EP2734505A1 - 3-(fluorvinyl)pyrazole und ihre verwendung - Google Patents
3-(fluorvinyl)pyrazole und ihre verwendungInfo
- Publication number
- EP2734505A1 EP2734505A1 EP12735557.6A EP12735557A EP2734505A1 EP 2734505 A1 EP2734505 A1 EP 2734505A1 EP 12735557 A EP12735557 A EP 12735557A EP 2734505 A1 EP2734505 A1 EP 2734505A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- mmol
- compound
- formula
- alkyl
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- AKGWZPXDUMWWQE-UHFFFAOYSA-N 5-(2-fluoroethenyl)-1H-pyrazole Chemical class FC=CC=1C=CNN=1 AKGWZPXDUMWWQE-UHFFFAOYSA-N 0.000 title abstract description 3
- 238000011282 treatment Methods 0.000 claims abstract description 34
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 33
- 201000010099 disease Diseases 0.000 claims abstract description 29
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 455
- 238000000034 method Methods 0.000 claims description 315
- -1 Hydroxy, hydroxymethyl Chemical group 0.000 claims description 156
- 239000011737 fluorine Substances 0.000 claims description 63
- 229910052731 fluorine Inorganic materials 0.000 claims description 63
- 239000002904 solvent Substances 0.000 claims description 58
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 55
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 52
- 230000008569 process Effects 0.000 claims description 49
- 150000003839 salts Chemical class 0.000 claims description 47
- 206010028980 Neoplasm Diseases 0.000 claims description 44
- 239000012453 solvate Substances 0.000 claims description 41
- 229910052739 hydrogen Inorganic materials 0.000 claims description 39
- 239000001257 hydrogen Substances 0.000 claims description 39
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
- 125000001424 substituent group Chemical group 0.000 claims description 31
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 24
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 23
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims description 22
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 21
- 238000002360 preparation method Methods 0.000 claims description 19
- 239000000460 chlorine Substances 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 18
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- 239000012442 inert solvent Substances 0.000 claims description 17
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 125000001153 fluoro group Chemical group F* 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 230000002265 prevention Effects 0.000 claims description 11
- 125000006239 protecting group Chemical group 0.000 claims description 11
- 125000004076 pyridyl group Chemical group 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- 210000004072 lung Anatomy 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 230000006806 disease prevention Effects 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 208000006011 Stroke Diseases 0.000 claims description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- 150000003217 pyrazoles Chemical class 0.000 claims description 7
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 7
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- 201000004681 Psoriasis Diseases 0.000 claims description 6
- 206010003119 arrhythmia Diseases 0.000 claims description 6
- 230000006793 arrhythmia Effects 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 6
- 230000000302 ischemic effect Effects 0.000 claims description 6
- 210000003734 kidney Anatomy 0.000 claims description 6
- 208000002780 macular degeneration Diseases 0.000 claims description 6
- 208000010125 myocardial infarction Diseases 0.000 claims description 6
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 5
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 5
- 206010019280 Heart failures Diseases 0.000 claims description 5
- 208000008601 Polycythemia Diseases 0.000 claims description 5
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000003566 oxetanyl group Chemical group 0.000 claims description 5
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 5
- ICFGFAUMBISMLR-UHFFFAOYSA-N 1h-pyrazole-5-carbaldehyde Chemical compound O=CC=1C=CNN=1 ICFGFAUMBISMLR-UHFFFAOYSA-N 0.000 claims description 4
- OPUVZRHORLQBSD-UHFFFAOYSA-N 2-(1h-pyrazol-5-ylmethylsulfonyl)-1,3-benzothiazole Chemical class N=1C2=CC=CC=C2SC=1S(=O)(=O)CC=1C=CNN=1 OPUVZRHORLQBSD-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- 150000001299 aldehydes Chemical class 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 230000003176 fibrotic effect Effects 0.000 claims 4
- 201000003068 rheumatic fever Diseases 0.000 claims 1
- 206010021143 Hypoxia Diseases 0.000 abstract description 7
- 230000003463 hyperproliferative effect Effects 0.000 abstract description 5
- 230000001146 hypoxic effect Effects 0.000 abstract description 5
- 230000001225 therapeutic effect Effects 0.000 abstract description 4
- 230000006978 adaptation Effects 0.000 abstract description 3
- 230000002491 angiogenic effect Effects 0.000 abstract description 3
- 230000002503 metabolic effect Effects 0.000 abstract description 3
- 238000009097 single-agent therapy Methods 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 2
- 229940127557 pharmaceutical product Drugs 0.000 abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 534
- 239000000243 solution Substances 0.000 description 301
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 219
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 196
- 239000000203 mixture Substances 0.000 description 154
- 238000005160 1H NMR spectroscopy Methods 0.000 description 133
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 118
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 99
- 239000003480 eluent Substances 0.000 description 99
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 90
- 238000002953 preparative HPLC Methods 0.000 description 83
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 81
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 75
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 74
- 229920006395 saturated elastomer Polymers 0.000 description 73
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 72
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 67
- 239000000741 silica gel Substances 0.000 description 66
- 229910002027 silica gel Inorganic materials 0.000 description 66
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 65
- 238000001035 drying Methods 0.000 description 65
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 62
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 62
- 239000012074 organic phase Substances 0.000 description 60
- 239000011541 reaction mixture Substances 0.000 description 57
- 238000003756 stirring Methods 0.000 description 56
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 50
- 229920002554 vinyl polymer Polymers 0.000 description 49
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 46
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 45
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 44
- 239000008346 aqueous phase Substances 0.000 description 44
- 239000007787 solid Substances 0.000 description 43
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 40
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 39
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 37
- 238000004440 column chromatography Methods 0.000 description 36
- 229910052938 sodium sulfate Inorganic materials 0.000 description 36
- 235000011152 sodium sulphate Nutrition 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 34
- 235000017557 sodium bicarbonate Nutrition 0.000 description 34
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- 238000001816 cooling Methods 0.000 description 33
- 239000000047 product Substances 0.000 description 33
- 238000005481 NMR spectroscopy Methods 0.000 description 32
- 235000019270 ammonium chloride Nutrition 0.000 description 32
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 32
- 235000019341 magnesium sulphate Nutrition 0.000 description 32
- OCKGFTQIICXDQW-ZEQRLZLVSA-N 5-[(1r)-1-hydroxy-2-[4-[(2r)-2-hydroxy-2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-4-methyl-3h-2-benzofuran-1-one Chemical compound C1=C2C(=O)OCC2=C(C)C([C@@H](O)CN2CCN(CC2)C[C@H](O)C2=CC=C3C(=O)OCC3=C2C)=C1 OCKGFTQIICXDQW-ZEQRLZLVSA-N 0.000 description 31
- 229910052786 argon Inorganic materials 0.000 description 31
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 30
- 239000012071 phase Substances 0.000 description 28
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 25
- 239000000706 filtrate Substances 0.000 description 24
- 239000000284 extract Substances 0.000 description 23
- 239000012043 crude product Substances 0.000 description 22
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 21
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 21
- 150000003254 radicals Chemical class 0.000 description 21
- 235000019253 formic acid Nutrition 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 20
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 19
- 238000005191 phase separation Methods 0.000 description 19
- 238000000825 ultraviolet detection Methods 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 18
- 239000011780 sodium chloride Substances 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 17
- 238000001914 filtration Methods 0.000 description 17
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 17
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 16
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 16
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 16
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 16
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 239000002585 base Substances 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
