ES2443845T3 - Sulfonamidas como inhibidores de proteínas de la familia BCL-2 para el tratamiento del cáncer - Google Patents
Sulfonamidas como inhibidores de proteínas de la familia BCL-2 para el tratamiento del cáncer Download PDFInfo
- Publication number
- ES2443845T3 ES2443845T3 ES10750124.9T ES10750124T ES2443845T3 ES 2443845 T3 ES2443845 T3 ES 2443845T3 ES 10750124 T ES10750124 T ES 10750124T ES 2443845 T3 ES2443845 T3 ES 2443845T3
- Authority
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- Spain
- Prior art keywords
- alkylene
- alkyl
- pyrimidin
- substituted
- 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.)
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- 206010028980 Neoplasm Diseases 0.000 title description 18
- 238000011282 treatment Methods 0.000 title description 15
- 201000011510 cancer Diseases 0.000 title description 12
- 229940124530 sulfonamide Drugs 0.000 title description 9
- 150000003456 sulfonamides Chemical class 0.000 title description 6
- 102000051485 Bcl-2 family Human genes 0.000 title description 5
- 108700038897 Bcl-2 family Proteins 0.000 title description 5
- 239000012268 protein inhibitor Substances 0.000 title description 4
- 229940121649 protein inhibitor Drugs 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 148
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 83
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 54
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 47
- 150000002367 halogens Chemical class 0.000 claims abstract description 45
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 29
- 125000001424 substituent group Chemical group 0.000 claims abstract description 27
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims abstract description 25
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 23
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 21
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 10
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 8
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims abstract description 7
- 125000004450 alkenylene group Chemical group 0.000 claims abstract description 7
- 229910052805 deuterium Inorganic materials 0.000 claims abstract description 7
- -1 bicyclic radical Chemical class 0.000 claims description 482
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 54
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 49
- 150000003839 salts Chemical class 0.000 claims description 42
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 41
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 26
- 229910052801 chlorine Inorganic materials 0.000 claims description 21
- 229910052731 fluorine Inorganic materials 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 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 18
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 16
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 15
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 14
- 125000003386 piperidinyl group Chemical group 0.000 claims description 13
- 125000004193 piperazinyl group Chemical group 0.000 claims description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 8
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 8
- 230000001028 anti-proliverative effect Effects 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 125000002757 morpholinyl group Chemical group 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 6
- 125000001188 haloalkyl group Chemical group 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 4
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 3
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- WBLIXGSTEMXDSM-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH2] WBLIXGSTEMXDSM-UHFFFAOYSA-N 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 7
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 2
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 abstract description 26
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 161
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 131
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 114
- 238000004128 high performance liquid chromatography Methods 0.000 description 95
- 230000014759 maintenance of location Effects 0.000 description 84
- 238000002531 positive electrospray ionisation time-of-flight mass spectrometry Methods 0.000 description 78
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- 239000000543 intermediate Substances 0.000 description 62
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 55
- 238000006243 chemical reaction Methods 0.000 description 50
