TW201643153A - 溴結構域抑制劑 - Google Patents
溴結構域抑制劑 Download PDFInfo
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- TW201643153A TW201643153A TW105111879A TW105111879A TW201643153A TW 201643153 A TW201643153 A TW 201643153A TW 105111879 A TW105111879 A TW 105111879A TW 105111879 A TW105111879 A TW 105111879A TW 201643153 A TW201643153 A TW 201643153A
- Authority
- TW
- Taiwan
- Prior art keywords
- alkyl
- compound
- hydrogen
- pharmaceutically acceptable
- acceptable salt
- Prior art date
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- 102000001805 Bromodomains Human genes 0.000 title abstract description 51
- 108050009021 Bromodomains Proteins 0.000 title abstract description 39
- 239000003112 inhibitor Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 434
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 201
- 125000000217 alkyl group Chemical group 0.000 claims description 341
- 229910052739 hydrogen Inorganic materials 0.000 claims description 226
- 239000001257 hydrogen Substances 0.000 claims description 225
- 150000003839 salts Chemical class 0.000 claims description 223
- 229910052736 halogen Inorganic materials 0.000 claims description 215
- 150000002367 halogens Chemical class 0.000 claims description 214
- -1 cycloalkylyne Chemical group 0.000 claims description 205
- 125000001072 heteroaryl group Chemical group 0.000 claims description 163
- 125000003118 aryl group Chemical group 0.000 claims description 151
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 143
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 139
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 132
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 127
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 123
- 229910052757 nitrogen Inorganic materials 0.000 claims description 101
- 125000003545 alkoxy group Chemical group 0.000 claims description 93
- 125000000304 alkynyl group Chemical group 0.000 claims description 59
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 55
- 239000008194 pharmaceutical composition Substances 0.000 claims description 48
- 125000003342 alkenyl group Chemical group 0.000 claims description 47
- 125000004434 sulfur atom Chemical group 0.000 claims description 45
- 229910052717 sulfur Inorganic materials 0.000 claims description 41
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 39
- SVSARCCKBMZNMR-UHFFFAOYSA-N [1-[2-[methyl-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethyl]amino]ethyl]pyridin-4-ylidene]methyl-oxoazanium;dichloride Chemical compound [Cl-].[Cl-].C1=CC(=C[NH+]=O)C=CN1CCN(C)CCN1C=CC(=C[NH+]=O)C=C1 SVSARCCKBMZNMR-UHFFFAOYSA-N 0.000 claims description 37
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 35
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 34
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 32
- 125000005357 cycloalkylalkynyl group Chemical group 0.000 claims description 26
- 125000005843 halogen group Chemical group 0.000 claims description 15
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical compound C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 claims description 15
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 13
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 13
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 13
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 125000005114 heteroarylalkoxy group Chemical group 0.000 claims description 8
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 6
- 125000004104 aryloxy group Chemical group 0.000 claims description 6
- BMVGRYYCVHUNTL-UHFFFAOYSA-N 4-(2-cyclopropyl-5-methylsulfonyl-1-benzofuran-7-yl)-2-methylisoquinolin-1-one Chemical compound CN1C=C(C2=C3OC(=CC3=CC(=C2)S(C)(=O)=O)C2CC2)C2=C(C=CC=C2)C1=O BMVGRYYCVHUNTL-UHFFFAOYSA-N 0.000 claims description 5
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 5
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 5
- JLGYTQNBVCXSHO-UHFFFAOYSA-N 4-methyl-6-(2-methyl-1-oxoisoquinolin-4-yl)-1,4-benzoxazin-3-one Chemical compound C1=CC=C2C(C3=CC=C4OCC(=O)N(C4=C3)C)=CN(C)C(=O)C2=C1 JLGYTQNBVCXSHO-UHFFFAOYSA-N 0.000 claims description 4
- 125000005112 cycloalkylalkoxy group Chemical group 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 3
- MLGFKZXLNZKATJ-UHFFFAOYSA-N 4-(1'-cyclobutylspiro[4h-1,3-benzodioxine-2,4'-piperidine]-6-yl)-2-methylisoquinolin-1-one Chemical compound C12=CC=CC=C2C(=O)N(C)C=C1C(C=C1CO2)=CC=C1OC2(CC1)CCN1C1CCC1 MLGFKZXLNZKATJ-UHFFFAOYSA-N 0.000 claims description 2
- AVRQZBKJBDYYDC-UHFFFAOYSA-N 4-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)-2-methylisoquinolin-1-one Chemical compound Cn1cc(-c2ccc3OCCNc3c2)c2ccccc2c1=O AVRQZBKJBDYYDC-UHFFFAOYSA-N 0.000 claims description 2
- 125000005038 alkynylalkyl group Chemical group 0.000 claims description 2
- 125000005343 heterocyclic alkyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 63
- 239000000203 mixture Substances 0.000 abstract description 177
- 238000000034 method Methods 0.000 abstract description 121
- 108090000623 proteins and genes Proteins 0.000 abstract description 51
- 206010028980 Neoplasm Diseases 0.000 abstract description 36