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- 238000000746 purification Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 12
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 12
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 11
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
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- CXBDYQVECUFKRK-UHFFFAOYSA-N 1-methoxybutane Chemical compound CCCCOC CXBDYQVECUFKRK-UHFFFAOYSA-N 0.000 description 9
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 9
- 230000008020 evaporation Effects 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 9
- 239000012280 lithium aluminium hydride Substances 0.000 description 9
- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 description 9
- 239000011591 potassium Substances 0.000 description 9
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- 239000011734 sodium Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- BMTAFVWTTFSTOG-UHFFFAOYSA-N Butylate Chemical compound CCSC(=O)N(CC(C)C)CC(C)C BMTAFVWTTFSTOG-UHFFFAOYSA-N 0.000 description 8
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 8
- 235000010290 biphenyl Nutrition 0.000 description 8
- 239000004305 biphenyl Substances 0.000 description 8
- 125000006267 biphenyl group Chemical group 0.000 description 8
- 238000002955 isolation Methods 0.000 description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 8
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 8
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- 102000004169 proteins and genes Human genes 0.000 description 8
- 230000035484 reaction time Effects 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 229910052708 sodium Inorganic materials 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 7
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- KVJXBPDAXMEYOA-CXANFOAXSA-N trilostane Chemical compound OC1=C(C#N)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@@]32O[C@@H]31 KVJXBPDAXMEYOA-CXANFOAXSA-N 0.000 description 1
- 229960001670 trilostane Drugs 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
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- 229960000294 triptorelin pamoate Drugs 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- FZFRVZDLZISPFJ-UHFFFAOYSA-N tungsten(6+) Chemical compound [W+6] FZFRVZDLZISPFJ-UHFFFAOYSA-N 0.000 description 1
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- 208000026517 ureter neoplasm Diseases 0.000 description 1
- 201000011476 ureteral benign neoplasm Diseases 0.000 description 1
- AUFUWRKPQLGTGF-FMKGYKFTSA-N uridine triacetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)NC(=O)C=C1 AUFUWRKPQLGTGF-FMKGYKFTSA-N 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 208000012991 uterine carcinoma Diseases 0.000 description 1
- 229960000653 valrubicin Drugs 0.000 description 1
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 1
- 229950010938 valspodar Drugs 0.000 description 1
- 108010082372 valspodar Proteins 0.000 description 1
- 229960002730 vapreotide Drugs 0.000 description 1
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- 229950000578 vatalanib Drugs 0.000 description 1
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 1
- ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N verteporfin Chemical compound C=1C([C@@]2([C@H](C(=O)OC)C(=CC=C22)C(=O)OC)C)=NC2=CC(C(=C2C=C)C)=NC2=CC(C(=C2CCC(O)=O)C)=NC2=CC2=NC=1C(C)=C2CCC(=O)OC ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N 0.000 description 1
- 229960003895 verteporfin Drugs 0.000 description 1
- 229950005577 vesnarinone Drugs 0.000 description 1
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 1
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- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 1
- ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A61K31/415—1,2-Diazoles
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- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
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- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
Definitions
- the present application relates to novel 3- (fluorovinyl) pyrazole derivatives, processes for their preparation, their use for the treatment and / or prevention of diseases and their use for the preparation of medicaments for the treatment and / or prevention of diseases, in particular for treatment and / or prevention of hyperproliferative and angiogenic disorders, as well as those diseases that arise through metabolic adaptation to hypoxic conditions.
- Such treatments may be monotherapy or in combination with other medicines or other therapeutic measures.
- Cancers are the result of uncontrolled cell growth of various tissues. In many cases, the new cells invade existing tissues (invasive growth) or they metastasize to distant organs. Cancers occur in various organs and often have tissue-specific disease courses. Therefore, the term cancer as a generic term describes a large group of defined diseases of various organs, tissues and cell types. In 2002, 4.4 million people worldwide were diagnosed with tumors of the breast, bowel, ovaries, lungs or prostate. For the same year, approximately 2.5 million deaths were reported as a result of these conditions (Globocan 2002 Report). In the US alone, over 1.25 million new cases and more than 500,000 cancer deaths were predicted for 2005. The majority of these new cases involve cancers of the intestine ( ⁇ 100,000), lung ( ⁇ 170,000), breast ( ⁇ 210,000) and prostate (- 230,000). A further 15% increase in cancer over the next 10 years is expected (American Cancer Society, Cancer Facts and Figures 2005).
- early stage tumors may be removed by surgical and radiotherapeutic measures.
- metastatic tumors can only be treated palliatively by chemotherapeutic agents.
- the goal here is to achieve the optimal combination of improving the quality of life and extending the lifetime.
- Chemotherapies often consist of combinations of cytotoxic drugs. The majority of these substances have a binding mechanism to tubulin, or they are compounds that interact with the formation and processing of nucleic acids. More recently, these include enzyme inhibitors that interfere with epigenetic DNA modification or cell cycle progression (eg, histone deacetylase inhibitors, Aurora kinase inhibitors). Since such therapies are toxic, more and more recently, targeted therapies are being used in which specific processes in the cell are blocked, without any high toxic load occurs. These include in particular inhibitors of kinases which inhibit the phosphorylation of receptors and signal transduction molecules. An example of this is imatinib, which is used very successfully for the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST).
- CML chronic myeloid leukemia
- GIST gastrointestinal stromal tumors
- EGFR kinase and HER2 blocking substances such as erlotinib and VEGFR kinase inhibitors such as sorafenib and sunitinib, which are used in renal cell carcinoma, liver carcinoma or advanced stages of GIST.
- Bevacizumab inhibits blood vessel growth, which hinders the rapid expansion of a tumor, as it requires a connection to the blood vessel system for a continuously functioning supply and disposal.
- hypoxia hypoxia
- FIH factor inhibiting HIF
- HIF can be degraded via the proteasome apparatus via the Hippel Lindau protein (part of a ubiquitin E3 ligase complex) (Maxwell, Wiesener et al., 1999). In the absence of oxygen, breakdown is avoided, the protein is up-regulated and leads to the transcription or blockade of the transcription of numerous (more than 100) other proteins (Semenza and Wang, 1992, Wang and Semenza, 1995).
- the transcription factor HIF is formed by the regulated a- and constitutively present aryl hydrocarbon receptor nuclear translocator (ARNT).
- ARNT aryl hydrocarbon receptor nuclear translocator
- the HIF subunits are bHLH (basic helix loop helix) proteins that dimerize via their HLH and PAS (per-Arnt-Sim) domain, which starts their transactivating activity (Jiang, Rue et al., 1996 ).
- HIF ⁇ protein In the major tumor entities, overexpression of the HIF ⁇ protein is correlated with increasing blood vessel density and enhanced VEGF expression (Hirota and Semenza, 2006). At the same time, the glucose metabolism is changed towards glycolysis, and the Krebs cycle is reduced in favor of the production of cell building blocks. This also implies a change in the fat metabolism. Such changes seem to ensure the survival of the tumors. On the other hand, if the activity of HIF is inhibited, then it would be possible to suppress the development of tumors.
- the object of the present invention was thus to provide novel compounds which act as inhibitors of the transactivating effect of the transcription factor HIF and as such can be used for the treatment and / or prevention of diseases, in particular hyperproliferative and angiogenic diseases such as cancers.
- WO 2005/030121 -A2 and WO 2007/065010-A2 describe the usefulness of certain pyrazole derivatives for inhibiting the expression of HIF and HIF-regulated genes in tumor cells.
- WO 2008/141731-A2 WO 2010/054762-A1, WO 2010/054763-A1 and WO 2010/054764-A1 disclose various heteroaryl-substituted pyrazole derivatives as inhibitors of the HIF-regulation pathway for the treatment of cancers.
- EP 1 310 485-A1 describes disubstituted heteroaryl compounds as TGF ⁇ inhibitors for the treatment of fibroses.
- WO 2008/097538-A1 discloses certain 2-phenylvinyl-substituted heterocyclic compounds for the treatment of Alzheimer's disease.
- WO 2009/121623 -A2 claims the use of 1,3-disubstituted pyrroles and pyrazoles for the treatment of muscular dystrophies.
