beispiel 69 Example 69
8-(2,4-Difluorphenyl)-9-{6-[(2S)-2-{3-[(3,3-dimethylbutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- -dihydro-5H-benzo [7] annulen-3-ol 8- (2,4-Difluorophenyl) -9- {6 - [(2S) -2- {3 - [(3,3-dimethylbutyl) sulfonyl] propyl} pyrrolidin-1-yl] hexyl} - dihydro-5H benzo [7] annulen-3-ol
100 mg (0.23 mmol) 9-(6-Bromhexyl)-8-(2,4-difluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 82 mg (0.28 mmol) (2S)-2- {3-[(3,3-Dimethylbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 59 mg der Titelverbindung erhalten. 100 mg (0.23 mmol) of 9- (6-bromohexyl) -8- (2,4-difluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 82 mg (0.28 mmol) ( 2S) -2- {3 - [(3,3-dimethylbutyl) sulfonyl] propyl} pyrrolidine according to the general procedure implemented. After preparative HPLC, 59 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.88 (s, 9H), 0.93 - 1.15 (m, 6H), 1.16 - 1.40 (m, 4H), 1.50 - 1.73 (m, 7H), 1.75 - 1.98 (m, 5H), 1.99 - 2.10 (m, 2H), 2.14 - 2.27 (m, 3H), 2.53 - 2.61 (m, 3H), 2.91
- 3.03 (m, 3H), 3.04 - 3.12 (m, 2H), 6.63 - 6.70 (m, 2H), 7.05 - 7.17 (m, 2H), 7.21 - 7.35 (m, 2H), 9.41 (br. s, 1H). 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.88 (s, 9H), 0.93-1.15 (m, 6H), 1.16-1.40 (m, 4H), 1.50-1.73 (m, 7H) , 1.75 - 1.98 (m, 5H), 1.99 - 2.10 (m, 2H), 2.14 - 2.27 (m, 3H), 2.53 - 2.61 (m, 3H), 2.91 3.03 (m, 3H), 3.04-3.12 (m, 2H), 6.63-6.70 (m, 2H), 7.05-7.17 (m, 2H), 7.21-7.35 (m, 2H), 9.41 (br. S, 1H).
MS (CI+) [M+H]+ = 616+. MS (CI + ) [M + H] + = 616 + .
Drehwert: [a] = - 30,3 ° (c = 1.0, CHC13). Rotation: [a] = - 30.3 ° (c = 1.0, CHC1 3 ).
Beispiel 70 Example 70
8-(2,4-Difluorphenyl)-9-{6-[(2R)-2-{3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-l- o [7] annulen-3-ol 8- (2,4-Difluorophenyl) -9- {6 - [(2R) -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin-1-o [7] annulene-3 -oil
100 mg (0.23 mmol) 9-(6-Bromhexyl)-8-(2,4-difluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 99 mg (0.32 mmol) (2R)-2- {3-[(4,4,4-Trifluorbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 95 mg der Titelverbindung erhalten. 100 mg (0.23 mmol) of 9- (6-bromohexyl) -8- (2,4-difluorophenyl) -6,7-dihydro-5H-benzo [7] annulene-3-ol were treated with 99 mg (0.32 mmol) ( 2R) -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidine according to the general procedure implemented. After preparative HPLC, 95 mg of the title compound were obtained.
'H-NMR (400MHz, DMSO-de): δ [ppm]= 0.93 - 1.16 (m, 6H), 1.16 - 1.41 (m, 4H), 1.52 - 1.72 (m, 5H), 1.78 - 2.09 (m, 9H), 2.22 (t, 3H), 2.35 - 2.48 (m, 2H), 2.53 - 2.62 (m, 3H), 2.94 - 3.01 (m, 1H), 3.08 - 3.14 (m, 2H), 3.14 - 3.20 (m, 2H), 6.63 - 6.70 (m, 2H), 7.05 - 7.18 (m, 2H), 7.22 - 7.35 (m, 2H), 9.44 (br. s, 1H). 'H-NMR (400MHz, DMSO-de): δ [ppm] = 0.93-1.16 (m, 6H), 1.16-1.41 (m, 4H), 1.52-1.72 (m, 5H), 1.78-2.09 (m, 9H), 2.22 (t, 3H), 2.35-2.48 (m, 2H), 2.53-2.62 (m, 3H), 2.94-3.01 (m, 1H), 3.08-3.14 (m, 2H), 3.14-3.20 ( m, 2H), 6.63-6.70 (m, 2H), 7.05-7.18 (m, 2H), 7.22-7.35 (m, 2H), 9.44 (br s, 1H).
MS (CI+) [M+H]+ = 642+. MS (CI + ) [M + H] + = 642 + .
Drehwert: [a] = 24,8 0 (c = 1.0, CHCI3). Rotation: [a] = 24.8 0 (c = 1.0, CHCI3).
Beispiel 71 Example 71
8-(3-Hydroxyphenyl)-9-{6-[(3R)-3-{2-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]ethyl}morpholin-4- yl] hexyl}-6,7-dihydro-5H-benzo [7] annulen-3-ol
8- (3-Hydroxyphenyl) -9- {6 - [(3R) -3- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} morpholin-4-yl] hexyl} - 6,7-dihydro-5H-benzo [7] annulen-3-ol
200 mg (0.48 mmol) 9-(6-Bromhexyl)-8-(3-hydroxyphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 200 mg (0.59 mmol) (3R)-3- {2-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]ethyl}morpholin entsprechend der allgemeinen Vorschrift umgesetzt. Anschließend wurde mittels präparativer HPLC gereinigt. Es fielen 90 mg (28% d. Th.) Produkt an. 200 mg (0.48 mmol) of 9- (6-bromohexyl) -8- (3-hydroxyphenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were mixed with 200 mg (0.59 mmol) (3R). -3- {2 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] ethyl} morpholine reacted according to the general procedure. It was then purified by preparative HPLC. There was 90 mg (28% of theory) of product.
'H-NMR (600 MHz, Cloroform-di): δ = 1.01 -1.18 (m, 4H), 1.19-1.26 (m, 2H), 1.27-1.37 (m, 2H), 1.94-2.02 (m, 1 H), 2.06-2.35 (m, 1 1H), 2.36-2.41 (m, 2H), 2.52-2.60 (m, 2H), 2.60-2.66 (m, 2H), 2.76 (ddd, 1H), 2.94 (ddd, 1H), 3.06-3.15 (m, 3H), 3.39 (dd, 1H), 3.61 (mc, 1H), 3.71 (dd, 1H), 3.76 (mc, 1H), 6.69-6.80 (m, 5H), 7.18 (d, 1H), 7.21 (t, 1H). 'H NMR (600 MHz, chloroform-di): δ = 1.01-1.18 (m, 4H), 1.19-1.26 (m, 2H), 1.27-1.37 (m, 2H), 1.94-2.02 (m, 1H ), 2.06-2.35 (m, 1 1H), 2.36-2.41 (m, 2H), 2.52-2.60 (m, 2H), 2.60-2.66 (m, 2H), 2.76 (ddd, 1H), 2.94 (ddd, 1H), 3.06-3.15 (m, 3H), 3.39 (dd, 1H), 3.61 (mc, 1H), 3.71 (dd, 1H), 3.76 (mc, 1H), 6.69-6.80 (m, 5H), 7.18 (d, 1H), 7.21 (t, 1H).
Beispiel 72 Example 72
8-(3-Fluorphenyl)-9-{5-[(2S)-2-{3-[(4,4,5,5,5-pentfluorpentyl)sulfonyl]propyl}pyrrolidin-l- enzo [7] annulen-3-ol 8- (3-fluorophenyl) -9- {5 - [(2S) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidin-1-eno [7] annulene -3-ol
100 mg (0.25 mmol) 9-(5-Brompentyl)-8-(3-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 109 mg (0.32 mmol) (2S)-2- {3-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 88 mg der Titelverbindung erhalten. 100 mg (0.25 mmol) of 9- (5-bromopentyl) -8- (3-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were mixed with 109 mg (0.32 mmol) (2S). -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 88 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.98 - 1.40 (m, 8H), 1.51 - 1.71 (m, 5H), 1.76 - 2.10 (m, 9H), 2.16 - 2.26 (m, 1H), 2.27 - 2.47 (m, 5H), 2.52 - 2.60 (m, 3H), 2.90 - 2.97 (m, 1H), 3.07 - 3.13 (m, 2H), 3.18 - 3.23 (m, 2H), 6.63 - 6.69 (m, 2H), 7.00 - 7.16 (m, 4H), 7.36 - 7.46 (m, 1H).
MS (CI+) [M+H]+ = 660+. 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.98-1.40 (m, 8H), 1.51-1.71 (m, 5H), 1.76-2.10 (m, 9H), 2.16-2.26 (m, 1H), 2.27 - 2.47 (m, 5H), 2.52 - 2.60 (m, 3H), 2.90 - 2.97 (m, 1H), 3.07 - 3.13 (m, 2H), 3.18 - 3.23 (m, 2H), 6.63 - 6.69 (m, 2H), 7.00 - 7.16 (m, 4H), 7.36 - 7.46 (m, 1H). MS (CI + ) [M + H] + = 660 + .
Drehwert: [a] = - 39,3 ° (c = 1.0, CHC13). Rotation: [a] = - 39.3 ° (c = 1.0, CHC1 3 ).
Beispiel 73 Example 73
8-(3-Fluorphenyl)-9-{5-[(2S)-2-{3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- enzo [7] annulen-3-ol 8- (3-fluorophenyl) -9- {5 - [(2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidin-1-eno [7] annulene -3-ol
100 mg (0.25 mmol) 9-(5-Brompentyl)-8-(3-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 104 mg (0.32 mmol) (2S)-2- {3-[(3,3,4,4,4-Pentafluorbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 113 mg der Titelverbindung erhalten. 100 mg (0.25 mmol) of 9- (5-bromopentyl) -8- (3-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were mixed with 104 mg (0.32 mmol) (2S). -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 113 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.98 - 1.41 (m, 8H), 1.53 - 1.74 (m, 5H), 1.76 - 2.11 (m, 7H), 2.16 - 2.27 (m, 1H), 2.27 - 2.38 (m, 2H), 2.52 - 2.73 (m, 5H), 2.91 - 2.98 (m, 1H), 3.21 - 3.26 (m, 2H), 3.38 - 3.43 (m, 2H), 6.62 - 6.69 (m, 2H), 7.00 - 7.17 (m, 4H), 7.37 - 7.45 (m, 1H). 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.98-1.41 (m, 8H), 1.53-1.74 (m, 5H), 1.76-2.11 (m, 7H), 2.16-2.27 (m, 1H), 2.27 - 2.38 (m, 2H), 2.52 - 2.73 (m, 5H), 2.91 - 2.98 (m, 1H), 3.21 - 3.26 (m, 2H), 3.38 - 3.43 (m, 2H), 6.62 - 6.69 (m, 2H), 7.00 - 7.17 (m, 4H), 7.37 - 7.45 (m, 1H).
MS (CI+) [M+H]+ = 645+. MS (CI + ) [M + H] + = 645 + .
Drehwert: [a] = - 38,9 0 (c = 1.0, CHCI3). Rotation: [a] = - 38.9 0 (c = 1.0, CHCI3).