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 46
- 238000000034 method Methods 0.000 description 39
- 239000000243 solution Substances 0.000 description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 38
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 38
- 239000000203 mixture Substances 0.000 description 38
- 238000005160 1H NMR spectroscopy Methods 0.000 description 35
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 35
- 239000011541 reaction mixture Substances 0.000 description 34
- 238000003818 flash chromatography Methods 0.000 description 32
- 235000019439 ethyl acetate Nutrition 0.000 description 30
- 239000000741 silica gel Substances 0.000 description 30
- 229910002027 silica gel Inorganic materials 0.000 description 30
- 229910052757 nitrogen Inorganic materials 0.000 description 29
- 239000012044 organic layer Substances 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 26
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 24
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 22
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 22
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
- 239000007787 solid Substances 0.000 description 22
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- 238000005481 NMR spectroscopy Methods 0.000 description 21
- 239000012267 brine Substances 0.000 description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 21
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 18
- 239000010410 layer Substances 0.000 description 18
- 238000006268 reductive amination reaction Methods 0.000 description 18
- 150000001412 amines Chemical class 0.000 description 16
- 239000000460 chlorine Substances 0.000 description 16
- 201000010099 disease Diseases 0.000 description 16
- 238000004896 high resolution mass spectrometry Methods 0.000 description 16
- XVHVBUNXLXLXKG-CYBMUJFWSA-N (2r)-4-morpholin-4-yl-1-phenylsulfanylbutan-2-amine Chemical compound C([C@@H](N)CSC=1C=CC=CC=1)CN1CCOCC1 XVHVBUNXLXLXKG-CYBMUJFWSA-N 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 229910052938 sodium sulfate Inorganic materials 0.000 description 15
- 235000011152 sodium sulphate Nutrition 0.000 description 15
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- 239000007832 Na2SO4 Substances 0.000 description 14
- 150000002576 ketones Chemical class 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 125000000217 alkyl group Chemical group 0.000 description 13
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 13
- 235000019341 magnesium sulphate Nutrition 0.000 description 13
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 12
- 239000002253 acid Chemical class 0.000 description 11
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 150000002430 hydrocarbons Chemical group 0.000 description 10
- 239000003112 inhibitor Substances 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- 125000004944 pyrazin-3-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 10
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 9
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 8
- 125000003118 aryl group Chemical group 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- AMNYAHNHKFYZOU-LLVKDONJSA-N (3r)-1-n,1-n-dimethyl-4-phenylsulfanylbutane-1,3-diamine Chemical compound CN(C)CC[C@@H](N)CSC1=CC=CC=C1 AMNYAHNHKFYZOU-LLVKDONJSA-N 0.000 description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 7
- HSDKYMBTTJDKGD-UHFFFAOYSA-N 3-(trifluoromethylsulfonyl)benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC(S(=O)(=O)C(F)(F)F)=C1 HSDKYMBTTJDKGD-UHFFFAOYSA-N 0.000 description 7
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 125000003282 alkyl amino group Chemical group 0.000 description 7
- 125000002619 bicyclic group Chemical group 0.000 description 7
- 239000013058 crude material Substances 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 6
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 description 6
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 description 6
- 108010090931 Proto-Oncogene Proteins c-bcl-2 Proteins 0.000 description 6
- 102000013535 Proto-Oncogene Proteins c-bcl-2 Human genes 0.000 description 6
- WEVYAHXRMPXWCK-FIBGUPNXSA-N acetonitrile-d3 Chemical compound [2H]C([2H])([2H])C#N WEVYAHXRMPXWCK-FIBGUPNXSA-N 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- IRBHAVWDSJLCAS-UHFFFAOYSA-N 2-(4-chlorophenyl)benzaldehyde Chemical compound C1=CC(Cl)=CC=C1C1=CC=CC=C1C=O IRBHAVWDSJLCAS-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 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 description 5
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 description 5
