CA2954751C - Indoles for use in influenza virus infection - Google Patents
Indoles for use in influenza virus infection Download PDFInfo
- Publication number
- CA2954751C CA2954751C CA2954751A CA2954751A CA2954751C CA 2954751 C CA2954751 C CA 2954751C CA 2954751 A CA2954751 A CA 2954751A CA 2954751 A CA2954751 A CA 2954751A CA 2954751 C CA2954751 C CA 2954751C
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- Prior art keywords
- mmol
- nmr
- amino
- mhz
- ppm
- Prior art date
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- 241000712461 unidentified influenza virus Species 0.000 title claims description 11
- 150000002475 indoles Chemical class 0.000 title description 2
- 230000009385 viral infection Effects 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 206010022000 influenza Diseases 0.000 claims abstract description 34
- 125000000623 heterocyclic group Chemical group 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 239000012453 solvate Substances 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 150000001732 carboxylic acid derivatives Chemical group 0.000 claims description 9
- 150000001408 amides Chemical class 0.000 claims description 8
- 239000003443 antiviral agent Substances 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
- 229960003971 influenza vaccine Drugs 0.000 claims description 6
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 229940124597 therapeutic agent Drugs 0.000 claims description 5
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 4
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 239000012472 biological sample Substances 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 230000010076 replication Effects 0.000 claims description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 5
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 247
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 204
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 180
- 239000000203 mixture Substances 0.000 description 176
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 143
- 238000000034 method Methods 0.000 description 140
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 136
- 239000000243 solution Substances 0.000 description 135
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 126
- 238000002360 preparation method Methods 0.000 description 104
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 103
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 95
- 239000011541 reaction mixture Substances 0.000 description 94
- 239000002904 solvent Substances 0.000 description 90
- 239000012044 organic layer Substances 0.000 description 89
- 239000007787 solid Substances 0.000 description 89
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 83
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 80
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 78
- 239000012071 phase Substances 0.000 description 77
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 74
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 68
- 235000019341 magnesium sulphate Nutrition 0.000 description 68
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 66
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 59
- 238000005481 NMR spectroscopy Methods 0.000 description 53
- 239000000377 silicon dioxide Substances 0.000 description 52
- 230000015572 biosynthetic process Effects 0.000 description 50
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 49
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
- 238000003786 synthesis reaction Methods 0.000 description 47
- 239000000543 intermediate Substances 0.000 description 43
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 42
- 238000000746 purification Methods 0.000 description 38
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 35
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 34
- 239000012267 brine Substances 0.000 description 33
- 238000001914 filtration Methods 0.000 description 33
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 33
- 230000005526 G1 to G0 transition Effects 0.000 description 32
- 239000000706 filtrate Substances 0.000 description 31
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 30
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 29
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 27
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 26
- 239000010410 layer Substances 0.000 description 25
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 24
- 235000019798 tripotassium phosphate Nutrition 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 23