- the present invention relates to compounds of the general formula (I)
- Ar having the substituent R 2 is a phenyl or pyridyl ring of the formula
- R 5 and R 6 independently of one another denote hydrogen, (C 1 -C 6 ) -alkyl or (C 3 -C 6) -cycloalkyl or
- R 5 and R 6 are linked together and together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain another heteroatom from the series N, O, S or S (0) 2 and which may be substituted up to two times, identically or differently, by a radical selected from fluorine, cyano, hydroxy, (C 1 -C 4) -alkoxy, oxo, (C 1 -C 4) -alkyl and (C 3 -C 6) -cycloalkyl where (C 1 -C 4) -alkyl may in turn be substituted up to three times by fluorine, R 3 is a substituent selected from the group consisting of halogen, cyano, pentafluorothio, tri (C 1 -C 4 ) -alkylsilyl, (C 1 -C 6 ) -alkyl, -NR 7 R 8 , -OR 8 , -SR 8 , - S (0) 2 -R
- R 7 is hydrogen or (C 1 -C 4 ) -alkyl
- R 8 is (C 1 -C 6 ) -alkyl or (C 3 -C 6 ) -cycloalkyl, (C 1 -C 6 ) -alkyl in turn having a radical selected from the series hydroxy,
- R 9 and R 10 are independently hydrogen or (Ci-C4) alkyl or linked together and together with the nitrogen atom to which they are attached form a pyrrolidine, piperidine or morpholine ring, and
- A is N or CR 4 , in which
- R 4 is hydrogen, fluorine, chlorine, cyano, methyl, trifluoromethyl or methoxy, and their salts, solvates and solvates of the salts.
- Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), subsequently as Embodiments mentioned compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), mentioned below are not already salts, solvates and solvates of the salts.
- the compounds of the invention may exist in different stereoisomeric forms, i. in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in atropisomers).
- the present invention therefore includes the enantiomers and diastereoisomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.
- the present invention encompasses all tautomeric forms.
- the present invention also includes all suitable isotopic variants of the compounds according to the invention.
- An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature.
- isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I.
- isotopic variants of a compound of the invention such as, in particular, those in which one or more radioactive isotopes are incorporated, may be useful, for example for the study of the mechanism of action or distribution of active ingredient in the body; Due to the comparatively easy production and detectability, compounds labeled with 3 H or 14 C isotopes in particular are suitable for this purpose.
- isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose;
- Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention.
- Isotopic variants of the compounds according to the invention can be prepared by generally customary processes known to the person skilled in the art, for example by the methods described below and those in the exemplary embodiments reproduced by appropriate isotopic modifications of the respective reagents and / or starting compounds.
- Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of 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, naphthalenedisulfonic, formic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
- Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic formic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic
- 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 from 1 to 16 carbon atoms.
- alkali metal salts for example sodium and potassium salts
- alkaline earth salts for example calcium and magnesium salts
- ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms 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 from 1 to 16 carbon atoms.
- Atoms such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, NN-diisopropylethylamine, monoethanolamine, diethanolamine, triethanolamine, dimethylaminoethanol, diethylaminoethanol, procaine, dicyclohexylamine, dibenzylamine, N-methylmorpholine, N-methylpiperidine, arginine, lysine and 1, 2 ethylene diamine.
- 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 N-oxides of pyridyl rings and tertiary cyclic amine moieties contained in compounds of this invention are also encompassed by the present invention.
- the present invention also includes prodrugs of the compounds of the invention.
- prodrugs refers to compounds which themselves may be biologically active or inactive, but are converted during their residence time in the body to compounds of the invention (for example metabolically or hydrolytically). Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
- (Ci-CeValkyl and in the context of the invention are a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms.
- Preferred is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, tert. Butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl and 3-hexyl.
- Tri- (C 1 -C 4 -alkylsilyl in the context of the invention is a silyl group having three identical or different straight-chain or branched alkyl substituents, each of which has 1 to 4 carbon atoms, by way of example and preferably: trimethylsilyl, tert-butyl dimethylsilyl and triisopropylsilyl.
- (C 1 -C 4 -alkylcarbonyl in the context of the invention represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms which is linked to the rest of the molecule via a carbonyl group [-C (0O) -], by way of example and with preference called: acetyl, propionyl, n-butyryl, where-butyryl, n-pentanoyl and pivaloyl.
- (C 1 -C 4 -Alkylcarbonyloxy in the context of the invention represents an oxy radical having a straight-chain or branched alkylcarbonyl substituent having 1 to 4 carbon atoms in the alkyl radical and is linked via the carbonyl group to the O atom, by way of example and by way of example: acetoxy, propionoxy, n-butyroxy, -butyroxy, n-pentanoyloxy and pivaloyloxy.
- C 2 -C 6 -alkenyl is a straight-chain or branched alkenyl radical having 2 to 6 carbon atoms and one double bond, a straight-chain or branched alkenyl radical having 2 to 4 carbon atoms being preferred -Prop-1-en-1-yl, allyl, isopropenyl, 2-methyl-2-propen-1-yl, n-but-1-en-1-yl, n-but-2-en-1-yl , n-but-3-en-1-yl, n-pent-2-en-1-yl, n -pent-3-en-1-yl, n-pent-4-en-1-yl, 3 Methylbut-2-en-1-yl and 4-methylpent-3-en-1-yl.
- (C 1 -C 6 -alkoxy and (C 1 -C 4 -alkoxy in the context of the invention represent a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms, preference is given to a straight-chain one or branched alkoxy radical having 1 to 4 carbon atoms.
- Examples which may be mentioned by preference include: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl and tert-butoxycarbonyl.
- (C 3 -C 6 -cycloalkyl in the context of the invention represents a monocyclic, saturated cycloalkyl group having 3 to 6 ring carbon atoms. Examples which may be mentioned are: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- C 3 -C 6 -cycloalkoxy in the context of the invention represents a monocyclic, saturated cycloalkyloxy radical having 3 to 6 ring carbon atoms in the cycloalkyl group, by way of example and by preference: cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy
- Heterocyclyl is in the context of the invention for a monocyclic, saturated heterocycle having a total of 4 to 6 ring atoms, which contains one or two ring heteroatoms from the series N, O, S and / or S (0) 2 and via a ring carbon atom or Preference is given to 4- or 5-membered heterocyclyl having one ring heteroatom from the series N or O and 6-membered heterocyclyl having one or two ring heteroatoms from the series N and / or O.
- Examples may be mentioned: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, thiolanyl, 1, 1-dioxideothiolanyl, 1,3-oxazolidinyl, 1,3-thiazolidinyl, piperidi nyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,3-dioxanyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl and 1,1-dioxothiomorpholinyl.
- Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine, fluorine or bromine, more preferably fluorine or chlorine.
- An oxo substituent in the context of the invention is an oxygen atom which is bonded via a double bond to a carbon atom.
- the meaning is independent of each other for all radicals which occur repeatedly.
- the radicals may be monosubstituted or polysubstituted. Substitution with one or two or three identical or different substituents is preferred. Particularly preferred is the substitution with one or two identical or different substituents. Very particular preference is given to the substitution with a substituent.
- Preferred in the context of the present invention are compounds of the formula (I) in which one of the two radicals R 1A and R 1B is fluorine and the other is hydrogen,
- R 2 is a substituent selected from the group chlorine, (C 1 -C 4 ) -alkyl, (C 3 -C 6) -cycloalkyl,
- Methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, -NR 5 R 6 and -C ( O) -NR 5 R 6 , with (C 1 -C 4) -alkyl in turn having a radical selected from the group consisting of hydroxy, acetoxy, cyclopropyl and cyclobutyl and may be substituted up to three times by fluorine and
- (C3-C6) -cycloalkyl and cyclopropyl and cyclobutyl may in turn be substituted up to two times, identically or differently, by a radical selected from among fluorine, methyl, trifluoromethyl, hydroxy, hydroxymethyl, methoxy and acetoxy, and in which
- R 5 and R 6 are linked together and form together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain a further heteroatom from the series N, O or S, and which has one radical - may be selected from the series cyano, hydroxy, methoxy, ethoxy, (Ci-C i) alkyl, cyclopropyl and cyclobutyl may be substituted, wherein (Ci-C i) alkyl in turn may be substituted up to three times with fluorine,
- R 3 is a substituent selected from pentafluorothio, trimethylsilyl, (C 1 -C 6 ) -alkyl, -OR 8 , -SR 8 , (C 3 -C 6 ) -cycloalkyl and 4- to 6-membered heterocyclyl, where (Ci -C 6) -alkyl in turn may be substituted by hydroxy or -OR 8 and up to six times by fluorine, and
- R 8 is (C 1 -C 4) -alkyl which may be substituted by one radical selected from the series hydroxy, methoxy and ethoxy and up to three times by fluorine, and
- A is N or CR 4 , in which
- R 4 is hydrogen, fluorine or chlorine, and their salts, solvates and solvates of the salts.