Beispiel 74 Example 74
8-(4-Fluorphenyl)-9-{5-[(2S)-2-{3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- yl] pentyl}-6,7-dihydro-5H-benzo [7] annulen-3-ol
8- (4-fluorophenyl) -9- {5 - [(2S) -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidin-1-yl] pentyl} - 6,7-dihydro-5H-benzo [7] annulen-3-ol
90 mg (0.22 mmol) 9-(5-Bromopentyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 98 mg (0.29 mmol) (2S)-2- {3-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 105 mg der Titelverbindung erhalten. 90 mg (0.22 mmol) of 9- (5-bromopentyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were mixed with 98 mg (0.29 mmol) (2S). -2- {3 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 105 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.96 - 1.39 (m, 8H), 1.50 - 1.72 (m, 5H), 1.75 - 2.09 (m, 9H), 2.19 (d, 1H), 2.26 - 2.48 (m, 4H), 2.52 - 2.59 (m, 3H), 2.89 - 2.96 (m, 1H), 3.07 - 3.14 (m, 2H), 3.18 - 3.23 (m, 2H), 6.62 - 6.69 (m, 2H), 7.10 - 7.22 (m, 3H), 7.23 - 7.29 (m, 2H). 'H NMR (400MHZ, DMSO-de): δ [ppm] = 0.96-1.39 (m, 8H), 1.50-1.72 (m, 5H), 1.75-2.09 (m, 9H), 2.19 (d, 1H) , 2.26 - 2.48 (m, 4H), 2.52 - 2.59 (m, 3H), 2.89 - 2.96 (m, 1H), 3.07 - 3.14 (m, 2H), 3.18 - 3.23 (m, 2H), 6.62 - 6.69 ( m, 2H), 7.10 - 7.22 (m, 3H), 7.23 - 7.29 (m, 2H).
MS (CI+) [M+H]+ = 660+. MS (CI + ) [M + H] + = 660 + .
Drehwert: [a] = - 38,6 ° (c = 1.0, CHC13). Rotation: [a] = - 38.6 ° (c = 1.0, CHC1 3 ).
Beispiel 75 Example 75
8-(4-Fluorphenyl)-9-{5-[(2S)-2-{3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- nzo [7] annulen-3-ol 8- (4-fluorophenyl) -9- {5 - [(2S) -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidin-1-nzo [7] annulene -3-ol
90 mg (0.22 mmol) 9-(5-Brompentyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 94 mg (0.29 mmol) (2S)-2- {3-[(3,3,4,4,4-Pentafluorbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 107 mg der Titelverbindung erhalten.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.98 - 1.39 (m, 8H), 1.51 - 1.74 (m, 5H), 1.76 - 2.09 (m, 7H), 2.12 - 2.23 (m, 1H), 2.27 - 2.36 (m, 2H), 2.53 (d, 5H), 2.89 - 2.95 (m, 1H), 3.20 - 3.27 (m, 2H), 3.38 - 3.44 (m, 2H), 6.62 - 6.68 (m, 2H), 7.10 - 7.22 (m, 3H), 7.23 - 7.29 (m, 2H), 9.35 (br. s, 1H). MS (CI+) [M+H]+ = 646+. 90 mg (0.22 mmol) of 9- (5-bromopentyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 94 mg (0.29 mmol) (2S). -2- {3 - [(3,3,4,4,4-pentafluorobutyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 107 mg of the title compound were obtained. 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.98-1.39 (m, 8H), 1.51-1.74 (m, 5H), 1.76-2.09 (m, 7H), 2.12-2.23 (m, 1H), 2.27-2.36 (m, 2H), 2.53 (d, 5H), 2.89-2.95 (m, 1H), 3.20-3.27 (m, 2H), 3.38-3.44 (m, 2H), 6.62-6.68 ( m, 2H), 7.10 - 7.22 (m, 3H), 7.23 - 7.29 (m, 2H), 9.35 (br, s, 1H). MS (CI + ) [M + H] + = 646 + .
Drehwert: [a] = - 44,1 ° (c = 1.0, CHC13). Rotation: [a] = - 44.1 ° (c = 1.0, CHC1 3 ).
Beispiel 76 Example 76
8-(4-Fluorphenyl)-9-{5-[(2R)-2-{4-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]butyl}pyrrolidin-l- len-3-ol 8- (4-Fluorophenyl) -9- {5 - [(2R) -2- {4 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] butyl} pyrrolidin-1-len-3-ol
120 mg (0.3 mmol) 9-(5-Brompentyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 125 mg (0.36 mmol) (2R)-2- {4-[(4,4,5,5,5-Pentafluorpentyl)sulfonyl]butyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 90 mg der Titelverbindung erhalten. 120 mg (0.3 mmol) of 9- (5-bromopentyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 125 mg (0.36 mmol) (2R). -2- {4 - [(4,4,5,5,5-pentafluoropentyl) sulfonyl] butyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 90 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-d6): δ [ppm]= 0.96 - 1.42 (m, 10H), 1.47 - 1.71 (m, 5H), 1.75 - 1.86 (m, 1H), 1.87 - 2.09 (m, 8H), 2.17 (d, 1H), 2.23 - 2.48 (m, 4H), 2.52 - 2.64 (m, 3H), 2.91 - 2.98 (m, 1H), 3.10 (t, 2H), 3.18 - 3.24 (m, 2H), 6.62 - 6.69 (m, 2H), 7.09 - 7.22 (m, 3H), 7.23 - 7.30 (m, 2H), 9.59 (br. s, 1H). 'H-NMR (400MHz, DMSO-d 6): δ [ppm] = 0.96 - 1.42 (m, 10H), 1:47 - 1.71 (m, 5H), 1.75 - 1.86 (m, 1H), 1.87 - 2:09 (m , 8H), 2.17 (d, 1H), 2.23 - 2.48 (m, 4H), 2.52 - 2.64 (m, 3H), 2.91 - 2.98 (m, 1H), 3.10 (t, 2H), 3.18 - 3.24 (m , 2H), 6.62 - 6.69 (m, 2H), 7.09 - 7.22 (m, 3H), 7.23 - 7.30 (m, 2H), 9.59 (br, s, 1H).
Beispiel 77 Example 77
8-(4-Fluorphenyl)-9-{5-[(2S)-2-{3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-l-yl]pentyl}- 6,7-dihydro-5H-benzo [7] annulen-3-ol
8- (4-fluorophenyl) -9- {5 - [(2S) -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidin-1-yl] pentyl} -6,7- dihydro-5H-benzo [7] annulen-3-ol
90 mg (0.22 mmol) 9-(5-Brompentyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 96 mg (0.32 mmol) (2S)-2- {3-[(4,4,4-Trifluorbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 79 mg der Titelverbindung erhalten. 90 mg (0.22 mmol) of 9- (5-bromopentyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 96 mg (0.32 mmol) (2S). -2- {3 - [(4,4,4-trifluorobutyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 79 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.96 - 1.40 (m, 8H), 1.50 - 1.70 (m, 5H), 1.76 - 2.09 (m, 9H), 2.15 - 2.24 (m, 1H), 2.25 - 2.35 (m, 2H), 2.36 - 2.48 (m, 2H), 2.52 - 2.59 (m, 3H), 2.90 - 2.96 (m, 1H), 3.07 - 3.14 (m, 2H), 3.14 - 3.20 (m, 2H), 6.62 - 6.69 (m, 2H), 7.09 - 7.22 (m, 3H), 7.23 - 7.31 (m, 2H), 9.45 (br. s, 1H). 'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.96-1.40 (m, 8H), 1.50-1.70 (m, 5H), 1.76-2.09 (m, 9H), 2.15-2.24 (m, 1H), 2.25 - 2.35 (m, 2H), 2.36 - 2.48 (m, 2H), 2.52 - 2.59 (m, 3H), 2.90 - 2.96 (m, 1H), 3.07 - 3.14 (m, 2H), 3.14 - 3.20 (m, 2H), 6.62-6.69 (m, 2H), 7.09 - 7.22 (m, 3H), 7.23 - 7.31 (m, 2H), 9.45 (br, s, 1H).
MS (CI+) [M+H]+ = 610+. MS (CI + ) [M + H] + = 610 + .
Drehwert: [a] = - 40,5 ° (c = 1.0, CHC13). Rotation: [a] = - 40.5 ° (c = 1.0, CHC1 3 ).
Beispiel 78 Example 78
8-(4-Fluorphenyl)-9-{5-[(2S)-2-{3-[(5,5,5-trifluorpentyl)sulfonyl]propyl}pyrrolidin-l-yl]pentyl}- -dihydro-5H-benzo [7] annulen-3-ol 8- (4-Fluorophenyl) -9- {5 - [(2S) -2- {3 - [(5,5,5-trifluoropentyl) sulfonyl] propyl} pyrrolidin-1-yl] pentyl} -dihydro-5H benzo [7] annulen-3-ol
90 mg (0.21 mmol) wurden 9-(5-Brompentyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3- ol mit 101 mg (0.32 mmol) (2S)-2- {3-[(5,5,5-Trifluorpentyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 90 mg der Titelverbindung erhalten.
'H-NMR (400MHZ, DMSO-d6): δ [ppm]= 0.94 - 1.38 (m, 8H), 1.49 - 2.10 (m, 16H), 2.13 - 2.23 (m, 1H), 2.23 - 2.38 (m, 4H), 2.52 - 2.59 (m, 3H), 2.89 - 2.97 (m, 1 H), 3.01 - 3.07 (m, 2H), 3.08 - 3.14 (m, 2H), 6.61 - 6.70 (m, 2H), 7.09 - 7.22 (m, 3H), 7.23 - 7.30 (m, 2H), 9.35 (br. s, 1H). 90 mg (0.21 mmol) were added to 9- (5-bromopentyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol with 101 mg (0.32 mmol) (2S). -2- {3 - [(5,5,5-trifluoropentyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 90 mg of the title compound were obtained. 'H-NMR (400MHz, DMSO-d 6): δ [ppm] = 0.94 - 1.38 (m, 8H), 1:49 to 2:10 (m, 16H), 2:13 to 2:23 (m, 1H), 2:23 to 2:38 (m , 4H), 2.52 - 2.59 (m, 3H), 2.89 - 2.97 (m, 1H), 3.01 - 3.07 (m, 2H), 3.08 - 3.14 (m, 2H), 6.61 - 6.70 (m, 2H), 7.09 - 7.22 (m, 3H), 7.23 - 7.30 (m, 2H), 9.35 (br, s, 1H).
MS (CI+) [M+H]+ = 624+. MS (CI + ) [M + H] + = 624 + .
Drehwert: [a] = - 40,1 ° (c = 1.0, CHC13). Rotation: [a] = - 40.1 ° (c = 1.0, CHC1 3 ).
Beispiel 79 Example 79
9-{5-[(2S)-2-{3-[(3,3-Dimethylbutyl)sulfonyl]propyl}pyrrolidin-l-yl]pentyl}-8-(4-fluorphenyl)- -dihydro-5H-benzo [7] annulen-3-ol 9- {5 - [(2S) -2- {3 - [(3,3-Dimethylbutyl) sulfonyl] propyl} pyrrolidin-1-yl] pentyl} -8- (4-fluorophenyl) -dihydro-5H-benzo [7] annulen-3-ol
90 mg (0.21 mmol) 9-(5-Brompentyl)-8-(4-fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol wurden mit 92 mg (0.32 mmol) (2S)-2- {3-[(3,3-Dimethylbutyl)sulfonyl]propyl}pyrrolidin entsprechend der allgemeinen Vorschrift umgesetzt. Nach präparativer HPLC wurden 66 mg der Titelverbindung erhalten. 90 mg (0.21 mmol) of 9- (5-bromopentyl) -8- (4-fluorophenyl) -6,7-dihydro-5H-benzo [7] annulen-3-ol were treated with 92 mg (0.32 mmol) (2S). -2- {3 - [(3,3-dimethylbutyl) sulfonyl] propyl} pyrrolidine reacted according to the general procedure. After preparative HPLC, 66 mg of the title compound were obtained.
'H-NMR (400MHZ, DMSO-de): δ [ppm]= 0.88 (s, 9H), 0.97 - 1.43 (m, 8H), 1.49 - 1.74 (m, 7H), 1.75'H-NMR (400MHZ, DMSO-de): δ [ppm] = 0.88 (s, 9H), 0.97- 1.43 (m, 8H), 1.49- 1.74 (m, 7H), 1.75
- 2.10 (m, 7H), 2.14 - 2.25 (m, 1 H), 2.26 - 2.36 (m, 2H), 2.52 - 2.60 (m, 3H), 2.89 - 2.96 (m, 1H), 2.97- 2.10 (m, 7H), 2.14 - 2.25 (m, 1H), 2.26 - 2.36 (m, 2H), 2.52 - 2.60 (m, 3H), 2.89 - 2.96 (m, 1H), 2.97
- 3.01 (m, 2H), 3.04 - 3.10 (m, 2H), 6.61 - 6.69 (m, 2H), 7.09 - 7.22 (m, 3H), 7.23 - 7.30 (m, 2H), 9.26 (br. s, 1H). - 3.01 (m, 2H), 3.04 - 3.10 (m, 2H), 6.61 - 6.69 (m, 2H), 7.09 - 7.22 (m, 3H), 7.23 - 7.30 (m, 2H), 9.26 (br. S, 1H).