- 238000006880 cross-coupling reaction Methods 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 5
- IVHGRBGVNATXFD-UHFFFAOYSA-N 1-chloro-4-[2-(iodomethyl)phenyl]benzene Chemical group C1=CC(Cl)=CC=C1C1=CC=CC=C1CI IVHGRBGVNATXFD-UHFFFAOYSA-N 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- 206010008342 Cervix carcinoma Diseases 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 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 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 4
- 125000003302 alkenyloxy group Chemical group 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 4
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 4
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 4
- 125000004414 alkyl thio group Chemical group 0.000 description 4
- 125000005133 alkynyloxy group Chemical group 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 201000010881 cervical cancer Diseases 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
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- 239000001257 hydrogen Substances 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 239000008177 pharmaceutical agent Substances 0.000 description 4
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 4
- 230000002062 proliferating effect Effects 0.000 description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical class [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- KPUWTTSCBIFJQH-UHFFFAOYSA-N 1-[[2-(4-chlorophenyl)phenyl]methyl]piperidin-4-one Chemical compound C1=CC(Cl)=CC=C1C1=CC=CC=C1CN1CCC(=O)CC1 KPUWTTSCBIFJQH-UHFFFAOYSA-N 0.000 description 3
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- 239000011593 sulfur Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 239000003277 telomerase inhibitor Substances 0.000 description 1
- SSOWVJRCWPTTLK-UHFFFAOYSA-N tert-butyl 3-bromo-6,8-dihydro-5h-[1,2,4]triazolo[4,3-a]pyrazine-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCN2C(Br)=NN=C21 SSOWVJRCWPTTLK-UHFFFAOYSA-N 0.000 description 1
- JZNWQLLPLOQGOI-UHFFFAOYSA-N tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)C(F)C1 JZNWQLLPLOQGOI-UHFFFAOYSA-N 0.000 description 1
- ANTSTNVAAVRTOL-UHFFFAOYSA-N tert-butyl 4-(benzotriazol-1-yloxy)-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate Chemical compound N1=NC2=CC=CC=C2N1OC1=C(CN(C(=O)OC(C)(C)C)C2)C2=NC=N1 ANTSTNVAAVRTOL-UHFFFAOYSA-N 0.000 description 1
- VGRWFJOIIYAUPW-JOCHJYFZSA-N tert-butyl 4-[[4-[[(2r)-4-morpholin-4-yl-1-phenylsulfanylbutan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylamino]-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate Chemical compound C([C@@H](NC1=CC=C(C=C1S(=O)(=O)C(F)(F)F)S(=O)(=O)NC=1N=CN=C2CN(CC2=1)C(=O)OC(C)(C)C)CSC=1C=CC=CC=1)CN1CCOCC1 VGRWFJOIIYAUPW-JOCHJYFZSA-N 0.000 description 1
- WNPCPHNVHJEGRJ-UHFFFAOYSA-N tert-butyl 4-chloro-2-(trifluoromethyl)-6,8-dihydro-5h-pyrido[3,4-d]pyrimidine-7-carboxylate Chemical compound N1=C(C(F)(F)F)N=C2CN(C(=O)OC(C)(C)C)CCC2=C1Cl WNPCPHNVHJEGRJ-UHFFFAOYSA-N 0.000 description 1
- XYHXUYOSXZHUSZ-UHFFFAOYSA-N tert-butyl 4-chloro-6,8-dihydro-5h-pyrido[3,4-d]pyrimidine-7-carboxylate Chemical compound N1=CN=C2CN(C(=O)OC(C)(C)C)CCC2=C1Cl XYHXUYOSXZHUSZ-UHFFFAOYSA-N 0.000 description 1
- BXXXVYDHJCLIKQ-UHFFFAOYSA-N tert-butyl 4-oxo-5,7-dihydro-1h-pyrrolo[3,4-d]pyrimidine-6-carboxylate Chemical compound N1=CNC(=O)C2=C1CN(C(=O)OC(C)(C)C)C2 BXXXVYDHJCLIKQ-UHFFFAOYSA-N 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- GLJYPTWEXBUATJ-UHFFFAOYSA-N tert-butyl 5-oxo-1,4-diazepane-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNC(=O)CC1 GLJYPTWEXBUATJ-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000004950 trifluoroalkyl group Chemical group 0.000 description 1
- CVYXKEPHZZIZMK-UHFFFAOYSA-N trifluoromethyl 6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate Chemical compound N1=CN=CC2=C1CN(CC2)C(=O)OC(F)(F)F CVYXKEPHZZIZMK-UHFFFAOYSA-N 0.000 description 1
- POXSDSRWVJZWCN-UHFFFAOYSA-N triphenylphosphanium;iodide Chemical compound I.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 POXSDSRWVJZWCN-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pyridine Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US24125109P | 2009-09-10 | 2009-09-10 | |
| US241251P | 2009-09-10 | ||
| PCT/EP2010/063169 WO2011029842A1 (en) | 2009-09-10 | 2010-09-08 | Sulfonamides as inhibitors of bcl-2 family proteins for the treatment of cancer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2443845T3 true ES2443845T3 (es) | 2014-02-20 |
Family
ID=43016684