- a particular embodiment of the present invention comprises compounds of the formula (I) in which
- R 1B is hydrogen, and their salts, solvates and solvates of the salts.
- Another particular embodiment of the present invention comprises compounds of the formula (I) in which
- R 1A is hydrogen and R 1B is fluorine, and their salts, solvates and solvates of the salts.
- Another particular embodiment of the present invention comprises compounds of the formula (I) in which
- Another particular embodiment of the present invention comprises compounds of formula (I) wherein A is CR 4 wherein
- R 4 is hydrogen or fluorine, and their salts, solvates and solvates of the salts.
- R 1B is hydrogen
- R 5 is hydrogen, R 6 is (C 1 -C 4 ) -alkyl, or
- R 5 and R 6 are linked together and together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain another heteroatom from the series N or O and which is selected from the group consisting of a series Cyano, hydroxy, (Ci-C4) -alkyl and cyclopropyl may be substituted, wherein (Ci-C i) -alkyl in turn may be substituted up to three times with fluorine, for a substituent selected from the series trifluoromethoxy, trifluoromethylsulfanyl, pentafluorothio, trimethylsilyl , (C 1 -C 4) -alkyl, cyclopropyl, cyclobutyl, cyclohexyl, oxetan-3-yl and tetrahydro-2H-pyran-4-yl, where (C 1 -C 4 ) -alkyl in turn with hydroxy and up to six times with fluorine may be substitute
- A is CR 4 , wherein R 4 is hydrogen or fluorine, and their salts, solvates and solvates of the salts.
- R 1A is hydrogen
- R 1B is fluorine
- R 5 is hydrogen
- R 6 is (C 1 -C 4 ) -alkyl, or
- R 5 and R 6 are linked together and together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain another heteroatom from the series N or O and which is selected from the group consisting of a series Cyano, hydroxy, (C 1 -C 4) -alkyl and cyclopropyl, where (C 1 -C 4) -alkyl in turn may be substituted up to three times by fluorine, a substituent selected from the series trifluoromethoxy, trifluoromethylsulfanyl, pentafluorothio, trimethylsilyl, (C 1 -C 4) -alkyl, cyclopropyl, cyclobutyl, cyclohexyl, oxetan-3-yl and tetrahydro-2H-pyran-4-yl, where (C 1 -C 4 ) -alkyl in turn substituted by hydroxyl and up to six times by fluorine can be and
- Cyclopropyl, cyclobutyl, cyclohexyl, oxetanyl and tetrahydropyranyl may in turn be substituted by fluorine or trifluoromethyl,
- R 1A is fluorine
- R 1B is hydrogen
- R 5 is hydrogen
- R 5 and R 6 are linked together and, together with the nitrogen atom to which they are attached, a substituted heterocycle of the formula
- ** denotes the point of attachment to the ring Ar
- R is a substituted isopropyl, isobutyl or cyclopropyl group of the formula
- ** denotes the point of attachment to the ring Ar, for trifluoromethyl, trifluoromethoxy, trifluoromethylsulfanyl, pentafluorothio, trimethylsilyl, tert. Butyl or a group of the formula where # denotes the point of attachment to the adjacent ring, and
- A is C-R in which
- R 4 is hydrogen or fluorine, and their salts, solvates and solvates of the salts.
- Another object of the present invention is a process for the preparation of the compounds of formula (I) according to the invention, characterized in that either
- PG is a suitable protective group, for example tetrahydro-2H-pyran-2-yl, in an inert solvent in the presence of a base with an aldehyde of the formula (III)
- X represents a leaving group such as, for example, chlorine, bromine, iodine, mesylate, triflate or tosylate, to give a compound of the formula (IA) according to the invention in which A, Ar, R and R have the abovementioned meanings, or [Bl] denotes a fluorinated arylmethylbenzothiazolylsulfone of the formula (VIII)
- PG is a suitable protecting group such as, for example, tetrahydro-2H-pyran-2-yl, to give a compound of the formula (XI) in which A, PG and R have the meanings given above, the protective group PG is then removed by conventional methods and the resulting pyrazole derivative of the formula (XII)
- X is a leaving group such as, for example, chlorine, bromine, iodine, mesylate, triflate or tosylate, to give a compound of the formula (IB) according to the invention in which A, Ar, R 2 and R 3 have the meanings given above, and the compounds of the formula (IA) or (IB) thus obtained are optionally separated into their enantiomers and / or diastereomers and / or with the corresponding (z ) Solvents and / or (ii) bases or acids into their solvates, salts and / or solvates of the salts.
- Suitable inert solvents for these reactions are, in particular, ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis (2-methoxyethyl) ether.
- ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane or bis (2-methoxyethyl) ether.
- non-nucleophilic alkali metal amides such as lithium diisopropylamide (LDA) or lithium, sodium or potassium bis (trimethylsilyl) amide (Li, Na, K-HMDS), or strong tertiary amine bases, such as l, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or l, 5-diazabicyclo [4.3.0] non-5-ene (DBN); preferred is lithium bis (trimethylsilyl) amide.
- LDA lithium diisopropylamide
- Li sodium or potassium bis (trimethylsilyl) amide
- strong tertiary amine bases such as l, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or l, 5-diazabicyclo [4.3.0] non-5-ene (DBN); preferred is lithium bis (trimethylsilyl) amide.
- the reactions are usually carried out in a temperature range from -30
- a temporary pyrazole protecting group PG in the compounds (IV) and (X) are, for example, such groups as tetrahydro-2H-pyran-2-yl ( ⁇ ), phenylsulfonyl, / tolylsulfonyl or tert. Butoxycarbonyl (Boc).
- the introduction and removal of these protective groups is carried out according to generally customary methods [see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999].
- the tetrahydropyranyl (THP) group is used.
- Their cleavage in the process steps (V) - > (VI) and (XI) - > (XII) is preferably carried out with the aid of anhydrous hydrogen chloride in an inert solvent such as 1, 4-dioxane.
- Inert solvents for process steps (VI) + (VII) -> (IA) and (XII) + (VII) -> (IB) are, for example, ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1, 2-dimethoxyethane or bis (2-methoxyethyl) ether, hydrocarbons such as benzene, toluene, xylene, ethylbenzene, pentane, hexane, cyclohexane or petroleum fractions, or dipolar aprotic solvents such as N, N-dimethylformamide ( DMF), N, N-dimethylacetamide (DMA), dimethylsulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU) or N-methylpyrrolidinone (NMP). It is
- Suitable bases for the process steps (VI) + (VII) -> ⁇ (IA) and (XII) + (VII) -> ⁇ (IB) are in particular alkali metal hydroxides such as sodium or potassium hydroxide, alkali metal alcoholates such as sodium or potassium tert ., Butoxide, alkali metal hydrides such as sodium or potassium hydride, or alkali amides such as lithium diisopropylamide or lithium, sodium or potassium bis (trimethylsilyl) amide.
- potassium tert-butoxide is used.
- an alkylation catalyst such as lithium bromide, sodium or potassium iodide, tetra-n-butylammonium bromide or benzyltriethylammonium chloride.
- the reactions are generally carried out in a temperature range from -20 ° C to + 100 ° C, preferably at 0 ° C to + 65 ° C.
- the reactions mentioned can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar); usually one works at normal pressure.
- transformations are carried out by customary methods known to those skilled in the art and include, for example, reactions such as nucleophilic or electrophilic substitution reactions, transition metal-mediated coupling reactions (eg Ullmann or Buchwald-Hartwig reaction), addition reactions of organometallic compounds (eg Grignard compounds or lithium organyls) to carbonyl compounds , Oxidation and reduction reactions, hydrogenation, alkylation, acylation, sulfonylation, amination, hydroxylation, the formation of nitriles, carboxylic esters and carboxylic acid amides, ester cleavage and hydrolysis, and the introduction and removal of temporary protecting groups.