MS (CI+) [M+H]+ = 584+. MS (CI + ) [M + H] + = 584 + .
Drehwert: [a] = - 40,1 0 (c = 1.0, CHCI3).
Biologische Beispiele Rotation: [a] = - 40.1 0 (c = 1.0, CHCI3). Biological examples
Abkürzungen und Akronyme: Abbreviations and acronyms:
ER Östrogen Rezeptor (Estrogen Receptor) ER estrogen receptor (estrogen receptor)
E2 17ß-Östradiol (17ß-Estradiol) E2 17β-oestradiol (17β-estradiol)
SERM Selektiver Östrogen Rezeptor Modulator (Selective Estrogen SERM Selective Estrogen Receptor Modulator (Selective Estrogen
Receptor Modulator) Receptor Modulator)
d Tag d day
Liter liter
OVX Ovariektomierte Tiere OVX ovariectomized animals
Pharmakologische Untersuchung der erfindungsgemäßen Verbindungen in vitro Pharmacological examination of the compounds according to the invention in vitro
Beispiel 72 (AntiÖstrogene Wirkung in MVLN Zellen) Example 72 (anti-estrogenic effect in MVLN cells)
Die antiÖstrogene Wirkung der beanspruchten Verbindungen wurde in MVLN Zellen in vitro durchgeführt. Bei MVLN Zellen (J Steroid Biochem Mol Biol. 1993 Sep; 46(3): 355-64) handelt es sich um Derivate der dem Fachmann bekannten hormonresponsiven MCF7-Brustkrebszelle (Adenocarcinoma Zellen aus Mammatumoren), die mit einem Luciferase-Reporter, gekoppelt an einen Östrogen-Sensitiven Promotor (pVit-tk), stabil transfiziert sind. Das pVit-tk-LUC Plasmid, welches zur Herstellung dieser Zelllinie verwendet wurde, enthält den Vitellogenin-Thymidin-Kinase Promotor. Die Zellen wurden zu den Experimenten in Dulbecco's Modified Eagle's Medium (DMEM ohne Phenolrot) supplementiert mit 10% fetalem Kälberserum (FCS), Penicillin, Streptomycin and 4 mM L-Glutamin kultiviert. Die Zellen wurden in obigem Medium für 3 Tage kultiviert. Danach wurde das Medium durch DMEM Medium ohne Phenolrot ausgetauscht, welches 5% Oströgen-freies Kälberserum (CCS) und 1 nmol/1 Fulvestrant enthält, und für 24 Stunden inkubiert. Danach wurde das DMEM Medium ein weiteres mal ausgetauscht (DMEM w/o, 5% CCS) und für 24 Stunden inkubiert, trypsinisiert und eingefroren. Für den Test wurden die Zellen aufgetaut und in 384-Loch Platten ausgesäht (20 μΐ, 6xl03 Zellen/Loch), welche 50 nl/Loch Testverbindung in Dimethylsulfoxid enthielten. Um die agonistische Wirkung am ER zu überprüfen, wurde 1 nmol/1 Fulvestrant zugegeben und die Zellen in aufsteigenden Konzentrationen der Testverbindung inkubiert. Als positive Kontrolle wurden die Zellen mit aufsteigenden Konzentrationen Östradiol versetzt. Als negative Kontrolle für eine Reportergeninduktion wurden die Zellen mit 1% DMSO versetzt. Um die antagonistische Wirkung der Testverbindung zu überprüfen, wurden die Zellen mit 0.1 nmol/1 Östradiol und aufsteigenden Konzentrationen der Testverbindung versetzt. Als Positivkontrolle für die Inhibierung der Reportergenexpression wurden die Zellen mit aufsteigenden Konzentrationen von Fulvestrant versetzt. 16 Stunden nach Beginn dieser Inkubationen wurde der Luciferasetest durchgeführt.
Die Bestimmung der Aktivität der induzierten Luziferase erlaubt einen direkten Schluss auf die Östrogenen Eigenschaften von Substanzen. Um die antiÖstrogenen Eigenschaften der Verbindungen zu ermitteln, wurden diese in Gegenwart von Östrogen auf ihr Potenzial untersucht, das durch Estradiol induzierte Luziferasesignal zu inhibieren. Die beanspruchten Verbindungen wurden wie beschrieben in MVLN-Zellen auf ihr antiÖstrogenes Potenzial hin untersucht (siehe Tabelle 1, zum Teil wurde die Aktivität der erfindungsgemäßen Verbindungen mehrfach bestimmt). Über den gesamten Strukturbereich zeigen diese Verbindungen eine hohe Potenz (IC50 Werte kleiner als 500 nM) und überwiegend sogar zwei- bzw. einstellig nanomolare IC50- Werte für die Inhibition der Östradiol- induzierten Luciferaseaktivität.
The anti-estrogenic activity of the claimed compounds was performed in MVLN cells in vitro. MVLN cells (J Steroid Biochem Mol Biol. 1993 Sep; 46 (3): 355-64) are derivatives of the MCF7 hormone-responsive breast cancer cell (adenocarcinoma mammary tumor cells) known to those skilled in the art coupled with a luciferase reporter to an estrogen-sensitive promoter (pVit-tk), stably transfected. The pVit-tk-LUC plasmid used to make this cell line contains the vitellogenin thymidine kinase promoter. The cells were cultured for the experiments in Dulbecco's Modified Eagle's Medium supplemented with 10% fetal calf serum (FCS), penicillin, streptomycin and 4 mM L-glutamine. The cells were cultured in the above medium for 3 days. Thereafter, the medium was exchanged with DMEM medium without phenol red containing 5% outcrop-free calf serum (CCS) and 1 nmol / 1 fulvestrant and incubated for 24 hours. Thereafter, the DMEM medium was changed once more (DMEM w / o, 5% CCS) and incubated for 24 hours, trypsinized and frozen. For the test, the cells were thawed and seeded in 384-well plates (20 μΐ, 6 × 10 3 cells / well) containing 50 μl / well test compound in dimethyl sulfoxide. To check the agonist activity on the ER, 1 nmol / 1 fulvestrant was added and the cells incubated in ascending concentrations of the test compound. As a positive control, the cells were spiked with ascending concentrations of estradiol. As a negative control for reporter gene induction, cells were spiked with 1% DMSO. To check the antagonistic activity of the test compound, the cells were spiked with 0.1 nmol / l of estradiol and ascending concentrations of the test compound. As a positive control for the inhibition of reporter gene expression, cells were spiked with increasing concentrations of fulvestrant. 16 hours after the start of these incubations, the luciferase assay was performed. The determination of the activity of the induced luciferase allows a direct conclusion on the estrogenic properties of substances. In order to determine the anti-estrogenic properties of the compounds, they were examined in the presence of estrogen for their potential to inhibit the estradiol-induced luciferase signal. The claimed compounds were tested as described in MVLN cells for their antiestrogenic potential (see Table 1, in part, the activity of the compounds of the invention was determined several times). Over the entire structural region, these compounds show a high potency (IC50 values less than 500 nM) and predominantly even two- or single-digit nanomolar IC50 values for the inhibition of estradiol-induced luciferase activity.
Tabelle 1 Table 1
Bsp. AntiÖstrogene Wirkung in vitro: MVLN Bsp. AntiÖstrogene Wirkung in vitro: MVLN Transaktivierung Antagonismus IC50 Transaktivierung Antagonismus IC50 For example, anti-estrogenic action in vitro: MVLN eg anti-estrogenic action in vitro: MVLN transactivation antagonism IC50 transactivation antagonism IC50
(nM) (nM) (nM) (nM)
1 5.6 42 27.1 1 5.6 42 27.1
2 3.7 42 22.1 2 3.7 42 22.1
2 3.1 43 18.4 2 3.1 43 18.4
3 26.0 43 9.3 3 26.0 43 9.3
3 31.4 44 19.2 3 31.4 44 19.2
4 56.1 44 27.4 4 56.1 44 27.4
4 83.9 45 4.0 4 83.9 45 4.0
5 6.1 46 27.7 5 6.1 46 27.7
5 6.2 46 31.0 5 6.2 46 31.0
6 37.0 47 31.8 6 37.0 47 31.8
6 26.5 47 36.2 6 26.5 47 36.2
7 46.9 48 13.6 7 46.9 48 13.6
7 35.2 48 6.0 7 35.2 48 6.0
8 39.5 48 16.9 8 39.5 48 16.9
8 19.4 48 18.6 8 19.4 48 18.6
9 7.2 49 19.4 9 7.2 49 19.4
9 6.4 49 19.2 9 6.4 49 19.2
10 59.7 49 11.1 10 59.7 49 11.1
10 129 49 8.3 10 129 49 8.3
11 31.3 50 15.7 11 31.3 50 15.7
11 40.0 50 26.4 11 40.0 50 26.4
12 6.8 51 28.1 12 6.8 51 28.1
12 8.2 51 16.0 12 8.2 51 16.0
13 36.2 52 22.2 13 36.2 52 22.2
13 37.8 52 17.5 13 37.8 52 17.5
14 108.4 53 48.3 14 108.4 53 48.3
14 98.5 53 37.1 14 98.5 53 37.1
15 41.3 54 10.1 15 41.3 54 10.1
16 25.4 54 8.2 16 25.4 54 8.2
17 23.8 55 17.2 17 23.8 55 17.2
18 51.8 55 15.2 18 51.8 55 15.2
19 18.9 56 10.4
36.1 56 4.519 18.9 56 10.4 36.1 56 4.5
46.0 57 7.546.0 57 7.5
16.4 57 4.5116.4 57 4.51
19.9 58 3.7219.9 58 3.72
38.9 58 3.638.9 58 3.6
34.4 59 6.8934.4 59 6.89
38.2 59 7.5938.2 59 7.59
46.5 60 24.4646.5 60 24.46
47.8 60 19.4447.8 60 19.44
16.3 61 1 1.516.3 61 1 1.5
1.7 61 8.671.7 61 8.67
2.5 62 5.562.5 62 5.56
17.5 62 5.1417.5 62 5.14
15.4 63 12.2915.4 63 12.29
4.0 63 1 1.514.0 63 1 1.51
4.3 64 9.414.3 64 9.41
17.9 64 8.2217.9 64 8.22
26.8 65 7.9126.8 65 7.91
10.2 65 3.1410.2 65 3.14
4.1 66 82.94.1 66 82.9
45.5 67 18.5245.5 67 18.52
25.6 68 30.7525.6 68 30.75
39.9 68 14.6339.9 68 14.63
14.7 69 7.1514.7 69 7.15
32.9 70 14.4632.9 70 14.46
8.6 70 13.848.6 70 13.84
8.5 71 -8.5 71 -
3.1 72 1603.1 72 160
3.5 72 1833.5 72 183
19.9 73 10519.9 73 105
20.2 73 12820.2 73 128
20.6 74 23820.6 74 238
18.1 74 24318.1 74 243
28.1 75 17228.1 75 172
32.0 76 24232.0 76 242
1.8 76 269
38 1.9 77 471 1.8 76 269 38 1.9 77 471
38 2.5 77 380 38 2.5 77 380
38 1.0 78 142 38 1.0 78 142
39 13.7 78 88.9 39 13.7 78 88.9
40 21.1 79 169 40 21.1 79 169
41 7.3 79 147 41 7.3 79 147
Beispiel 73 (Effekt auf die Stabilität des ERa proteins) Example 73 (effect on the stability of the ERa protein)
Neben der Inhibition der transkriptionellen Aktivität des Östrogenrezeptors (ERs) beeinflussen Antiöströgene das Expressionsniveau des ER in den Zielgeweben über eine Stimulation des proteolytischen Abbaus des ERs. Im Vergleich mit einem ER-E2 Komplex hat der ER gebunden im Komplex mit dem reinen Antiöstrogen Fulvestrant eine substantiell kürzere Halbwertszeit. Im Gegenzug dazu wird die ER-Stabilität durch das SERM Tamoxifen verstärkt, so dass es insgesamt zu einer ER-Stablisierung kommt. In der Summe ist davon auszugehen, dass die Fähigkeit reiner AntiÖstrogene und bestimmter SERMs die ER-Degradation zu induzieren, signifikant zur Gesamtwirkung der Verbindungen beiträgt. Verbindungen, die eine destabilisierende Eigenschaft zeigen, aber gleichzeitig die gewünschten gewebespezifischen agonistischen Qualitäten wie z.B. Knochenprotektion zeigen, sollten insgesamt ein überlegenes pharmakologischen Profil vorweisen, da sie ein geringeres Nebenwirkungspotential wie z.B. die Stimulation des Endometriums haben. In addition to inhibiting the transcriptional activity of the estrogen receptor (ER), anti-inflammatory genes influence the level of expression of the ER in the target tissues via stimulation of proteolytic degradation of the ER. Compared with an ER-E2 complex, the ER bound in complex with the pure antiestrogen fulvestrant has a substantially shorter half-life. In return, the ER stability is enhanced by the Tamoxifen SERM, resulting in overall ER stabilization. In sum, it is expected that 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. Show overall superior pharmacological profile, as they have a lower side effect potential, such as have the stimulation of the endometrium.