- 201000011510 cancer Diseases 0.000 abstract description 35
- 102000004169 proteins and genes Human genes 0.000 abstract description 33
- 108010033040 Histones Proteins 0.000 abstract description 26
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 23
- 201000010099 disease Diseases 0.000 abstract description 16
- 102000006947 Histones Human genes 0.000 abstract description 14
- 230000001404 mediated effect Effects 0.000 abstract description 10
- 230000005764 inhibitory process Effects 0.000 abstract description 8
- 230000001613 neoplastic effect Effects 0.000 abstract description 7
- 230000006718 epigenetic regulation Effects 0.000 abstract description 6
- DTERQYGMUDWYAZ-ZETCQYMHSA-N N(6)-acetyl-L-lysine Chemical group CC(=O)NCCCC[C@H]([NH3+])C([O-])=O DTERQYGMUDWYAZ-ZETCQYMHSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 361
- 235000019439 ethyl acetate Nutrition 0.000 description 188
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 144
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 135
- 238000005481 NMR spectroscopy Methods 0.000 description 119
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 78
- 239000011734 sodium Substances 0.000 description 74
- 239000012044 organic layer Substances 0.000 description 69
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 68
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 55
- 239000000243 solution Substances 0.000 description 53
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 49
- 239000007787 solid Substances 0.000 description 47
- 125000004432 carbon atom Chemical group C* 0.000 description 42
- 239000012267 brine Substances 0.000 description 39
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 39
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 39
- 239000000460 chlorine Substances 0.000 description 37
- 230000002829 reductive effect Effects 0.000 description 37
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 32
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 32
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 32
- 235000018102 proteins Nutrition 0.000 description 32
- 239000011541 reaction mixture Substances 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 29
- 125000002947 alkylene group Chemical group 0.000 description 28
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 25
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 24
- 239000000706 filtrate Substances 0.000 description 24
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 108091005625 BRD4 Proteins 0.000 description 20
- 102100029895 Bromodomain-containing protein 4 Human genes 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 20
- 239000000126 substance Substances 0.000 description 20
- 108010077544 Chromatin Proteins 0.000 description 18
- 210000003483 chromatin Anatomy 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 125000001424 substituent group Chemical group 0.000 description 17
- 238000001816 cooling Methods 0.000 description 16
- 229920006395 saturated elastomer Polymers 0.000 description 16
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 15
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 15
- 125000002837 carbocyclic group Chemical group 0.000 description 15
- 125000004452 carbocyclyl group Chemical group 0.000 description 15
- ZCRZCMUDOWDGOB-UHFFFAOYSA-N ethanesulfonimidic acid Chemical compound CCS(N)(=O)=O ZCRZCMUDOWDGOB-UHFFFAOYSA-N 0.000 description 15
- 125000003709 fluoroalkyl group Chemical group 0.000 description 15
- 230000008569 process Effects 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- 229910052799 carbon Inorganic materials 0.000 description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 14
- 238000010651 palladium-catalyzed cross coupling reaction Methods 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 14
- WYLZKEAKTKRGKT-UHFFFAOYSA-N 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one Chemical compound CN1C(=O)C(C)=CC(B2OC(C)(C)C(C)(C)O2)=C1 WYLZKEAKTKRGKT-UHFFFAOYSA-N 0.000 description 13
- 239000002585 base Substances 0.000 description 13
- 230000002401 inhibitory effect Effects 0.000 description 13
- 238000013518 transcription Methods 0.000 description 13
- 230000035897 transcription Effects 0.000 description 13
- 108091005575 Bromodomain-containing proteins Proteins 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 125000003277 amino group Chemical group 0.000 description 11
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 11
- HMVOWYNRRUSKJE-UHFFFAOYSA-N 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one Chemical compound Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O HMVOWYNRRUSKJE-UHFFFAOYSA-N 0.000 description 10
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
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- 229940002612 prodrug Drugs 0.000 description 10
- NVNPLEPBDPJYRZ-UHFFFAOYSA-N 1-(bromomethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CBr)C=C1 NVNPLEPBDPJYRZ-UHFFFAOYSA-N 0.000 description 9
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
- 125000005884 carbocyclylalkyl group Chemical group 0.000 description 9