- reactions such as nucleophilic or electrophilic substitution reactions, transition metal-mediated coupling reactions (eg Ullmann or Buchwald-Hartwig reaction), addition reactions of organometallic compounds (eg Grignard compounds or lithium organyls) to carbonyl compounds , Oxidation and reduction reactions, hydrogenation, alkylation, acylation, sul
- compounds of the formula (I) according to the invention can also be prepared by initially substituting other functional groups outside the scope of R 2 or R 2 in the starting compounds of the process variants described above instead of the substituents R 2 and / or R 3 R 3 , which are then converted by subsequent, familiar to those skilled transformations (as exemplified above) into the respective substituents R 2 and R 3 .
- substituents such as "precursor" to R 2 and / or R 3 serving functional Groups are radicals such as nitro, hydroxy, methanesulfonate (mesylate), trifluoromethanesulfonate (triflate), formyl, alkylcarbonyl, hydroxycarbonyl and alkoxycarbonyl [cf.
- a-fluorinated benzothiazolylsulfones of the formulas (II), (IV) and (VIII) can be prepared by reacting a compound of the formula (XIII)
- M is a group of the formula
- Y is a leaving group such as, for example, chlorine, bromine, iodine, mesylate, triflate or tosylate, in an inert solvent with the sodium salt of 2-mercapto-1,3-benzothiazole (XIV)
- M has the abovementioned meaning
- M is oxidized and, after ⁇ -deprotonation by means of a base, then oxidized with a suitable fluorination agent, such as, for example, N-fluorobenzenesulfonimide, to give a compound of the formula (XVII)
- reaction sequence (XIII) + (XIV) -> ⁇ (XV) -> ⁇ (XVI) -> ⁇ (XVII) is carried out in analogy to literature processes for the preparation of fluorine-substituted benzothiazolylsulfones [see, eg, PR Blakemore, J. Chem. Soc. Perkin Trans. 1, 2563-2585 (2002); E. Pfund et al., J. Org. Chem. 72, 7871-7877 (2007), and other references cited therein].
- dipolar aprotic solvents such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N, N'-dimethyl propylene ( DMPU) or N-methylpyrrolidinone ( ⁇ ); preferably N, N-dimethylformamide is used.
- Suitable oxidizing agents for process step (XV) -> (XVI) are peracids such as peroxyacetic acid or w-chloroperoxybenzoic acid (mCPBA), peroxides such as hydrogen peroxide, if appropriate in the presence of a molybdenum (vi) or tungsten (VI) catalyst , or persalts such as Oxone ® or potassium permanganate; Preference is given to using w-chloroperbenzoic acid.
- peracids such as peroxyacetic acid or w-chloroperoxybenzoic acid (mCPBA)
- peroxides such as hydrogen peroxide, if appropriate in the presence of a molybdenum (vi) or tungsten (VI) catalyst
- persalts such as Oxone ® or potassium permanganate
- Suitable bases for the ⁇ -deprotonation of the compound (XVI) are non-nucleophilic bases such as sodium or potassium tert-butylate, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide; Lithium diisopropylamide is preferably used.
- the subsequent fluorination to compound (XVII) is preferably carried out with the aid of N-fluorobenzenesulfonimide (NFSI).
- N-fluorobenzenesulfonimide N-fluorobenzenesulfonimide
- other electrophilic fluorinating agents can be used, such as Selectfluor TM (F-TEDA), 1-fluoropyridinium tetrafluoroborate or 1-fluoropyridinium trifluoromethanesulfonate.
- the compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.
- the compounds according to the invention are highly potent inhibitors of the HIF regulation pathway.
- the compounds according to the invention have an advantageous pharmacokinetic profile which makes them suitable for oral administration.
- the compounds according to the invention are particularly suitable for the treatment of hyperproliferative disorders in humans and in mammals in general.
- the compounds can inhibit, block, reduce or decrease cell proliferation and cell division and, on the other hand, enhance apoptosis.
- the hyperproliferative diseases for the treatment of which the compounds according to the invention can be used include, among others, psoriasis, keloids, scarring and other proliferative disorders of the skin, benign diseases such as benign prostatic hyperplasia (BPH), and in particular the group of tumor diseases.
- breast carcinomas and breast tumors include, but are not limited to, the following diseases: breast carcinomas and breast tumors (ductal and lobular forms, also in situ), respiratory tumors (small cell and non-small cell carcinoma, bronchial carcinoma), brain tumors (eg of the brain stem and hypothalamus, astrocytoma, medulloblastoma, ependymoma, neuro-ectodermal and pineal tumors), tumors of the digestive organs (esophagus, stomach, gallbladder, small intestine, large intestine, rectum), liver tumors (including hepatocellular carcinoma, cholangiocarcinoma and mixed hepatocellular cholangiocarcinoma) , Tumors of the head and neck (larynx, hypopharynx, nasopharynx, oropharynx, lips and oral cavity), skin tumors (squamous cell carcinoma, Kaposi's sarcoma, malignant melanom
- proliferative blood diseases in solid form and as circulating blood cells such as lymphomas, leukemias and myeloproliferative diseases, for example acute myeloid, acute lymphoblastic, chronic lymphocytic, chronic myelogenous and hairy cell leukemia, as well as AIDS-correlated lymphomas, Hodgkin's lymphomas, Non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma and lymphoma in the central nervous system.
- lymphomas such as lymphomas, leukemias and myeloproliferative diseases, for example acute myeloid, acute lymphoblastic, chronic lymphocytic, chronic myelogenous and hairy cell leukemia, as well as AIDS-correlated lymphomas, Hodgkin's lymphomas, Non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma and lymphoma in the central nervous
- treatment or “treating” is used conventionally within the context of this invention and means the care, care and supervision of a patient with the aim of combating, reducing, alleviating or alleviating a disease or health deviation and the living conditions to be affected by this disease, such as cancer.
- the compounds according to the invention act as modulators of the HIF regulation pathway and are therefore also suitable for the treatment of diseases which are associated with a detrimental expression of the HIF transcription factor. This applies in particular to the transcription factors HIF- ⁇ and HIF-2a.
- harmful expression of HIF herein means a non-normal physiological presence of HIF protein. This may be due to excessive synthesis of the protein (due to mRNA or translation), reduced degradation or insufficient counterregulation in the function of the transcription factor.
- HIF- ⁇ ⁇ and HIF-2a regulate more than 100 genes. This concerns proteins which play a role in angiogenesis and are therefore directly tumor-relevant, and also those which influence the glucose, amino acid and lipid metabolism as well as cell migration, metastasis and DNA repair or by suppression of apoptosis survival improve the tumor cells. Others act more indirectly via inhibition of the immune response and upregulation of angiogenic factors in inflammatory cells. HIF also plays an important role in the stem cells, in particular the tumor stem cells, which are reported to have elevated HIF levels. Inhibition of the HIF-regulation pathway by the compounds of the present invention thus also therapeutically influences tumor stem cells which do not have a high proliferation rate and therefore are only insufficiently affected by cytotoxic substances (see Semenza, 2007, Weidemann and Johnson, 2008).
- HIF inhibitors - such as the compounds of the present invention - are therapeutically useful in those contexts in which, for example, adaptation of cells to hypoxic situations causes additional damage, as damaged cells, if not functioning properly, can cause further damage.
- An example of this is the formation of epileptic foci in partially destroyed tissue after strokes.
- cardiovascular disease when ischemic processes occur in the heart or brain as a result of thromboembolic events, inflammation, wounding, intoxication or other causes. These can lead to damage such as a locally slowed down action potential, which in turn can cause arrhythmias or chronic heart failure.
- transient form e.g. Through apnea, it may under certain circumstances come to an essential increase in blood pressure, which can lead to known sequelae such as stroke and myocardial infarction.
- the inhibition of the HIF-regulation pathway as achieved by the compounds according to the invention can therefore also be used in diseases such as cardiac insufficiency, arrhythmia, myocardial infarction, Apnea-induced hypertension, pulmonary hypertension, transplantation ischemia, reperfusion injury, stroke and macular degeneration, as well as recovery of nerve function after traumatic injury or transection may be helpful.