Der Effekt der beanspruchten Verbindungen auf die Stabilität des ERs wurde in T47D- Brustkrebszellen (T-47D (ATCC® HTB-133™)) analysiert (siehe Tabelle 3, Spalte ER- Destabilisierung normiert [%]). Diese Zellen exprimieren den ER in funktioneller Form. 24 Stunden vor Beginn der Experimente wurden lx 106 Zellen in 3 ml Medium (DMD 5% CCS) in 6 Loch-Platten inkubiert. 24 Stunden nach Beginn dieser Inkubation wurden die Zellen mit den Testverbindungen (10" 7 mol/l) oder - als Vehikelkontrolle - DMSO (finale Konzentration 0.01%), oder Tamoxifen bzw. Fulvestrant (10"7 mol/l) versetzt. 24 Stunden nach dieser Stimulation wurden die Zellkerne der Zellen durch den nuclear extract kit von Active Motif nach Herstelleranleitung extrahiert. Der Proteingehalt des Zellkernextrakts wurde durch den BCA protein assay kit von Novagen nach Herstelleranleitung bestimmt. 5 μg Protein wurden verwendet, um den Gehalt an nuklearem ERa mittels ELISA zu bestimmen (NR Sandwich von Active Motif # 49796). Der ERa Proteingehalt wurde mittels folgender Formel bestimmt: The effect of the claimed compounds on the stability of ERs was in T47D breast cancer cells (T-47D (ATCC HTB-133 ® ™)) was analyzed (see Table 3, column ER- destabilization normalized [%]). These cells express the ER in functional form. Twenty-four hours before the start of the experiments, 10 × 10 6 cells were incubated in 3 ml of medium (DMD 5% CCS) in 6-well plates. 24 hours of the beginning of this incubation, the cells were treated with the test compounds (10 "7 mol / l) or - as a vehicle control - DMSO (final concentration 0.01%), or Tamoxifen or Fulvestrant (10" 7 mol / l) was added. 24 hours after this stimulation, cell nuclei were extracted by Active Motif's nuclear extract kit according to the manufacturer's instructions. The protein content of the cell nuclear extract was determined by the BCA protein assay kit from Novagen according to the manufacturer's instructions. 5 μg protein was used to determine the level of nuclear ERa by ELISA (NR Sandwich from Active Motif # 49796). The ERa protein content was determined by the following formula:
V FRn testcpd 0/ pDrj ZK156901.Faslodex V FRn testcpd 0 / pDrj ZK156901.Faslodex
O/rnn testcpd _ /O t TXU DMSO - /O t TXU DMSO O / rnn testcpd _ / O t TXU DMSO - / O t TXU DMSO
norm ~~ 0/ C D ZK183823.0H-Tamoxifen 0/ C D ZK156901.Faslodex standard ~~ 0 / CD ZK183823.0H-Tamoxifen 0 / CD ZK156901.Faslodex
/obKU DMSO - /obKU DMSO
Als Vergleich diente die Behandlung mit dem vollständigen Destabilisator Fulvestrant (0% ER), dem Stabilisator Tamoxifen (100% ER) sowie dem Kontrollmedium (ca 30%> ER). Verbindungen mit einem ER-Gehalt von kleiner 30%> wurden als destablisierend eingestuft. / obKU DMSO - / obKU DMSO The treatment was compared with the complete destabilizer fulvestrant (0% ER), the stabilizer tamoxifen (100% ER) and the control medium (approx. 30%> ER). Compounds with an ER content of less than 30%> were classified as destabilizing.
Wie beschrieben wurden die beanspruchten Substanzen auf ihre Wirkung auf die Stabilität des ERa Proteins hin untersucht (siehe Tabelle 2). Über den Großteil des beanspruchten Strukturbereichs zeigen die Substanzen eine destabilisierende Wirkung auf den ERa-Gehalt (verbleibender relativer ERa-Gehalt von kleiner oder gleich 30%), sind jedoch zum überwiegenden Teil weniger destabilisierend als Fulvestrant (vollständige Destablisierung des ER). As described, the claimed substances were tested for their effect on the stability of the ERα protein (see Table 2). Over the majority of the claimed structural area, the substances have a destabilizing effect on the ERa content (remaining relative ERα content of less than or equal to 30%), but are for the most part less destabilizing than fulvestrant (complete destablization of the ER).
Tabelle 2 Table 2
Bsp. ER-Destabilisierung Bsp. ER-Destabilisierung Bsp. ER-Destabilisierung normiert [%] normiert [%] normiert [%] Ex. ER destabilization Ex. ER destabilization Ex. ER destabilization normalized [%] normalized [%] normalized [%]
1 -0.2 28 8.07 55 -2.66 1 -0.2 28 8.07 55 -2.66
2 5.48 29 56 1.65 2 5.48 29 56 1.65
3 -6.9 30 -1.2 57 2.18 3 -6.9 30 -1.2 57 2.18
4 41.26 31 -2.3 58 2.02 4 41.26 31 -2.3 58 2.02
5 1.32 32 0.4 59 2.27 5 1.32 32 0.4 59 2.27
6 6.72 33 -2.38 60 2.0 6 6.72 33 -2.38 60 2.0
7 27.5 34 -2.2 61 3.1 7 27.5 34 -2.2 61 3.1
8 -0.97 35 -3.7 62 3.0 8 -0.97 35 -3.7 62 3.0
9 -4.3 36 3.3 63 - 9 -4.3 36 3.3 63 -
10 -0.18 37 -2.2 64 1.35 10 -0.18 37 -2.2 64 1.35
11 6.53 38 -2.7 65 4.61 11 6.53 38 -2.7 65 4.61
12 -0.38 39 -0.3 66 2.07 12 -0.38 39 -0.3 66 2.07
13 28.1 40 -0.3 67 2.83 13 28.1 40 -0.3 67 2.83
14 28.8 41 1.5 68 - 14 28.8 41 1.5 68 -
15 -0.3 42 2.2 69 0.1 15 -0.3 42 2.2 69 0.1
16 - 43 1.3 70 - 16 - 43 1.3 70 -
17 -3.4 44 3.0 71 -17 -3.4 44 3.0 71 -
18 -0.9 45 2.8 72 3.8 18 -0.9 45 2.8 72 3.8
19 -1.7 46 8.5 73 5.0 19 -1.7 46 8.5 73 5.0
20 -8.0 47 0.7 74 0.6 20 -8.0 47 0.7 74 0.6
21 1.6 48 -1.7 75 7.9 21 1.6 48 -1.7 75 7.9
22 1.02 49 3.7 76 0.15 22 1.02 49 3.7 76 0.15
23 -6.2 50 4.8 77 25.4 23 -6.2 50 4.8 77 25.4
24 30.9 51 22.6 78 3.68
25 -0.18 52 26.9 79 9.8124 30.9 51 22.6 78 3.68 25 -0.18 52 26.9 79 9.81
26 18.9 53 25.0 26 18.9 53 25.0
27 8.63 54 1.43 27 8.63 54 1.43
Beispiel 74 (Antiuteruswachstumstest an der adulten Ratte) Example 74 (adult rat anti-uterus growth test)
Der Uterus östrogensubstituierter Ratten kann als Testmodell genutzt werden, um eine direkte Wirkung von Substanzen mit antiÖstrogenen Eigenschaften nachzuweisen. Der Parameter der Östrogenwirkung ist das bei Ratten durch Östradiol induzierte Uteruswachstum, welches durch gleichzeitige Gabe einer Substanz mit antiöstogener Wirkung gehemmt wird. The uterus of estrogen-substituted rats can be used as a test model to detect a direct effect of substances with anti-estrogenic properties. The parameter of estrogen action is estrogen-induced uterine growth in rats, which is inhibited by concomitant administration of an anti-estrogenic substance.
Die Versuchstiere (n=5-6 Tiere/Gruppe) wurden vor Versuchsbeginn ovariektomiert, um den Einfluss endogener Östrogene auszuschließen. Nach einer Phase von 6 bis 10 Tagen werden die Testsubstanzen s.c. an 3 aufeinanderfolgenden Tagen (dl-d3) in Kombination mit einer Substitutionsdosis von 1.5 μg/kg/Tag 17ß-Östradiol behandelt. Als Positivkontrolle dient 17ß- Östradiol alleine, als Negativkontrolle die Vehikel-Gruppe. Am Tag 4 (d4) werden die Tiere getötet, Uteri und Vaginae werden herauspräpariert und gewogen. Die Organgewichte werden auf mg/100 g Körpergewicht umgerechnet, dann der Mittelwert und die Standardabweichung für jede Dosierung berechnet. Die Hemmung des durch 17ß-Östradiol induzierten Uterus- bzw. Vaginalwachstums wird als Hemmung in % angegeben. The experimental animals (n = 5-6 animals / group) were ovariectomized before the start of the experiment in order to exclude the influence of endogenous estrogens. After a period of 6 to 10 days, the test substances s.c. treated on 3 consecutive days (dl-d3) in combination with a substitution dose of 1.5 μg / kg / day of 17β-oestradiol. As a positive control serves 17ß- estradiol alone, as a negative control the vehicle group. On day 4 (d4) the animals are sacrificed, uteri and vaginae are dissected out and weighed. Organ weights are converted to mg / 100 g body weight, then the mean and standard deviation calculated for each dose. Inhibition of 17ß-estradiol-induced uterine and vaginal growth, respectively, is expressed as% inhibition.
Die erfindungsgemäßen Verbindungen weisen zum großen Teil eine deutlich ausgeprägte Hemmung des durch 17ß-Östradiol induzierten Uteruswachstums auf. The compounds of the present invention exhibit, to a large extent, a marked inhibition of 17ß-estradiol-induced uterine growth.
Die ausgewählten beanspruchten Substanzen wurden in adulten weiblichen Ratten wie beschrieben auf ihre antiÖstrogene, inhibierende Wirkung auf das Uterusgewicht hin untersucht. Die Substanzen zeigen in der eingesetzten Dosierung eine deutliche antiÖstrogene in vivo-Wirkung (Tabelle 3). The selected claimed substances were examined in adult female rats as described for their antiestrogenic, uterine weight inhibitory effect. The substances show in the dosage used a significant anti-estrogenic in vivo effect (Table 3).