- -1 elixirs Substances 0.000 description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- 238000003818 flash chromatography Methods 0.000 description 20
- 239000000741 silica gel Substances 0.000 description 20
- 229910002027 silica gel Inorganic materials 0.000 description 20
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 18
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 18
- 239000012230 colorless oil Substances 0.000 description 18
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 16
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 16
- 229910021120 PdC12 Inorganic materials 0.000 description 15
- LCDCPQHFCOBUEF-UHFFFAOYSA-N pyrrolidine-1-carboxamide Chemical compound NC(=O)N1CCCC1 LCDCPQHFCOBUEF-UHFFFAOYSA-N 0.000 description 15
- 235000017557 sodium bicarbonate Nutrition 0.000 description 15
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 15
- 239000003643 water by type Substances 0.000 description 15
- 239000000843 powder Substances 0.000 description 14
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
- 229910000024 caesium carbonate Inorganic materials 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 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 12
- NXWWGWDHJHWFAZ-MNOVXSKESA-N ClC1=NC=C(C(=N1)N[C@H]1C[C@H](CCC1)NC(C1=NC=CC=C1)=O)F Chemical compound ClC1=NC=C(C(=N1)N[C@H]1C[C@H](CCC1)NC(C1=NC=CC=C1)=O)F NXWWGWDHJHWFAZ-MNOVXSKESA-N 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- 239000012298 atmosphere Substances 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- 235000015320 potassium carbonate Nutrition 0.000 description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- DEDKKOOGYIMMBC-UHFFFAOYSA-N 2,6-dichloro-5-fluoropyridine-3-carbonitrile Chemical compound FC1=CC(C#N)=C(Cl)N=C1Cl DEDKKOOGYIMMBC-UHFFFAOYSA-N 0.000 description 10
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 10
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 10
- 229910052731 fluorine Inorganic materials 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 9
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 9
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 9
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 9
- 238000004808 supercritical fluid chromatography Methods 0.000 description 9
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 9
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 8
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 8
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 8
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 8
- WTXXSZUATXIAJO-OWBHPGMISA-N (Z)-14-methylpentadec-2-enoic acid Chemical compound CC(CCCCCCCCCC\C=C/C(=O)O)C WTXXSZUATXIAJO-OWBHPGMISA-N 0.000 description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 7
- WHPFEQUEHBULBW-UHFFFAOYSA-N 2,4-dichloro-5-fluoropyrimidine Chemical compound FC1=CN=C(Cl)N=C1Cl WHPFEQUEHBULBW-UHFFFAOYSA-N 0.000 description 7
- DOSSHBKOJPDKRH-HHQFNNIRSA-N Cl.ClC1=NC=C(C(=N1)N[C@@H]1C[C@@H](CCC1)N)F Chemical compound Cl.ClC1=NC=C(C(=N1)N[C@@H]1C[C@@H](CCC1)N)F DOSSHBKOJPDKRH-HHQFNNIRSA-N 0.000 description 7
- 241000700605 Viruses Species 0.000 description 7
- 229910052801 chlorine Inorganic materials 0.000 description 7
- MNRNSFOFHFYHNP-UHFFFAOYSA-N cyclohexane-1,3-diamine Chemical compound NC1[CH]CCC(N)C1 MNRNSFOFHFYHNP-UHFFFAOYSA-N 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- 235000019253 formic acid Nutrition 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 230000002209 hydrophobic effect Effects 0.000 description 7
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 7
- NQPDZGIKBAWPEJ-UHFFFAOYSA-M valerate Chemical compound CCCCC([O-])=O NQPDZGIKBAWPEJ-UHFFFAOYSA-M 0.000 description 7
- 239000005711 Benzoic acid Substances 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- FNIMHVTVWZMNCU-RJUBDTSPSA-N Cl.N[C@H]1C[C@H](CCC1)NC1=NC(=C(C#N)C=C1F)Cl Chemical compound Cl.N[C@H]1C[C@H](CCC1)NC1=NC(=C(C#N)C=C1F)Cl FNIMHVTVWZMNCU-RJUBDTSPSA-N 0.000 description 6
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000034994 death Effects 0.000 description 6
- 231100000517 death Toxicity 0.000 description 6
- 238000010511 deprotection reaction Methods 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 6
- 208000037797 influenza A Diseases 0.000 description 6
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 description 6
- 230000002441 reversible effect Effects 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 238000002255 vaccination Methods 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 235000010233 benzoic acid Nutrition 0.000 description 5
- WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 description 5
- 125000003963 dichloro group Chemical group Cl* 0.000 description 5