- diseases such as cardiac insufficiency, arrhythmia, myocardial infarction, Apnea-induced hypertension, pulmonary hypertension, transplantation ischemia, reperfusion injury, stroke and macular degeneration, as well as recovery of nerve function after traumatic injury or transection may be helpful.
- the compounds of the present invention can also be used to treat fibroses of lung and lung associated with HIF Kidney to prevent or curb.
- inflammatory joint diseases such as various forms of arthritis
- inflammatory bowel diseases such as, for example, Crohn's disease.
- Chugwash polycythemia is mediated by HIF-2a activity during erythropoiesis in, among others, the spleen.
- the compounds according to the invention as inhibitors of the HIF regulatory pathway, are therefore also suitable for suppressing the excessive formation of erythrocytes here and thus for alleviating the effects of this disease.
- the compounds of the present invention may also be used to treat diseases associated with excessive or abnormal angiogenesis.
- diabetic retinopathy include diabetic retinopathy, ischemic retinal vein occlusion and retinopathy in preterm birth (see Aiello et al., 1994, Peer et al., 1995), age-related macular degeneration (AMD, Lopez et al., 1996), neovascular glaucoma, psoriasis , retrolental fibroplasia, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, and restenosis after vascular implantation.
- AMD age-related macular degeneration
- Increased blood supply is also associated with cancerous neoplastic tissue, leading to accelerated tumor growth.
- the growth of new blood and lymph vessels facilitates the formation of metastases and thus the spread of the tumor.
- New lymphoid and blood vessels are also detrimental to allografts in immune-privileged tissues, such as the eye, which, for example, increases susceptibility to rejection.
- Compounds of the present invention can therefore also be used to treat any of the aforementioned disorders, for example by inhibiting growth or reducing the number of blood vessels. This can be achieved via inhibition of endothelial cell proliferation or other mechanisms to prevent or attenuate vascularization and via reduction of neoplastic cells by apoptosis.
- HIF- ⁇ In obesity there is an accumulation of HIF- ⁇ in adipose tissue and thus a HIF-mediated shift in the energy metabolism in the direction of glycolysis, so that more glucose is consumed as an energy source. At the same time this leads to a reduced fat metabolism and thus to an accumulation of fats in the tissue.
- the substances according to the invention are therefore also suitable for the treatment of HIF- ⁇ -mediated accumulation of fats in tissue, especially in obesity disease.
- Another object of the present invention is the use of the compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
- 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 prevention of diseases, in particular the aforementioned diseases.
- Another object of the present invention is the use of the compounds of the invention in a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
- Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
- the compounds according to the invention can be used alone or as needed in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesired and unacceptable side effects.
- Another object of the present invention are therefore pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases.
- the compounds of the present invention may be combined with known anti-hyperproliferative, cytostatic or cytotoxic agents for the treatment of cancers.
- the combination of the compounds according to the invention with other substances which are commonly used for cancer therapy or else with radiation therapy is therefore particularly indicated since hypoxic regions of a tumor respond only slightly to the said conventional therapies, whereas the compounds of the present invention in particular exert their activity there. Examples of suitable combination active ingredients are:
- the compounds of the present invention may be combined with anti-hyperproliferative agents, which may be by way of example, without being exhaustive:
- the compounds of the present invention can also be combined with biological therapeutics such as antibodies (eg, Avastin, Rituxan, Erbitux, Herceptin) and recombinant proteins, which additively or synergistically enhance the effects of inhibiting HIF signaling pathway transfer.
- Inhibitors of the HIF regulatory pathway such as the compounds of the present invention, can also provide positive effects in combination with other anti-angiogenic therapies, such as Avastin, axitinib, recentin, regorafenib, sorafenib, or sunitinib.
- Combinations with proteasome and mTOR inhibitors as well as with anti-hormones and steroidal meta- Bolus enzyme inhibitors are also particularly suitable because of their favorable side effect profile.
- the combination of compounds of the present invention with other cytostatic or cytotoxic agents can achieve the following objectives: improved efficacy in slowing down the growth of a tumor, reducing its size, or even its total elimination relative to one Single agent treatment;
- the compounds of the invention may also be used in conjunction with radiotherapy and / or surgical intervention.
- compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
- the compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent. For these administration routes, the compounds according to the invention can be administered in suitable administration forms.
- the compounds of the invention rapidly and / or modified donating the application forms, which Compounds according to the invention in crystalline and / or amorphised and / or dissolved form, such as tablets (uncoated or coated tablets, for example, with enteric or delayed-dissolving or insoluble coatings, which control the release of the compound of the invention) in the oral cavity quickly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragées, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
- Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
- a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
- absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
- parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
- Inhalation medicines including powder inhalers, nebulizers
- nasal drops solutions or sprays
- lingual, sublingual or buccal tablets films / wafers or capsules
- suppositories ear or ophthalmic preparations
- vaginal capsules aqueous suspensions (lotions, shake mixtures)
- lipophilic suspensions ointments
- creams transdermal therapeutic systems (eg plasters)
- milk pastes, foams, powdered powders, implants or stents.
- the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
- excipients e.g., microcrystalline cellulose, lactose, mannitol
- solvents e.g, liquid polyethylene glycols
- emulsifiers and dispersing or wetting agents e.g., sodium dodecyl sulfate, polyoxysorbitol oleate
- binders e.g., polyvinylpyrrolidone
- synthetic and natural polymers e.g.
- Albumin e.g antioxidants such as ascorbic acid
- dyes eg inorganic pigments such as iron oxides
- Device type MS Micromass ZQ
- Device type HPLC HP 1 100 series
- UV DAD Column: Phenomenex Gemini 3 ⁇ , 30 mm x 3 mm
- Eluent A 1 l of water + 0.5 ml of 50% strength formic acid
- eluent B 1 l of acetonitrile + 0.5 ml of 50% strength formic acid
- Flow 0.0 min 1 ml / min -> 2.5 min / 3.0 min / 4.5 min 2 ml / min
- Oven 50 ° C
- UV detection 210 nm.
- Method 4 Device Type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex syn ergi 2.5 ⁇ MAX-RP 100A Mercury, 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% strength formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% strength formic acid; Gradient: 0.0 min 90% A -> 0.1 min 90% A -> 3.0 min 5% A -> 4.0 min 5% A -> 4.01 min 90% A; Flow: 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.
- Method 5 (LC MS):
- Device type MS Micromass Quattro Micro
- Device type HPLC Agilent series 1100
- Eluent A 1 l of water + 0.5 ml of 50% strength formic acid
- eluent B 1 l of acetonitrile + 0.5 ml of 50% strength formic acid
- Oven 50 ° C
- Flow 2 ml / min
- UV detection 210 ⁇ m.
- Device Type MS Waters ZQ; Device type HPLC: Agilent series 1100; UV DAD; Column: Thermo Hypersil GOLD 3 ⁇ , 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% strength formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% strength formic acid; Gradient: 0.0 min 100% A -> ⁇ 3.0 min 10% A -> ⁇ 4.0 min 10% A; Oven: 55 ° C; Flow: 2 ml / min; UV detection: 210 nm.
- Method 46 (preparative HPLC): column: Daicel Chiralpak AZ-H, 5 ⁇ m, 250 mm ⁇ 30 mm; Eluent: isohexane / ethanol 60:40; Flow: 40 ml / min; Temperature: 25 ° C; UV detection: 220 nm.
- the aqueous phase was extracted twice with 50 ml of ethyl acetate each time, and the combined organic phases were dried over sodium sulfate, filtered and concentrated.
- the aqueous phase was subsequently extracted three times with 30 ml of dichloromethane each time, and these combined extracts were likewise dried over sodium sulphate, filtered and concentrated.
- the two crude product batches thus obtained were combined and purified by column chromatography (silica gel, mobile phase first cyclohexane / ethyl acetate 2: 1, then ethyl acetate). After drying under high vacuum, 331 mg (70% of theory) of the title compound were obtained.