Tabelle 3 Table 3
Claims
1. Verbindungen der allgemeinen!7 ormel (I): 1. General connections! 7 formula (I):
(i) (i)
worin wherein
R1, R2, R3 und R4 unabhängig voneinander für Wasserstoff, Ci-Cö-Alkyl, Ci-C6-Alkoxy, Halogen- Ci-C6-alkyl, Hydroxy-Ci-Cö-alkyl, Halogen-Ci-C6-alkoxy, Hydroxy-C2-C6- alkoxy, Halogen, Hydroxy, Nitril, Ci-C4-Alkyl-C(=0)- oder Ci-C4-Alkyl-S02- stehen; R 1 , R 2 , R 3 and R 4 independently of one another for hydrogen, Ci-Cö-alkyl, Ci-C6-alkoxy, halogen-Ci-C6-alkyl, hydroxy-Ci-Cö-alkyl, halogen-Ci-C6- alkoxy, hydroxy-C2-C6- alkoxy, halogen, hydroxy, nitrile, Ci-C 4 -alkyl-C(=0)- or Ci-C 4 -alkyl-S0 2 -;
R5, R6und R7 unabhängig voneinander für Wasserstoff, Halogen, Ci-C i-Alkyl oder Nitril stehen; R 5 , R 6 and R 7 independently represent hydrogen, halogen, Ci-C i-alkyl or nitrile;
R8, R9 für Wasserstoff, Hydroxy oder Fluor stehen, jedoch sind R8 und R9 nicht gleichzeitig Hydroxy oder nicht gleichzeitig Hydroxy und Fluor; R 8 , R 9 are hydrogen, hydroxy or fluorine, but R 8 and R 9 are not simultaneously hydroxy or not simultaneously hydroxy and fluorine;
Xi für -O-CH2-, -CH2- oder -CH2-CH2- steht; Xi represents -O-CH2-, -CH2- or -CH2-CH2-;
X2 für Stickstoff oder -CH- steht; X 2 represents nitrogen or -CH-;
Y für Ci-C/i-Alkyl, per- oder teilfluoriertes Ci-C/i-Alkyl oder per- oder teilfluoriertes C3-C8-Cycloalkyl steht; Y represents Ci-C/i-alkyl, per- or partially fluorinated Ci-C/i-alkyl or per- or partially fluorinated C3-C8-cycloalkyl;
Q für -SO2-, -SO-, -S- oder -O- steht; Q represents -SO2-, -SO-, -S- or -O-;
m für 4, 5, 6 oder 7 steht; m represents 4, 5, 6 or 7;
q für 1 , 2, 3 oder 4 steht; q represents 1, 2, 3 or 4;
t für 0, 1, 2, 3 oder 4 steht t stands for 0, 1, 2, 3 or 4
und ihre Salze, Solvate oder Solvate der Salze, einschließlich aller Kristallmodifikationen. and their salts, solvates or solvates of salts, including all crystal modifications.
2. Verbindungen nach Anspruch 1, worin
R1, R2, R3 und R4 unabhängig voneinander für Wasserstoff, Ci-Cö-Alkyl, Ci-C6-Alkoxy, Halogen- Ci-C6-alkyl, Hydroxy-Ci-Cö-alkyl, Halogen-Ci-C6-alkoxy, Hydroxy-C2-C6- alkoxy, Halogen, Hydroxy, Nitril, Ci-C4-Alkyl-C(=0)- oder Ci-C4-Alkyl-S02- stehen; 2. Compounds according to claim 1, wherein R 1 , R 2 , R 3 and R 4 independently of one another for hydrogen, Ci-Cö-alkyl, Ci-C6-alkoxy, halogen-Ci-C6-alkyl, hydroxy-Ci-Cö-alkyl, halogen-Ci-C6- alkoxy, hydroxy-C2-C6- alkoxy, halogen, hydroxy, nitrile, Ci-C 4 -alkyl-C(=0)- or Ci-C 4 -alkyl-S0 2 -;
R5, R6und R7 unabhängig voneinander für Wasserstoff, Halogen, Ci-C3-Alkyl oder Nitril stehen; R 5 , R 6 and R 7 independently represent hydrogen, halogen, Ci-C3-alkyl or nitrile;
R8, R9 für Wasserstoff, Hydroxy oder Fluor stehen, jedoch sind R8 und R9 nicht gleichzeitig Hydroxy oder nicht gleichzeitig Hydroxy und Fluor; R 8 , R 9 are hydrogen, hydroxy or fluorine, but R 8 and R 9 are not simultaneously hydroxy or not simultaneously hydroxy and fluorine;
Xi für -O-CH2-, -CH2- oder -CH2-CH2- steht; Xi represents -O-CH2-, -CH2- or -CH2-CH2-;
X2 für -CH- steht; X 2 represents -CH-;
Y für Ci-C i-Alkyl, per- oder teilfluoriertes Ci-C i-Alkyl oder per- oder teilfluoriertes C3-C8-Cycloalkyl steht; Y represents Ci-C i-alkyl, per- or partially fluorinated Ci-C i-alkyl or per- or partially fluorinated C3-C8 cycloalkyl;
Q für -SO2-, -SO- oder -S- steht; Q stands for -SO2-, -SO- or -S-;
m für 5 oder 6 steht; m represents 5 or 6;
q für 1, 2, 3 oder 4 steht; q represents 1, 2, 3 or 4;
t für 0, 1, 2, 3 oder 4 steht t stands for 0, 1, 2, 3 or 4
und ihre Salze, Solvate oder Solvate der Salze, einschließlich aller Kristallmodifikationen. and their salts, solvates or solvates of salts, including all crystal modifications.
3. Verbindungen nach Anspruch 2, worin R1, R2, R3 und R4 unabhängig voneinander für Wasserstoff, Ci-C/i-Alkyl, Ci-C i-Alkoxy, Halogen, 3. Compounds according to claim 2, wherein R 1 , R 2 , R 3 and R 4 independently represent hydrogen, Ci-C / i-alkyl, Ci-C i-alkoxy, halogen,
Hydroxy, Nitril oder Ci-C3-Alkyl-SC>2- stehen; hydroxy, nitrile or Ci-C3-alkyl-SC>2-;
R5, R6und R7 unabhängig voneinander für Wasserstoff, Halogen, Ci-C3-Alkyl oder Nitril stehen; R 5 , R 6 and R 7 independently represent hydrogen, halogen, Ci-C3-alkyl or nitrile;
R8, R9 für Wasserstoff, Hydroxy oder Fluor stehen, jedoch sind R8 und R9 nicht gleichzeitig Hydroxy oder nicht gleichzeitig Hydroxy und Fluor; R 8 , R 9 are hydrogen, hydroxy or fluorine, but R 8 and R 9 are not simultaneously hydroxy or not simultaneously hydroxy and fluorine;
Xi für -O-CH2-, -CH2- oder -CH2-CH2- steht; Xi represents -O-CH2-, -CH2- or -CH2-CH2-;
X2 für -CH- steht; X 2 represents -CH-;
Y für Ci-C/i-Alkyl, per- oder teilfluoriertes Ci-C/i-Alkyl oder per- oder teilfluoriertes C3-C8-Cycloalkyl steht; Y represents Ci-C/i-alkyl, per- or partially fluorinated Ci-C/i-alkyl or per- or partially fluorinated C3-C8-cycloalkyl;
Q für -SO2- oder -S- steht; Q stands for -SO2- or -S-;
m für 5 oder 6 steht;
q für 1 , 2, 3 oder 4 steht; m represents 5 or 6; q represents 1, 2, 3 or 4;
t für 1 , 2, 3 oder 4 steht t stands for 1, 2, 3 or 4
und ihre Salze, Solvate oder Solvate der Salze, einschließlich aller Kristallmodifikationen. and their salts, solvates or solvates of salts, including all crystal modifications.
4. Verbindungen nach Anspruch 3, worin 4. Compounds according to claim 3, wherein
R1, R2, R3 und R4 unabhängig voneinander für Wasserstoff, Halogen oder Hydroxy stehen; R 1 , R 2 , R 3 and R 4 independently represent hydrogen, halogen or hydroxy;
R5, R6und R7 unabhängig voneinander für Wasserstoff oder Halogen stehen; R 5 , R 6 and R 7 independently represent hydrogen or halogen;
R8, R9 für Wasserstoff, Hydroxy oder Fluor stehen, jedoch sind R8 und R9 nicht gleichzeitig Hydroxy oder nicht gleichzeitig Hydroxy und Fluor; R 8 , R 9 are hydrogen, hydroxy or fluorine, but R 8 and R 9 are not simultaneously hydroxy or not simultaneously hydroxy and fluorine;
Xi für -O-CH2- oder -CH2- steht; Xi represents -O-CH2- or -CH 2 -;
X2 für -CH- steht; X 2 represents -CH-;
Y für Ci-C i-Alkyl oder per- oder teilfluoriertes Ci-C i-Alkyl steht; Y represents Ci-C i-alkyl or per- or partially fluorinated Ci-C i-alkyl;
Q für -SO2- steht; Q stands for -SO2-;
m für 5 oder 6 steht; m represents 5 or 6;
q für 2, 3 oder 4 steht; q represents 2, 3 or 4;
t für 2, 3 oder 4 steht t stands for 2, 3 or 4
und ihre Salze, Solvate oder Solvate der Salze, einschließlich aller Kristallmodifikationen. and their salts, solvates or solvates of salts, including all crystal modifications.
5. Verbindungen nach Anspruch 4, worin R1, R2, R3 und R4 unabhängig voneinander für Wasserstoff, Fluor oder Hydroxy stehen; 5. Compounds according to claim 4, wherein R 1 , R 2 , R 3 and R 4 independently represent hydrogen, fluorine or hydroxy;
R5, R6und R7 unabhängig voneinander für Wasserstoff oder Fluor stehen; R 5 , R 6 and R 7 independently represent hydrogen or fluorine;
R8, R9 für Wasserstoff, Hydroxy oder Fluor stehen, jedoch sind R8 und R9 nicht gleichzeitig Hydroxy oder nicht gleichzeitig Hydroxy und Fluor; R 8 , R 9 are hydrogen, hydroxy or fluorine, but R 8 and R 9 are not simultaneously hydroxy or not simultaneously hydroxy and fluorine;
Xi für -O-CH2- oder -CH2- steht; Xi represents -O-CH2- or -CH 2 -;
X2 für -CH- steht; X 2 represents -CH-;
Y für eine tert-Butylgruppe, CF3 oder C2F5 steht; Y represents a tert-butyl group, CF3 or C2F5;
Q für -SO2- steht; Q stands for -SO2-;
m für 5 oder 6 steht; m represents 5 or 6;
q für 2, 3 oder 4 steht;
t für 2, 3 oder 4 steht q represents 2, 3 or 4; t stands for 2, 3 or 4
und ihre Salze, Solvate oder Solvate der Salze, einschließlich aller Kristallmodifikationen. and their salts, solvates or solvates of salts, including all crystal modifications.