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES10750124.9T Active ES2443845T3 (es) | 2009-09-10 | 2010-09-08 | Sulfonamidas como inhibidores de proteínas de la familia BCL-2 para el tratamiento del cáncer |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US8809352B2 (enExample) |
| EP (1) | EP2475661B1 (enExample) |
| JP (1) | JP2013504536A (enExample) |
| KR (1) | KR20120078715A (enExample) |
| CN (1) | CN102498111A (enExample) |
| AU (1) | AU2010294292B2 (enExample) |
| BR (1) | BR112012005343A2 (enExample) |
| CA (1) | CA2772989A1 (enExample) |
| EA (1) | EA020586B1 (enExample) |
| ES (1) | ES2443845T3 (enExample) |
| MX (1) | MX2012003007A (enExample) |
| WO (1) | WO2011029842A1 (enExample) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SG192126A1 (en) * | 2011-01-25 | 2013-09-30 | Univ Michigan | Bcl-2/bcl-xl inhibitors and therapeutic methods using the same |
| JP2015503515A (ja) | 2011-12-23 | 2015-02-02 | ノバルティス アーゲー | Ｂｃｌ２と結合相手の相互作用を阻害するための化合物および組成物 |
| EA201491264A1 (ru) | 2011-12-23 | 2014-11-28 | Новартис Аг | Соединения для ингибирования взаимодействия bcl-2 с партнерами по связыванию |
| LT6064B (lt) | 2012-10-15 | 2014-08-25 | Vilniaus Universitetas | Fluorinti benzensulfonamidai kaip karboanhidrazės inhibitoriai |
| SG10201704327RA (en) | 2013-10-14 | 2017-06-29 | Eisai R&D Man Co Ltd | Selectively substituted quinoline compounds |
| MX363708B (es) | 2013-10-14 | 2019-03-29 | Eisai R&D Man Co Ltd | Compuestos de quinolina selectivamente sustituidos. |
| US10195213B2 (en) | 2015-03-13 | 2019-02-05 | Unity Biotechnology, Inc. | Chemical entities that kill senescent cells for use in treating age-related disease |
| CN108349924A (zh) | 2015-08-12 | 2018-07-31 | 纪念斯隆凯特林癌症中心 | 苯磺酰氨基-苯并呋喃衍生物及其用途 |
| AU2017206731A1 (en) * | 2016-01-11 | 2018-08-02 | Merrimack Pharmaceuticals, Inc. | Inhibiting B-cell lymphoma 2 (Bcl-2) and related proteins |
| US10570119B2 (en) | 2016-01-11 | 2020-02-25 | Merrimack Pharmaceuticals, Inc. | Inhibiting ataxia telangiectasia and Rad3-related protein (ATR) |
| HUE071493T2 (hu) | 2018-04-29 | 2025-09-28 | Beigene Switzerland Gmbh | Bcl-2 inhibitorok |
| US11198699B2 (en) | 2019-04-02 | 2021-12-14 | Aligos Therapeutics, Inc. | Compounds targeting PRMT5 |
| BR112022019525A2 (pt) | 2020-04-15 | 2023-11-14 | Beigene Ltd | Composto, composição farmacêutica e método para tratar doenças apoptóticas desreguladas |
| EP4538273A1 (en) * | 2022-06-10 | 2025-04-16 | Hitgen Inc. | Compound and use thereof in preparation of bcl-xl inhibitor |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE372330T1 (de) * | 2002-03-21 | 2007-09-15 | Abbott Lab | N-sulfonylurea-apoptosis-förderer |
| US20040157836A1 (en) * | 2002-10-08 | 2004-08-12 | Comess Kenneth M. | Sulfonamides having antiangiogenic and anticancer activity |
| JP2007524596A (ja) | 2003-02-28 | 2007-08-30 | トランスフォーム・ファーマシューティカルズ・インコーポレイテッド | 共結晶医薬組成物 |
| CN101039662A (zh) * | 2004-08-20 | 2007-09-19 | 密执安州立大学董事会 | 抗－细胞凋亡bcl－2家族成员的小分子抑制剂及其应用 |
| CN101535280B (zh) * | 2006-11-15 | 2012-06-27 | 健泰科生物技术公司 | 芳基磺酰胺化合物 |
| FR2912145B1 (fr) * | 2007-02-02 | 2009-03-06 | Servier Lab | Nouveaux derives tricycliques,leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
-
2010
- 2010-09-08 AU AU2010294292A patent/AU2010294292B2/en not_active Ceased
- 2010-09-08 CA CA2772989A patent/CA2772989A1/en not_active Abandoned
- 2010-09-08 BR BR112012005343A patent/BR112012005343A2/pt not_active IP Right Cessation
- 2010-09-08 KR KR1020127009091A patent/KR20120078715A/ko not_active Withdrawn
- 2010-09-08 MX MX2012003007A patent/MX2012003007A/es active IP Right Grant
- 2010-09-08 EP EP10750124.9A patent/EP2475661B1/en not_active Not-in-force
- 2010-09-08 CN CN2010800396704A patent/CN102498111A/zh active Pending
- 2010-09-08 US US13/394,525 patent/US8809352B2/en not_active Expired - Fee Related
- 2010-09-08 JP JP2012528347A patent/JP2013504536A/ja active Pending
- 2010-09-08 ES ES10750124.9T patent/ES2443845T3/es active Active
- 2010-09-08 WO PCT/EP2010/063169 patent/WO2011029842A1/en not_active Ceased
- 2010-09-08 EA EA201200472A patent/EA020586B1/ru not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CA2772989A1 (en) | 2011-03-17 |
| BR112012005343A2 (pt) | 2016-03-22 |
| EP2475661A1 (en) | 2012-07-18 |
| JP2013504536A (ja) | 2013-02-07 |
| WO2011029842A1 (en) | 2011-03-17 |
| EA020586B1 (ru) | 2014-12-30 |
| AU2010294292B2 (en) | 2013-07-18 |
| CN102498111A (zh) | 2012-06-13 |
| MX2012003007A (es) | 2012-04-11 |
| EP2475661B1 (en) | 2013-10-23 |
| AU2010294292A1 (en) | 2012-03-01 |
| US8809352B2 (en) | 2014-08-19 |
| US20120165298A1 (en) | 2012-06-28 |
| KR20120078715A (ko) | 2012-07-10 |
| EA201200472A1 (ru) | 2012-10-30 |
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