- Step 6 2- ( ⁇ [5-Methyl-1- (4-methylbenzyl) -1H-pyrazol-3-yl] methyl ⁇ sulfonyl) -1,3-benzothiazole
- Example 2A 2- ( ⁇ fluoro [5-methyl-1 - (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-3-yl] methyl ⁇ sulfonyl) -1,3-benzothiazole (diastereomeric and Enantiomer engemisch)
- the crude product obtained after filtration and evaporation of the solvent was purified by MPLC (silica gel, eluent cyclohexane / ethyl acetate 10: 1-> 5: 1). It was first isolated a minor fraction, which after removal of the solvent gave 940 mg of a mixture consisting of about 70% of the title compound and about 30% of the isomeric ( ⁇ ) compound. After removal of the solvent and drying under high vacuum, the main fraction gave 1.23 g (68% of theory) of the isomerically pure title compound.
- a suspension of dichloro (dimethyl) titanium in a heptane / dichloromethane mixture was prepared as follows: 100 ml (100 mmol) of a 1 M solution of titanium tetrachloride in dichloromethane was cooled to -30 ° C., 100 ml (100 mmol) was added dropwise. a 1 M solution of Dimethylzmk in heptane and stirred for 30 min at -30 ° C after.
- this suspension was cooled to -40 ° C and a solution of 10 g (39.5 mmol) l- (4-bromophenyl) -2,2,2-trifluoro -ethanone added in 50 ml of dichloromethane.
- the mixture was stirred for 5 min at -40 ° C, then allowed to come the temperature to RT and stirred for a further 2 h at RT.
- 50 ml of water were slowly added dropwise and then diluted with a further 300 ml of water.
- Step 3 1 Bromo-4- (1,1,1-trifluoro-2-methylpropan-2-yl) benzene
- Step 4 4- (1,1,1-trifluoro-2-methylpropan-2-yl) benzaldehyde
- Step 5 3 - ⁇ (Z) -1-Fluoro-2- [4- (1,1-trifluoro-2-methylpropan-2-yl) phenyl] vinyl ⁇ -5-methyl-1H-pyrazole
- the aqueous phase was extracted once with 200 ml of ethyl acetate and the combined organic phases were dried over sodium sulfate, filtered and concentrated.
- the residue was treated with 35 ml of a 4 N solution of hydrogen chloride in dioxane and the mixture was stirred at RT overnight. Subsequently, the mixture was treated with 100 ml of ethyl acetate and washed twice with 100 ml of dilute aqueous sodium bicarbonate solution.
- the organic phase was dried over sodium sulfate, filtered and concentrated.
- the residue was purified by preparative HPLC (Method 15). After drying under high vacuum, 1.37 g (62% of theory) of the title compound were obtained.
- Step 1 1 - [4-Bromo-2-fluoro-3 - (trimethylsilyl) phenyl] -2,2,2-trifluoro-ethanone
- Step 2 1 - (4-Bromo-2-fluoro-phenyl) -2,2,2-trifluoro-ethanone
- a suspension of dichloro (dimethyl) titanium in a heptane / dichloromethane mixture was prepared as follows: 160 mL (160 mmol) of a 1M solution of titanium tetrachloride in dichloromethane was cooled to -30 ° C, then 160 mL (160 mL) was added dropwise mmol) of a 1 M solution of dimethylzinc in heptane and the mixture was stirred for 30 minutes at -30 ° C after. The suspension was then cooled to -40 ° C. and a solution of 19.4 g (65.9 mmol, purity 92%) of the compound from Example 8A / Step 2 in 80 ml of dichloromethane was added.
- the combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated.
- the residue was first purified by column chromatography (silica gel, eluent cyclohexane / ethyl acetate 95: 5) and then by preparative HPLC (Method 16).
- the combined product fractions of the preparative HPLC were neutralized with solid sodium bicarbonate and concentrated to a residual volume of aqueous phase. After extracting twice with ethyl acetate, the combined organic phases were dried over magnesium sulfate, filtered and concentrated.
- Step 8 3 - ⁇ (Z) -1-Fluoro-2- [3-fluoro-4- (1,1-trifluoro-2-methylpropan-2-yl) phenyl] vinyl ⁇ -5-methyl-1 H-pyrazol
- Activated zinc bromide on montmorillonite was first prepared as follows: 1.40 g (6.22 mmol) of zinc bromide in 56 ml of methanol were added, 5.6 g of montmorillonite K10 were added, and the mixture was stirred at RT for 1 h. After removing the methanol, the remaining powder was heated for 1 h at 200 ° C bath temperature in a sand bath and then allowed to cool under argon.
- the title compound was then prepared as follows: 10.0 g (53.7 mmol) of 1-phenyl-1- (trifluoromethyl) cyclopropane were initially charged in 50 ml of pentane. 6.1 g (5.37 mmol) of the above-obtained activated zinc bromide were added to montmorillonite and then slowly added dropwise while stirring in the dark 27.7 ml (537 mmol) of bromine. The mixture was then further stirred overnight at RT in the dark. It was then slowly added dropwise 150 ml of a saturated aqueous sodium sulfite solution with ice cooling and stirred for a further 30 min at RT until the mixture was decolorized.
- reaction mixture was warmed to RT, treated with 300 ml of 10% hydrochloric acid and the phases were separated.
- the aqueous phase was extracted with 150 ml of diethyl ether, and the combined organic phases were washed successively with 200 ml of saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under excessively low vacuum. This gave 16.30 g (> 100% of theory, purity 96%) of the title compound which still contained solvent residues.
- Step 3 3 - [(Z) -1-Fluoro-2- ⁇ 4- [1- (trifluoromethyl) cyclopropyl] phenyl ⁇ vinyl] -5-methyl-1H-pyrazole
- the mixture was then washed with 300 ml of dilute aqueous ammonium chloride solution and 200 ml of ethyl acetate are added and the phases are separated.
- the aqueous phase was extracted once with 200 ml of ethyl acetate and the combined organic phases were dried over sodium sulfate, filtered and concentrated.
- the residue was treated with 30 ml of a 4N solution of hydrogen chloride in dioxane and the mixture was stirred at RT overnight. It was then washed with 150 ml of tert. Butyl methyl ether and the mixture was washed twice with 200 ml of dilute aqueous sodium bicarbonate solution.
- Step 1 3 - [() -2- (4-Cyclohexylphenyl) -1-fluorovinyl] -5-methyl-1- (tetrahydro-yl) -1H-pyrazole (racemate)
- Step 2 3 - [() -2- (4-Cyclohexylphenyl) -1-fluorovinyl] -5-methyl-1H-pyrazole
- Step 1 3 - [(Z) -1-Fluoro-2- (4-isobutylphenyl) vinyl] -5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole (racemate)
- Step 2 3 - [(Z) -1-Fluoro-2- (4-isobutylphenyl) vinyl] -5-methyl-1H-pyrazole
- Step 2 4- (1,1,3,3,3,3-Hexafluoro-2-hydroxypropan-2-yl) benzaldehyde
- the cold bath was finally removed and stirring continued at RT.
- the reaction mixture was then cooled again to about - 20 ° C and treated with about 500 ml of saturated aqueous ammonium chloride solution.
- most of the THF was removed on a rotary evaporator.
- the remaining aqueous residue was diluted with 1000 ml of water, and it was extracted three times with about 500 ml of dichloromethane.
- the combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and the solvent was removed on a rotary evaporator.
- Step 4 3- ⁇ (Z) -1-Fluoro-2- [4- (4-fluorotetrahydro-2H-pyran-4-yl) -phenyl] -vinyl ⁇ -5-methyl-1H-pyrazole
- Step 1 Tert-butyl-2 - [(4- ⁇ (Z) -2-fluoro-2- [5-methyl-1- (tetrahydro-2H-pyran-2-yl) -LH-pyrazole-3 - yl] vinyl ⁇ phenyl) sulfanyl] -2-methylpropanoate (racemate)
- Step 2 N- (4- ⁇ (Z) -2-Fluoro-2- [5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-3-yl] -vinyl ⁇ benzyl ) -N-isopropylpropan-2-amine (racemate)
- Step 3 N- ⁇ 4 - [(2-Fluoro-2- (5-methyl-1H-pyrazol-3-yl) vinyl] benzyl ⁇ -N-isopropylpropane
- Step 2 4- ⁇ 5 - [(Z) -2-Fluoro-2- (5-methyl-1H-pyrazol-3-yl) -vinyl] -pyridin-2-yl ⁇ -2,6-dimethyl-morpholine
- Step 1 tert. Butyl 4- ⁇ [tert. -butyl (diphenyl) silyl] oxy ⁇ piperidine-1-carboxylate
- the product was isolated by MPLC (about 50 g silica gel, ethyl acetate ⁇ ethyl acetate / triethylamine 9: 1). After evaporation of the product fractions and drying in a high vacuum, 1.45 g (83% of theory) of the title compound were obtained.