6. Verbindungen nach Anspruch 1 bis 5 mit der Bezeichnung 6. Compounds according to claims 1 to 5 with the designation
2-Fluor-8-(4-fluor-3-hydroxyphenyl)-9- {6-[(2R)-2- {4-[(4,4,5,5,5-pentafluorpentyl)- sulfonyl]butyl}pyrrolidin-l-yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(3- Fluorphenyl)-9- {6-[(2S)-2- {3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-6,7- dihydro-5H-benzo [7] annulen-3 -ol 2-Fluoro-8-(4-fluoro-3-hydroxyphenyl)-9- {6-[(2R)-2-{4-[(4,4,5,5,5-pentafluoropentyl)-sulfonyl]butyl} pyrrolidin-l-yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(3-fluorophenyl)-9- {6-[(2S)-2- {3-[ (3,3,3-trifluoropropyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3 -ol
8-(4-Fluorphenyl)-9- {6-[(2R)-2- {2-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]ethyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(4-Fluorophenyl)-9-{6-[(2R)-2-{2-[(4,4,5,5,5-pentafluoropentyl)sulfonyl]ethyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(4-Fluo^henyl)-9- {6-[(2R)-2- {2-[(3,3,3 rifluorpropyl)sulfonyl]ethyl}pyrrolidin-l-yl]hexyl} - 6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(4-Fluo^henyl)-9-{6-[(2R)-2-{2-[(3,3,3rifluoropropyl)sulfonyl]ethyl}pyrrolidin-l-yl]hexyl} - 6,7 -dihydro-5H-benzo[7]annulen-3-ol
8-(4-Fluo^henyl)-9- {6-[(2S)-2- {2-[(4,4,4 rifluorbutyl)sulfonyl]ethyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(4-Fluo^henyl)-9-{6-[(2S)-2-{2-[(4,4,4rifluorobutyl)sulfonyl]ethyl}pyrrolidin-l-yl]hexyl}- 6,7 -dihydro-5H-benzo[7]annulen-3-ol
8-(4-Fluo^henyl)-9- {6-[(2R)-2- {2-[(4,4,4 rifluorbutyl)sulfonyl]ethyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(4-Fluo^henyl)-9-{6-[(2R)-2-{2-[(4,4,4rifluorobutyl)sulfonyl]ethyl}pyrrolidin-l-yl]hexyl}- 6,7 -dihydro-5H-benzo[7]annulen-3-ol
8-(4-Fluo^henyl)-9- {6-[(2R)-2- {2-[(3,3,3 rifluorpropyl)sulfonyl]ethyl}pyrrolidin-l-yl]hexyl} - 6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(4-Fluo^henyl)-9-{6-[(2R)-2-{2-[(3,3,3rifluoropropyl)sulfonyl]ethyl}pyrrolidin-l-yl]hexyl} - 6,7 -dihydro-5H-benzo[7]annulen-3-ol
8-(4-Fluorphenyl)-9- {6-[(2S)-2- {2-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]ethyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(4-Fluorophenyl)-9-{6-[(2S)-2-{2-[(4,4,5,5,5-pentafluoropentyl)sulfonyl]ethyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol
2-Fluor-8-(4-fluorphenyl)-9- {6-[(2S)-2- {2-[(4,4,5,5,5- pentafluorpentyl)sulfonyl]ethyl}pyrrolidin-l-yl]hexyl} -6,7-dihydro-5H-benzo[7]annulen-3-ol 2-Fluor-8-(4-fluorphenyl)-9- {6-[(2R)-2- {2-[(4,4,5,5,5- pentafluorpentyl)sulfonyl]ethyl}pyrrolidin-l-yl]hexyl} -6,7-dihydro-5H-benzo[7]annulen-3-ol2- Fluor-8-(4-fluorphenyl)-9- {6-[(2R)-2- {2-[(4,4,4-trifluorbutyl)sulfonyl]ethyl}pyrrolidin-l - yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 2-Fluoro-8-(4-fluorophenyl)-9-{6-[(2S)-2-{2-[(4,4,5,5,5-pentafluoropentyl)sulfonyl]ethyl}pyrrolidin-l-yl ]hexyl} -6,7-dihydro-5H-benzo[7]annulen-3-ol 2-fluoro-8-(4-fluorophenyl)-9- {6-[(2R)-2- {2-[( 4,4,5,5,5-pentafluoropentyl)sulfonyl]ethyl}pyrrolidin-l-yl]hexyl} -6,7-dihydro-5H-benzo[7]annulen-3-ol2-fluoro-8-(4- fluorophenyl)-9-{6-[(2R)-2-{2-[(4,4,4-trifluorobutyl)sulfonyl]ethyl}pyrrolidin-l - yl]hexyl}-6,7-dihydro-5H-benzo [7]annulen-3-ol
2-Fluor-8-(4-fluo^henyl)-9- {6-[(2S)-2- {2-[(4,4,4 rifluorbutyl)sulfonyl]ethyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 2-Fluoro-8-(4-fluoro^henyl)-9- {6-[(2S)-2- {2-[(4,4,4 rifluorobutyl)sulfonyl]ethyl}pyrrolidin-l-yl]hexyl} -6,7-dihydro-5H-benzo[7]annulen-3-ol
2-Fluor-8-(4-fluo^henyl)-9- {6-[(2S)-2- {2-[(3,3,3 rifluo^ropyl)sulfonyl]ethyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 2-Fluoro-8-(4-fluoro^henyl)-9- {6-[(2S)-2- {2-[(3,3,3 rifluoro^ropyl)sulfonyl]ethyl}pyrrolidin-l-yl] hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol
2-Fluor-8-(4-fluo^henyl)-9- {6-[(2R)-2- {2-[(3,3,3 rifluo^ropyl)sulfonyl]ethyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol
4-Fluor-8-(4-fluorphenyl)-9- {6-[(2R)-2- {4-[(4,4,5,5,5- pentafluo^entyl)sulfonyl]butyl}pyrrolidin-l -yl]hexyl} -6,7-dihydro-5H-benzo[7]annulen-3-ol4 Fluor-8-(4-fluorphenyl)-9- {6-[(2S)-2- {3-[(4,4,5,5,5- pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 4-Fluor-8-(4-fluorphenyl)-9- {6-[(2S)-2- {3-[(3,3,4,4,4- pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l -yl]hexyl} -6,7-dihydro-5H-benzo[7]annulen-3-o8- (3,4-Difluorphenyl)-9- {6-[(2S)-2- {3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 2-Fluoro-8-(4-fluoro^henyl)-9- {6-[(2R)-2- {2-[(3,3,3rifluoro^ropyl)sulfonyl]ethyl}pyrrolidin-l-yl] hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 4-Fluoro-8-(4-fluorophenyl)-9-{6-[(2R)-2-{4-[(4,4,5,5,5-pentafluo^entyl)sulfonyl]butyl}pyrrolidine-l -yl]hexyl} -6,7-dihydro-5H-benzo[7]annulen-3-ol4 Fluoro-8-(4-fluorophenyl)-9- {6-[(2S)-2- {3-[( 4,4,5,5,5-pentafluoropentyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 4-fluoro-8-(4 -fluorophenyl)-9- {6-[(2S)-2- {3-[(3,3,4,4,4- pentafluorobutyl)sulfonyl]propyl}pyrrolidin-l -yl]hexyl} -6,7- dihydro-5H-benzo[7]annulene-3-o8-(3,4-difluorophenyl)-9-{6-[(2S)-2-{3-[(4,4,5,5,5-pentafluoropentyl )sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(3,4-Difluo^henyl)-9- {6-[(2S)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(3,4-Difluoro^henyl)-9- {6-[(2S)-2- {3-[(3,3,4,4,4-pentafluorobutyl)sulfonyl]propyl}pyrrolidin-l yl] hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(3,4-Difluo^henyl)-9- {6-[(2R)-2- {2-[(4,4,5,5,5-pente^^ 8-(3,4-Difluo^henyl)-9- {6-[(2R)-2- {2-[(4,4,5,5,5-pente^^
yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(3,4-Difluorphenyl)-9- {6-[(2S)-2- {3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(3,4-Difluorophenyl)-9-{6-[(2S)-2-{3-[(3,3,3-trifluoropropyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-6, 7-dihydro-5H-benzo[7]annulen-3-ol
8-(3,5-Difluo^henyl)-9- {6-[(2R)-2- {4-[(4,4,5,5,5-pentafluo^entyl)sulfonyl]butyl}pyrrolidin-^ yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(3,5-Difluo^henyl)-9- {6-[(2R)-2- {4-[(4,4,5,5,5-pentafluo^entyl)sulfonyl]butyl}pyrrolidine-^ yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(3,5-Difluo^henyl)-9- {6-[(2R)-2- {2-[(4,4,5,5,5-pentafluo^entyl)sulfonyl]ethyl}pyrrolidm^ yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(3,5-Difluo^henyl)-9- {6-[(2R)-2- {2-[(4,4,5,5,5-pentafluo^entyl)sulfonyl]ethyl}pyrrolidm^yl ]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(2,4-Difluo^henyl)-9- {6-[(2S)-2- {2-[(4,4,5,5,5-pentafluo^entyl)sulfonyl]ethyl}pyrrolidm^ yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(2,4-Difluo^henyl)-9- {6-[(2S)-2- {2-[(4,4,5,5,5-pentafluo^entyl)sulfonyl]ethyl}pyrrolidm^yl ]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(2,4-Difluo^henyl)-9- {6-[(2S)-2- {2-[(4,4,4 rifluorbutyl)sulfonyl]ethyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(2,4-Difluoro^henyl)-9-{6-[(2S)-2-{2-[(4,4,4rifluorobutyl)sulfonyl]ethyl}pyrrolidin-l-yl]hexyl}-6 ,7-dihydro-5H-benzo[7]annulen-3-ol
8-(2,4-Difluo^henyl)-9- {6-[(2S)-2- {2-[(3,3,3-trifluorpropyl)sulfonyl]ethyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(2,4-Difluoro^henyl)-9- {6-[(2S)-2- {2-[(3,3,3-trifluoropropyl)sulfonyl]ethyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(2,4-Difluorphenyl)-9- {6-[(2S)-2- {3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(2,4-Difluorophenyl)-9-{6-[(2S)-2-{3-[(3,3,3-trifluoropropyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-6, 7-dihydro-5H-benzo[7]annulen-3-ol
8- (3,4-Difluo^henyl)-9- {6-[(2R)-2- {4-[(4,4,5,5,5-pentafluo^entyl)sulfonyl]butyl}pyrrolidin-l yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(3,4-Difluo^henyl)-9-{6-[(2R)-2-{4-[(4,4,5,5,5-pentafluo^entyl)sulfonyl]butyl}pyrrolidine-l yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol
9- {6-[(3R)-3- {2-[(4,4,5,5,5-Pentafluo^entyl)sulfonyl]ethyl}mo^holin-4-yl]hexyl}-8-phenyl- 6,7-dihydro-5H-benzo[7]annulen-3-ol 9- {6-[(3R)-3- {2-[(4,4,5,5,5-Pentafluo^entyl)sulfonyl]ethyl}mo^holin-4-yl]hexyl}-8-phenyl- 6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(4-Fluo^henyl)-9- {6-[(2R)-2- {4-[(4,4,5,5,5-pentafluo^entyl)sulfonyl]butyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol
8- (4-Fluo^henyl)-9- {6-[(2R,4R)-4-fluor-2- {3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin- l-yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(4-Fluo^henyl)-9- {6-[(2R)-2- {4-[(4,4,5,5,5-pentafluo^entyl)sulfonyl]butyl}pyrrolidin-l-yl ]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(4-Fluo^henyl)-9-{6-[(2R,4R)-4-fluoro-2-{3-[(4,4,4-trifluorobutyl)sulfonyl]propyl}pyrrolidin-l-yl ]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol
9- [6-(4,4-Difluor-2- {3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-l-yl)hexyl]-8-(4- fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol 9-[6-(4,4-Difluoro-2-{3-[(4,4,4-trifluorobutyl)sulfonyl]propyl}pyrrolidin-l-yl)hexyl]-8-(4-fluorophenyl)-6, 7-dihydro-5H-benzo[7]annulen-3-ol
(3R,5R)-l- {6-[8-(4-Fluorphenyl)-3-hydroxy-6,7-dihydro-5H-benzo[7]annulen-9-yl]hexyl}-5- {3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-3-ol (3R,5R)-l-{6-[8-(4-fluorophenyl)-3-hydroxy-6,7-dihydro-5H-benzo[7]annulen-9-yl]hexyl}-5- {3- [(4,4,4-trifluorobutyl)sulfonyl]propyl}pyrrolidin-3-ol