- 125000004122 cyclic group Chemical group 0.000 description 9
- 239000005457 ice water Substances 0.000 description 9
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 102100033641 Bromodomain-containing protein 2 Human genes 0.000 description 8
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- 101000871850 Homo sapiens Bromodomain-containing protein 2 Proteins 0.000 description 8
- 101000871851 Homo sapiens Bromodomain-containing protein 3 Proteins 0.000 description 8
- 125000005323 thioketone group Chemical group 0.000 description 8
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 7
- PHPYXVIHDRDPDI-UHFFFAOYSA-N 2-bromo-1h-benzimidazole Chemical class C1=CC=C2NC(Br)=NC2=C1 PHPYXVIHDRDPDI-UHFFFAOYSA-N 0.000 description 7
- 102100021574 Bromodomain adjacent to zinc finger domain protein 2B Human genes 0.000 description 7
- 102100029894 Bromodomain testis-specific protein Human genes 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 101000971143 Homo sapiens Bromodomain adjacent to zinc finger domain protein 2B Proteins 0.000 description 7
- 101000794028 Homo sapiens Bromodomain testis-specific protein Proteins 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 125000004429 atom Chemical group 0.000 description 7
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- 208000035475 disorder Diseases 0.000 description 7
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- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 6
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 6
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 5
- ABAGKHWCTWMUDH-UHFFFAOYSA-N 5-bromo-1,3-difluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=C(F)C=C(Br)C=C1F ABAGKHWCTWMUDH-UHFFFAOYSA-N 0.000 description 5
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- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical group C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 4
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- VEFNVMSUKDCQDF-UHFFFAOYSA-N 6-bromo-2-methyl-4-nitro-1h-benzimidazole Chemical compound BrC1=CC([N+]([O-])=O)=C2NC(C)=NC2=C1 VEFNVMSUKDCQDF-UHFFFAOYSA-N 0.000 description 4
- XWALISSRSGMCSU-UHFFFAOYSA-N 6-bromo-2-methylisoquinolin-1-one Chemical compound BrC1=CC=C2C(=O)N(C)C=CC2=C1 XWALISSRSGMCSU-UHFFFAOYSA-N 0.000 description 4
- IRYJFUNUDRADTJ-UHFFFAOYSA-N 6-bromo-4-nitro-1h-benzimidazole Chemical compound [O-][N+](=O)C1=CC(Br)=CC2=C1N=CN2 IRYJFUNUDRADTJ-UHFFFAOYSA-N 0.000 description 4
- BPZFSVJSHGNBOR-UHFFFAOYSA-N 6-bromo-5-methoxy-2-methyl-3H-1,2-benzothiazole 1,1-dioxide Chemical compound COC1=CC2=C(C=C1Br)S(=O)(=O)N(C)C2 BPZFSVJSHGNBOR-UHFFFAOYSA-N 0.000 description 4
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
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- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 4
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- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- 238000002560 therapeutic procedure Methods 0.000 description 1
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- XDLNRRRJZOJTRW-UHFFFAOYSA-N thiohypochlorous acid Chemical compound ClS XDLNRRRJZOJTRW-UHFFFAOYSA-N 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
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- INQOMBQAUSQDDS-FIBGUPNXSA-N trideuterio(iodo)methane Chemical compound [2H]C([2H])([2H])I INQOMBQAUSQDDS-FIBGUPNXSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- 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
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
-
- 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
- C07D401/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D413/02—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
- C07D413/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
-
- 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
- C07D471/06—Peri-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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| TWI838964B (zh) * | 2021-11-17 | 2024-04-11 | 南韓商日東製藥股份有限公司 | 異噁唑衍生物的製備方法及其中間體 |
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| TWI838964B (zh) * | 2021-11-17 | 2024-04-11 | 南韓商日東製藥股份有限公司 | 異噁唑衍生物的製備方法及其中間體 |
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| EP3283077A2 (en) | 2018-02-21 |
| JP6856543B2 (ja) | 2021-04-07 |
| CA2982588A1 (en) | 2016-10-20 |
| US10494371B2 (en) | 2019-12-03 |
| ES2868355T3 (es) | 2021-10-21 |
| AU2016249273A1 (en) | 2017-11-09 |
| AU2016249273B2 (en) | 2020-07-09 |
| ECSP17070706A (es) | 2017-12-01 |
| PH12017501888A1 (en) | 2018-03-05 |
| MX2017013207A (es) | 2018-02-19 |
| EP3831383A1 (en) | 2021-06-09 |
| EP3283077B1 (en) | 2021-03-10 |
| AR104259A1 (es) | 2017-07-05 |
| US20180134710A1 (en) | 2018-05-17 |
| WO2016168682A2 (en) | 2016-10-20 |
| US10807982B2 (en) | 2020-10-20 |
| JP2018511626A (ja) | 2018-04-26 |
| IL255006A0 (en) | 2017-12-31 |
| EA201792229A1 (ru) | 2018-05-31 |
| KR20170135938A (ko) | 2017-12-08 |
| CO2017011484A2 (es) | 2018-01-31 |
| US9908885B2 (en) | 2018-03-06 |
| CN107635558A (zh) | 2018-01-26 |
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