- Step 1 tert. Butyl-3 - ⁇ [tert. -butyl (diphenyl) silyl] oxy ⁇ azetidine-1-carboxylate
- Step 2 3 - ⁇ [tert. Butyl (diphenyl) silyl] oxy ⁇ azetidine
- Step 2 1 - [3 - ( ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ methyl) phenyl] cyclopropylacetate
- Step 4 1- (3- ⁇ [(Methylsulfonyl) oxy] methyl ⁇ phenyl) cyclopropylacetate
- Step 2 3 - (2-Hydroxypropan-2-yl) benzylmethanesulfonate
- Step 5 [3 - (1 - ⁇ [(Triisopropylsilyl) oxy] methyl ⁇ cyclopropyl) phenyl] methanol
- Step 6 3 - (1 - ⁇ [(Triisopropylsilyl) oxy] methyl ⁇ cyclopropyl) benzylmethanesulfonate
- Step 1 1 - (3-Bromophenyl) -2-methylpropan-2-ol
- Step 4 3 - (2-Hydroxy-2-methylpropyl) benzylmethanesulfonate
- Step 1 6- [(3,4-Dimethoxybenzyl) (methyl) amino] nicotinic acid
- Step 2 ⁇ 6- [(3,4-Dimethoxybenzyl) (methyl) amino] pyridin-3-yl ⁇ methanol
- Step 3 5- (Chloromethyl) -N- (3,4-dimethoxybenzyl) -N-methylpyridin-2-amine dihydrochloride
- Example 33A [(3 - ⁇ (Z) -1-Fluoro-2- [4- (trifluoromethoxy) phenyl] vinyl ⁇ -5-methyl-1H-pyrazol-1-yl) methyl] benzoic acid
- Example 38A 2- ( ⁇ 4- [(Z) -2- ⁇ 1 - [(6-Chloropyridin-3-yl) methyl] -5-methyl-1H-pyrazol-3-yl ⁇ -2-fluorovinyl] phenyl ⁇ - sulfanyl) -2-methylpropanoic acid
- the aqueous phase was back-extracted once with ethyl acetate; this ethyl acetate phase was discarded.
- the aqueous phase was then adjusted to pH 5 with 1 N hydrochloric acid and extracted twice with ethyl acetate.
- the Ethyl acetate extracts were combined with the previously obtained ethyl acetate-containing mixture, dried over magnesium sulfate, filtered and concentrated.
- the residue was purified by column chromatography (silica gel, eluent dichloromethane / methanol 95: 5). The solid obtained after removal of the solvent was stirred with pentane, filtered off and dried under high vacuum. 313 mg (48% of theory, purity 99%) of the title compound were obtained.
- Example 39A 5- [(3 - ⁇ (Z) -2- [3-Chloro-4- (trifluoromethoxy) phenyl] -1-fluorovinyl ⁇ -5-methyl-1H-pyrazol-1-yl) methyl] -N- (3,4-dimethoxybenzyl) -N-methylpyridin-2-amine
- Step 3 1 - [5-Methyl-1- (4-methylbenzyl) -1H-pyrazol-3-yl] -2- [4- (trifluoromethoxy) phenyl] ethane 1,2-dione
- the residue was purified first by column chromatography (silica gel, eluent cyclohexane / ethyl acetate 9: 1) and then by preparative HPLC (Method 16).
- the product fractions of the preparative HPLC were concentrated to a small residual volume of aqueous phase on a rotary evaporator and treated with saturated aqueous sodium bicarbonate solution.
- the resulting solid was filtered off, washed three times with water and dried under high vacuum. 74 mg (49% of theory) of the title compound were obtained.
- Step 2 2- ⁇ [4- (trifluoromethoxy) benzyl] sulfonyl ⁇ -1,3-benzothiazole
- Example 2A / step 6 Analogously to the process described under Example 2A / step 6, from 6.50 g (17.4 mmol) of the compound from Example 44A / Step 2 and 11 g (34.8 mmol) of N-fluorobenzenesulfonimide (NFSI) 4.1 g (61% of theory) the title compound. Purification of the crude product was carried out by silica gel chromatography with cyclohexane / ethyl acetate 10: 1 as the eluent.
- NFSI N-fluorobenzenesulfonimide
- Step 2 3- ⁇ () -2-Fluoro-2- [4- (trifluoromethoxy) phenyl] vinyl ⁇ -5-methyl-1- (tetrahydro)
- Step 3 3- ⁇ () -2-Fluoro-2- [4- (trifluoromethoxy) phenyl] vinyl ⁇ -5-methyl-1H-pyrazole
- Step 1 Methyl 3 - (pyrrolidin-1-ylcarbonyl) benzoate
- the product fractions were concentrated to a small residual volume of water on a rotary evaporator and adjusted to a pH of 7 with saturated aqueous sodium bicarbonate solution. It was then extracted twice with 30 ml of ethyl acetate, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. After drying under high vacuum, 85 mg (45% of theory, purity 93%) of the title compound were obtained.
- the crude product was first purified by column chromatography (silica gel, eluent cyclohexane / ethyl acetate 4: 1) and the resulting product fraction was subsequently purified by preparative HPLC (Method 28). After drying in vacuo, 1.38 g (72% of theory) of the title compound were obtained.
- a microwave oven Biotage Initiator with dynamic control of the irradiation power
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CA2919397C (en) | 2013-09-09 | 2021-05-18 | Peloton Therapeutics, Inc. | Aryl ethers as hif-2.alpha. inhibitors for the treatment of cancer |
EP3083639B1 (en) | 2013-12-16 | 2019-05-29 | Peloton Therapeutics, Inc. | Cyclic sulfone and sulfoximine analogs and uses thereof |
NZ727818A (en) | 2014-06-03 | 2020-06-26 | Idorsia Pharmaceuticals Ltd | Pyrazole compounds and their use as t-type calcium channel blockers |
WO2016145045A1 (en) | 2015-03-11 | 2016-09-15 | Peloton Therapeutics, Inc. | Compositions for use in treating glioblastoma |
WO2016144826A1 (en) | 2015-03-11 | 2016-09-15 | Peloton Therapeutics, Inc. | Substituted pyridines and uses thereof |
EP3267792A4 (en) | 2015-03-11 | 2018-09-26 | Peloton Therapeutics, Inc. | Compositions for use in treating pulmonary arterial hypertension |
US10807948B2 (en) | 2015-03-11 | 2020-10-20 | Peloton Therapeutics, Inc. | Aromatic compounds and uses thereof |
WO2016168510A1 (en) | 2015-04-17 | 2016-10-20 | Peloton Therapeutics, Inc. | Combination therapy of a hif-2-alpha inhibitor and an immunotherapeutic agent and uses thereof |
US9796697B2 (en) | 2015-06-12 | 2017-10-24 | Peloton Therapeutics, Inc. | Tricyclic inhibitors of HIF-2-alpha and uses thereof |
MX2019007117A (es) | 2016-12-16 | 2019-09-16 | Idorsia Pharmaceuticals Ltd | Combinacion farmaceutica que comprende un bloqueador del canal de calcio de tipo t. |
MA47409A (fr) | 2017-02-06 | 2019-12-11 | Idorsia Pharmaceuticals Ltd | Nouveau procédé de synthèse de 1-aryl-1-trifluorométhylcyclopropanes |
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US20230365589A1 (en) | 2020-09-18 | 2023-11-16 | Sumitomo Pharma Co., Ltd. | Novel amine derivatives |
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UY34200A (es) | 2013-02-28 |
US20130150325A1 (en) | 2013-06-13 |
WO2013011033A1 (de) | 2013-01-24 |
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