8-(3-Hydroxyphenyl)-9- {6-[(2S)-2- {3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin- l-yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(3-Hydroxyphenyl)-9- {6-[(2S)-2- {3-[(4,4,5,5,5-pentafluoropentyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(4-Fluorphenyl)-9- {6-[(2S)-2- {3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(4-Fluorophenyl)-9-{6-[(2S)-2-{3-[(4,4,5,5,5-pentafluoropentyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(3-Fluorphenyl)-9- {6-[(2S)-2- {3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(3-Fluorophenyl)-9-{6-[(2S)-2-{3-[(4,4,5,5,5-pentafluoropentyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(3,5-Difluorphenyl)-9- {6-[(2S)-2- {3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin- l-yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(3,5-Difluorophenyl)-9-{6-[(2S)-2-{3-[(4,4,5,5,5-pentafluoropentyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl }-6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(3-Hydroxyphenyl)-9- {6-[(2S)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(3-Hydroxyphenyl)-9- {6-[(2S)-2- {3-[(3,3,4,4,4-pentafluorobutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(4-Fluorphenyl)-9- {6-[(2S)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(4-Fluorophenyl)-9-{6-[(2S)-2-{3-[(3,3,4,4,4-pentafluorobutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(3,5-Difluo^henyl)-9- {6-[(2S)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(3,5-Difluoro^henyl)-9-{6-[(2S)-2-{3-[(3,3,4,4,4-pentafluorobutyl)sulfonyl]propyl}pyrrolidin-l-yl ]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(2-Fluorphenyl)-9- {6-[(2S)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(2-Fluorophenyl)-9-{6-[(2S)-2-{3-[(3,3,4,4,4-pentafluorobutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(2-Fluorphenyl)-9- {6-[(2R)-2- {3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(2-Fluorophenyl)-9-{6-[(2R)-2-{3-[(4,4,5,5,5-pentafluoropentyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(4-Fluorphenyl)-9- {6-[(2R)-2- {3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(4-Fluorophenyl)-9-{6-[(2R)-2-{3-[(4,4,5,5,5-pentafluoropentyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(3-Fluorphenyl)-9- {6-[(2R)-2- {3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(3-Fluorophenyl)-9-{6-[(2R)-2-{3-[(4,4,5,5,5-pentafluoropentyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(3-Hydroxyphenyl)-9- {6-[(2R)-2- {3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin- l-yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(3-Hydroxyphenyl)-9- {6-[(2R)-2- {3-[(4,4,5,5,5-pentafluoropentyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(4-Fluorphenyl)-9- {6-[(2R)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(3-Fluorphenyl)-9- {6-[(2R)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(4-Fluorophenyl)-9-{6-[(2R)-2-{3-[(3,3,4,4,4-pentafluorobutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(3-Fluorophenyl)-9-{6-[(2R)-2-{3-[(3,3,4,4,4-pentafluorobutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(3-Fluorphenyl)-9- {6-[(2S)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(3-Fluorophenyl)-9-{6-[(2S)-2-{3-[(3,3,4,4,4-pentafluorobutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(4-Fluo^henyl)-9- {6-[(2R)-2- {3-[(4,4,4 rifluorbutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl} 6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(4-Fluo^henyl)-9- {6-[(2R)-2- {3-[(4,4,4rifluorobutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl} 6,7- dihydro-5H-benzo[7]annulen-3-ol
8-(3-Fluo^henyl)-9- {6-[(2R)-2- {3-[(4,4,4 rifluorbutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl} 6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(3-Fluo^henyl)-9- {6-[(2R)-2- {3-[(4,4,4rifluorobutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl} 6,7- dihydro-5H-benzo[7]annulen-3-ol
8-(4-Fluorphenyl)-9- {6-[(2R)-2- {3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(4-Fluorophenyl)-9- {6-[(2R)-2- {3-[(3,3,3-trifluoropropyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-6,7- dihydro-5H-benzo[7]annulen-3-ol
8-(3-Fluorphenyl)-9- {6-[(2R)-2- {3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(3-Fluorophenyl)-9- {6-[(2R)-2- {3-[(3,3,3-trifluoropropyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-6,7- dihydro-5H-benzo[7]annulen-3-ol
8-(3,5-Difluorphenyl)-9- {6-[(2R)-2- {3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(3,5-Difluorophenyl)-9-{6-[(2R)-2-{3-[(3,3,3-trifluoropropyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-6, 7-dihydro-5H-benzo[7]annulen-3-ol
8-(4-Fluo^henyl)-9- {6-[(2S)-2- {3-[(4,4,4 rifluorbutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl} 6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(4-Fluo^henyl)-9- {6-[(2S)-2- {3-[(4,4,4rifluorobutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl} 6,7- dihydro-5H-benzo[7]annulen-3-ol
8- (4-Fluorphenyl)-9- {6-[(2S)-2- {3-[(5,5,5-trifluorpentyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(4-Fluorophenyl)-9-{6-[(2S)-2-{3-[(5,5,5-trifluoropentyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-6,7- dihydro-5H-benzo[7]annulen-3-ol
9- {6-[(2S)-2- {3-[(3,3-Dimethylbutyl)sulfonyl]propyl}pyrrolidin-l -yl]hexyl} -8-(4-fluorphenyl) 6,7-dihydro-5H-benzo[7]annulen-3-ol 9-{6-[(2S)-2-{3-[(3,3-dimethylbutyl)sulfonyl]propyl}pyrrolidin-l -yl]hexyl} -8-(4-fluorophenyl) 6,7-dihydro-5H -benzo[7]annulen-3-ol
8-(4-Fluorphenyl)-9- {6-[(2S)-2- {3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(4-Fluorophenyl)-9- {6-[(2S)-2- {3-[(3,3,3-trifluoropropyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-6,7- dihydro-5H-benzo[7]annulen-3-ol
8- (3-Fluorphenyl)-9- {6-[(2S)-2- {3-[(5,5,5-trifluorpentyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(3-Fluorophenyl)-9-{6-[(2S)-2-{3-[(5,5,5-trifluoropentyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-6,7- dihydro-5H-benzo[7]annulen-3-ol
9- {6-[(2S)-2- {3-[(3,3-Dimethylbutyl)sulfonyl]propyl}pyrrolidin-l -yl]hexyl} -8-(3-fluorphenyl) 6,7-dihydro-5H-benzo[7]annulen-3-ol 9-{6-[(2S)-2-{3-[(3,3-dimethylbutyl)sulfonyl]propyl}pyrrolidin-l -yl]hexyl} -8-(3-fluorophenyl) 6,7-dihydro-5H -benzo[7]annulen-3-ol
8-(2,4-Difluo^henyl)-9- {6-[(2S)-2- {3-[(4,4,5,5,5-pentafluo^entyl)sulfonyl]propyl}pyrrolidin- l-yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(2,4-Difluo^henyl)-9- {6-[(2S)-2- {3-[(4,4,5,5,5-pentafluo^entyl)sulfonyl]propyl}pyrrolidine- l -yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(2,4-Difluo^henyl)-9- {6-[(2S)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(2,4-Difluoro^henyl)-9- {6-[(2S)-2- {3-[(3,3,4,4,4-pentafluorobutyl)sulfonyl]propyl}pyrrolidin-l yl] hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(2,4-Difluorphenyl)-9- {6-[(2S)-2- {3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(2,4-Difluo^henyl)-9- {6-[(2S)-2- {3-[(5,5,5-trifluorpentyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(2,4-Difluorophenyl)-9-{6-[(2S)-2-{3-[(4,4,4-trifluorobutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-6, 7-dihydro-5H-benzo[7]annulen-3-ol 8-(2,4-Difluoro^henyl)-9- {6-[(2S)-2- {3-[(5,5,5-trifluoropentyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(3-Fluo^henyl)-9- {6-[(2S)-2- {3-[(4,4,4 rifluorbutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(3-Fluo^henyl)-9-{6-[(2S)-2-{3-[(4,4,4rifluorobutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}- 6,7 -dihydro-5H-benzo[7]annulen-3-ol
8-(2-Fluorphenyl)-9- {6-[(2S)-2- {3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(2-Fluorophenyl)-9- {6-[(2S)-2- {3-[(3,3,3-trifluoropropyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-6,7- dihydro-5H-benzo[7]annulen-3-ol
8-(2,4-Difluo^henyl)-9- {6-[(2R)-2- {3-[(4,4,5,5,5-pentafluo^entyl)sulfonyl]propyl}pyrrolidin^ l-yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(2,4-Difluo^henyl)-9- {6-[(2R)-2- {3-[(4,4,5,5,5-pentafluo^entyl)sulfonyl]propyl}pyrrolidine^ l -yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(2,4-Difluo^henyl)-9- {6-[(2R)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin- l-yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(2,4-Difluoro^henyl)-9-{6-[(2R)-2-{3-[(3,3,4,4,4-pentafluorobutyl)sulfonyl]propyl}pyrrolidin-l-yl ]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(2,4-Difluorphenyl)-9- {6-[(2R)-2- {3-[(3,3,3-trifluorpropyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(2,4-Difluorophenyl)-9-{6-[(2R)-2-{3-[(3,3,3-trifluoropropyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-6, 7-dihydro-5H-benzo[7]annulen-3-ol
8-(2,4-Difluo^henyl)-9- {6-[(2S)-2- {3-[(3,3-dimethylbutyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(2,4-Difluoro^henyl)-9-{6-[(2S)-2-{3-[(3,3-dimethylbutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-6, 7-dihydro-5H-benzo[7]annulen-3-ol
8-(2,4-Difluorphenyl)-9- {6-[(2R)-2- {3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(2,4-Difluorophenyl)-9-{6-[(2R)-2-{3-[(4,4,4-trifluorobutyl)sulfonyl]propyl}pyrrolidin-l-yl]hexyl}-6, 7-dihydro-5H-benzo[7]annulen-3-ol
8-(3-Hydroxyphenyl)-9- {6-[(3R)-3- {2-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]ethyl}morpholin-4- yl]hexyl}-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(3-Hydroxyphenyl)-9- {6-[(3R)-3- {2-[(4,4,5,5,5-pentafluoropentyl)sulfonyl]ethyl}morpholin-4-yl]hexyl}- 6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(3-Fluorphenyl)-9- {5-[(2S)-2- {3-[(4,4,5,5,5-pentfluorpentyl)sulfonyl]propyl}pyrrolidin-l- yl]pentyl} -6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(3-Fluorophenyl)-9-{5-[(2S)-2-{3-[(4,4,5,5,5-pentfluoropentyl)sulfonyl]propyl}pyrrolidin-l-yl]pentyl} - 6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(3-Fluorphenyl)-9- {5-[(2S)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl]pentyl} -6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(3-Fluorophenyl)-9-{5-[(2S)-2-{3-[(3,3,4,4,4-pentafluorobutyl)sulfonyl]propyl}pyrrolidin-l-yl]pentyl} - 6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(4-Fluo^henyl)-9- {5-[(2S)-2- {3-[(4,4,5,5,5-pentafluorpentyl)sulfonyl]propyl}pyrrolidin-l- yl]pentyl} -6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(4-Fluo^henyl)-9-{5-[(2S)-2-{3-[(4,4,5,5,5-pentafluoropentyl)sulfonyl]propyl}pyrrolidin-l-yl]pentyl } -6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(4-Fluorphenyl)-9- {5-[(2S)-2- {3-[(3,3,4,4,4-pentafluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl]pentyl} -6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(4-Fluorophenyl)-9-{5-[(2S)-2-{3-[(3,3,4,4,4-pentafluorobutyl)sulfonyl]propyl}pyrrolidin-l-yl]pentyl} - 6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(4-Fluo^henyl)-9- {5-[(2R)-2- {4-[(4,4,5,5,5-pentafluo^entyl)sulfonyl]butyl}pyrrolidin-l- yl]pentyl} -6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(4-Fluo^henyl)-9-{5-[(2R)-2-{4-[(4,4,5,5,5-pentafluo^entyl)sulfonyl]butyl}pyrrolidin-l-yl ]pentyl} -6,7-dihydro-5H-benzo[7]annulen-3-ol
8-(4-Fluorphenyl)-9- {5-[(2S)-2- {3-[(4,4,4-trifluorbutyl)sulfonyl]propyl}pyrrolidin-l- yl]pentyl} -6, 8-(4-Fluorophenyl)-9-{5-[(2S)-2-{3-[(4,4,4-trifluorobutyl)sulfonyl]propyl}pyrrolidin-l-yl]pentyl}-6,
7-dihydro-5H-benzo[7]annulen-3-ol 7-dihydro-5H-benzo[7]annulen-3-ol
8-(4-Fluorphenyl)-9- {5-[(2S)-2- {3-[(5,5,5-trifluorpentyl)sulfonyl]propyl}pyrrolidin-l- yl]pentyl} -6,7-dihydro-5H-benzo[7]annulen-3-ol
9- {5-[(2S)-2- {3-[(3,3-Dimethylbutyl)sulfonyl]propyl}pyrrolidin-l-yl]pentyl} -8-(4- fluorphenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol 8-(4-Fluorophenyl)-9- {5-[(2S)-2- {3-[(5,5,5-trifluoropentyl)sulfonyl]propyl}pyrrolidin-l-yl]pentyl} -6,7- dihydro-5H-benzo[7]annulen-3-ol 9-{5-[(2S)-2-{3-[(3,3-dimethylbutyl)sulfonyl]propyl}pyrrolidin-l-yl]pentyl} -8-(4-fluorophenyl)-6,7-dihydro- 5H-benzo[7]annulen-3-ol
Verbindung, wie in einem der Ansprüche 1 bis 6 definiert, zur Verwendung bei der Behandlung und/oder Prophylaxe von Krankheiten. A compound as defined in any one of claims 1 to 6 for use in the treatment and/or prophylaxis of diseases.
Verwendung einer Verbindung, wie in einem der Ansprüche 1 bis 6 definiert, zur Herstellung eines Arzneimittels zur Behandlung und/oder Prophylaxe von Krankheiten. Use of a compound as defined in any one of claims 1 to 6 for the manufacture of a medicament for the treatment and/or prophylaxis of diseases.
9. Verbindung der Formel (I), wie in einem der Ansprüche 1 bis 6 definiert, zur Verwendung in einem Verfahren zur Inhibition der Ovulation, zur Hemmung der Spermienreifung, zur Linderung der Symptome der Andropause und Menopause, d. h. zur männlichen und weiblichen Hormonersatztherapie, zur Prävention bzw. Prophylaxe und zur Behandlung von mit der Dysmenorrhoe einhergehenden Beschwerden, von dysfunktionellen uterinen Blutungen, der Akne, von kardiovaskulären Erkrankungen, der Hypercholesterinämie und der Hyperlipidämie, der Artherosclerose, der Proliferation arterieller Glattmuskelzellen, des Atemnotsyndroms bei Neugeborenen, des primären pulmonaren Bluthochdrucks, der Osteoporose, des Knochenverlusts bei postmenopausalen Frauen, bei hysterektomierten Frauen oder bei Frauen, die mit LHRH Agonisten oder Antagonisten behandelt wurden, der rheumatoiden Artritis, der Alzheimerschen Krankheit, der Endometriose, von Myomen, von hormonabhängigen Tumoren (auch bei prämenopausalen Frauen), wie zum Beispiel Mamma- oder Endometriumscarcinom, der Unfruchtbarkeit, von prostatischen Erkrankungen, von benignen Erkrankungen der Brust, wie z.B. Mastopathie, von Schlaganfall, von Alzheimer und von anderen Erkrankungen des zentralen Nervensystems, die mit dem Zelltod von Neuronen einhergehen. 9. A compound of formula (I) as defined in any one of claims 1 to 6 for use in a method for inhibiting ovulation, inhibiting sperm maturation, alleviating the symptoms of andropause and menopause, i.e. H. for male and female hormone replacement therapy, for the prevention or prophylaxis and for the treatment of symptoms associated with dysmenorrhea, dysfunctional uterine bleeding, acne, cardiovascular diseases, hypercholesterolemia and hyperlipidemia, atherosclerosis, the proliferation of arterial smooth muscle cells, and respiratory distress syndrome newborns, primary pulmonary hypertension, osteoporosis, bone loss in postmenopausal women, in hysterectomized women or in women treated with LHRH agonists or antagonists, rheumatoid artritis, Alzheimer's disease, endometriosis, fibroids, hormone-dependent tumors ( also in premenopausal women), such as breast or endometrial cancer, infertility, prostatic diseases, benign diseases of the breast such as mastopathy, stroke, Alzheimer's disease and other diseases of the central nervous system associated with the cell death of neurons accompanied.
10. Verwendung gemäß Anspruch 8 zur Herstellung eines Arzneimittels zur Inhibition der Ovulation, zur Hemmung der Spermienreifung, zur Linderung der Symptome der Andropause und Menopause, d. h. zur männlichen und weiblichen Hormonersatztherapie, zur Prävention bzw. Prophylaxe und zur Behandlung von mit der Dysmenorrhoe einhergehenden Beschwerden, von dysfunktionellen uterinen Blutungen, der Akne, von kardiovaskulären Erkrankungen, der Hypercholesterinämie und der Hyperlipidämie, der Artherosclerose, der Proliferation arterieller Glattmuskelzellen, des Atemnotsyndroms bei Neugeborenen, des primären pulmonaren Bluthochdrucks, der Osteoporose, des Knochenverlusts bei postmenopausalen Frauen, bei hysterektomierten Frauen oder bei Frauen, die mit LHRH Agonisten oder Antagonisten behandelt wurden, der rheumatoiden Artritis, der Alzheimerschen Krankheit, der Endometriose, von Myomen, von hormonabhängigen Tumoren (auch bei prämenopausalen Frauen), wie zum Beispiel Mamma- oder Endometriumscarcinom, der Unfruchtbarkeit, von prostatischen Erkrankungen, von benignen
Erkrankungen der Brust, wie z.B. Mastopathie, von Schlaganfall, von Alzheimer und von anderen Erkrankungen des zentralen Nervensystems, die mit dem Zelltod von Neuronen einhergehen. 10. Use according to claim 8 for the production of a medicament for inhibiting ovulation, for inhibiting sperm maturation, for alleviating the symptoms of andropause and menopause, ie for male and female hormone replacement therapy, for prevention or prophylaxis and for treating complaints associated with dysmenorrhea , dysfunctional uterine bleeding, acne, cardiovascular disease, hypercholesterolemia and hyperlipidemia, atherosclerosis, arterial smooth muscle cell proliferation, neonatal respiratory distress syndrome, primary pulmonary hypertension, osteoporosis, bone loss in postmenopausal women, in hysterectomized women, or in women who have been treated with LHRH agonists or antagonists, rheumatoid artritis, Alzheimer's disease, endometriosis, myomas, hormone-dependent tumors (also in premenopausal women), such as breast or endometrial cancer, infertility, prostatic diseases , from benign Breast diseases such as mastopathy, stroke, Alzheimer's disease and other diseases of the central nervous system that involve cell death of neurons.
11. Arzneimittel enthaltend eine Verbindung, wie in einem der Ansprüche 1 bis 6 definiert, in Kombination mit einem oder mehreren weiteren Wirkstoffen, insbesondere mit Aromataseinhibitoren, 17beta HSDl Inhibitoren, Steroid Sulfatase (STS)-Inhibitoren, LHRH- Analoga, LHRH Antagonisten, GnRH-Agonisten und -Antagonisten, Kisspeptin Rezeptor (KISSR)-Antagonisten, selektiven Androgen Rezeptor Modulatoren (SARMs), Androgenen, selektiven Progesteron Rezeptor Modulatoren (SPRMs), Gestagenen, Progesteron-Rezeptor- Antagonisten, oralen Kontrazeptiva, Östrogenen, Inhibitoren der Mitogen Aktivierten Protein (MAP) Kinasen sowie Inhibitoren der MAP Kinasen, Kinasen (Mkk3/6, Mekl/2, Erkl/2) Inhibitoren der Proteinkinasen B (PKBa/ß/γ; Aktl/2/3), Inhibitoren der Phosphoinositid-3- Kinasen (PI3K), Inhibitoren der Cyclin-abhängigen Kinase (CDK1/2), Inhibitoren des Hypoxie Induzierten Signalweges (HIFI alpha Inhibitoren, Aktivatoren der Prolylhydroxylasen), Histon Deacetylase (HDAC)-Inhibitoren, Prostaglandin F Rezeptor (FP) (PTGFR)-Antagonisten und Nicht-steroidale Enzündungshemmern (NSAIDs) zur Behandlung der Endometriose. 11. Medicaments containing a compound as defined in one of claims 1 to 6, in combination with one or more other active ingredients, in particular with aromatase inhibitors, 17beta HSD1 inhibitors, steroid sulfatase (STS) inhibitors, LHRH analogues, 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, mitogen activated protein inhibitors (MAP) kinases and inhibitors of the MAP kinases, kinases (Mkk3/6, Mekl/2, Erkl/2) inhibitors of the protein kinases B (PKBa/ß/γ; Aktl/2/3), inhibitors of the phosphoinositide 3-kinases ( PI3K), inhibitors of cyclin-dependent kinase (CDK1/2), inhibitors of the hypoxia-induced signaling pathway (HIFI alpha inhibitors, activators of prolyl hydroxylases), histone deacetylase (HDAC) inhibitors, prostaglandin F receptor (FP) (PTGFR) antagonists and Non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of endometriosis.
12. Arzneimittel enthaltend eine Verbindung, wie in einem der Ansprüche 1 bis 6 definiert, in Kombination mit einem inerten, nichttoxischen, pharmazeutisch geeigneten Hilfsstoff. 12. Medicaments containing a compound as defined in any one of claims 1 to 6, in combination with an inert, non-toxic, pharmaceutically suitable excipient.
13. Arzneimittel nach Anspruch 11 oder 12 zur Inhibition der Ovulation, zur Hemmung der Spermienreifung, zur Linderung der Symptome der Andropause und Menopause, d. h. zur männlichen und weiblichen Hormonersatztherapie, zur Prävention bzw. Prophylaxe und zur Behandlung von mit der Dysmenorrhoe einhergehenden Beschwerden, von dysfunktionellen uterinen Blutungen, der Akne, von kardiovaskulären Erkrankungen, der Hypercholesterinämie und der Hyperlipidämie, der Artherosclerose, der Proliferation arterieller Glattmuskelzellen, des Atemnotsyndroms bei Neugeborenen, des primären pulmonaren Bluthochdrucks, der Osteoporose, des Knochenverlusts bei postmenopausalen Frauen, bei hysterektomierten Frauen oder bei Frauen, die mit LHRH Agonisten oder Antagonisten behandelt wurden, der rheumatoiden Artritis, der Alzheimerschen Krankheit, der Endometriose, von Myomen, von hormonabhängigen Tumoren, wie zum Beispiel Mamma- oder Endometriumscarcinom, der Unfruchtbarkeit, von prostatischen Erkrankungen, von benignen Erkrankungen der Brust, wie z.B. Mastopathie, von Schlaganfall, von Alzheimer und von anderen Erkrankungen des zentralen Nervensystems, die mit dem Zelltod von Neuronen einhergehen.
13. Medicament according to claim 11 or 12 for inhibiting ovulation, inhibiting sperm maturation, alleviating the symptoms of andropause and menopause, d. H. for male and female hormone replacement therapy, for the prevention or prophylaxis and for the treatment of symptoms associated with dysmenorrhea, dysfunctional uterine bleeding, acne, cardiovascular diseases, hypercholesterolemia and hyperlipidemia, atherosclerosis, the proliferation of arterial smooth muscle cells, and respiratory distress syndrome newborns, primary pulmonary hypertension, osteoporosis, bone loss in postmenopausal women, in hysterectomized women or in women treated with LHRH agonists or antagonists, rheumatoid artritis, Alzheimer's disease, endometriosis, fibroids, hormone-dependent tumors, such as breast or endometrial carcinoma, infertility, prostatic diseases, benign diseases of the breast such as mastopathy, stroke, Alzheimer's disease and other diseases of the central nervous system that are associated with the cell death of neurons.
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