- 108010037444 diisopropylglutathione ester Proteins 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 229940093499 ethyl acetate Drugs 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 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 5
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 5
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Substances IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 4
- 102000005348 Neuraminidase Human genes 0.000 description 4
- 108010006232 Neuraminidase Proteins 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- WDUDHEOUGWAKFD-UHFFFAOYSA-N ditert-butyl(cyclopenta-2,4-dien-1-yl)phosphane;iron(2+) Chemical compound [Fe+2].CC(C)(C)P(C(C)(C)C)C1=CC=C[CH-]1.CC(C)(C)P(C(C)(C)C)C1=CC=C[CH-]1 WDUDHEOUGWAKFD-UHFFFAOYSA-N 0.000 description 4
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 4
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 4
- 230000001932 seasonal effect Effects 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- OBSACSBMTRJNPH-BDAKNGLRSA-N tert-butyl n-[(1s,3r)-3-aminocyclohexyl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](N)C1 OBSACSBMTRJNPH-BDAKNGLRSA-N 0.000 description 4
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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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
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- 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
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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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| PCT/EP2015/068257 WO2016020526A1 (en) | 2014-08-08 | 2015-08-07 | Indoles for use in influenza virus infection |
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| CA2954751A1 CA2954751A1 (en) | 2016-02-11 |
| CA2954751C true CA2954751C (en) | 2023-01-17 |
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| CN104151312B (zh) | 2009-06-17 | 2016-06-15 | 沃泰克斯药物股份有限公司 | 流感病毒复制抑制剂 |
| UA118010C2 (uk) | 2011-08-01 | 2018-11-12 | Вертекс Фармасьютікалз Інкорпорейтед | Інгібітори реплікації вірусів грипу |
| AU2015298876B2 (en) | 2014-08-08 | 2020-02-13 | Janssen Sciences Ireland Uc | Indoles for use in influenza virus infection |
| EP3294717B1 (en) | 2015-05-13 | 2020-07-29 | Vertex Pharmaceuticals Inc. | Methods of preparing inhibitors of influenza viruses replication |
| WO2016183120A1 (en) | 2015-05-13 | 2016-11-17 | Vertex Pharmaceuticals Incorporated | Inhibitors of influenza viruses replication |
| CN106854205B (zh) | 2015-12-09 | 2019-07-09 | 广东东阳光药业有限公司 | 流感病毒复制抑制剂及其使用方法和用途 |
| CA3007758A1 (en) * | 2016-01-07 | 2017-07-13 | Janssen Sciences Ireland Uc | Functionalized pentanoic acids for use in influenza viral infections |
| WO2017133670A1 (en) * | 2016-02-05 | 2017-08-10 | Savira Pharmaceuticals Gmbh | Pyridine and pyrimidine derivatives and their use in treatment, amelioration or prevention of influenza |
| WO2018033082A1 (en) * | 2016-08-16 | 2018-02-22 | Sunshine Lake Pharma Co., Ltd. | Inhibitors of influenza virus replication, application methods and uses thereof |
| US10647693B2 (en) | 2016-08-30 | 2020-05-12 | North & South Brother Pharmacy Investment Company Limited | Inhibitors of influenza virus replication, application methods and uses thereof |
| SG11201901894TA (en) * | 2016-09-05 | 2019-04-29 | Guangdong Raynovent Biotech Co Ltd | Anti-influenza virus pyrimidine derivatives |
| WO2018108125A1 (en) | 2016-12-15 | 2018-06-21 | Sunshine Lake Pharma Co., Ltd. | Inhibitors of influenza virus replication and uses thereof |
| EP4306166A3 (en) | 2016-12-23 | 2024-06-26 | Aquinnah Pharmaceuticals Inc. | Compounds, compositions and methods of use |
| WO2018127096A1 (en) | 2017-01-05 | 2018-07-12 | Sunshine Lake Pharma Co., Ltd. | Inhibitors of influenza virus replication and uses thereof |
| CN110446711B (zh) | 2017-03-02 | 2022-02-15 | 广东东阳光药业有限公司 | 流感病毒复制抑制剂及其用途 |
| CN108727369B (zh) * | 2017-04-25 | 2023-06-09 | 广东东阳光药业有限公司 | 流感病毒复制抑制剂及其用途 |
| CA3092315C (en) * | 2018-03-05 | 2023-08-29 | Jian Xiong | Crystal form and salt form of pyridopyrazole compound and preparation method therefor |
| JP7450017B2 (ja) | 2019-07-22 | 2024-03-14 | 広東衆生睿創生物科技有限公司 | ピリミジン誘導体の優位な塩形およびその結晶形 |
| CN113045475A (zh) * | 2019-12-27 | 2021-06-29 | 上海泓博智源医药股份有限公司 | 一种5-溴-7-甲基吲哚的制备方法 |
| TW202216720A (zh) * | 2020-07-20 | 2022-05-01 | 美商尼道生物科學公司 | 作為雄激素受體調節劑的吲哚化合物 |
| US20240010643A1 (en) * | 2020-09-18 | 2024-01-11 | Sunshine Lake Pharma Co., Ltd. | Preparation method of substituted pyrimidine piperazine compounds |
| KR20250103814A (ko) * | 2022-10-12 | 2025-07-07 | 메이즈 테라퓨틱스, 인코퍼레이티드 | 용질 담체 계열 6a 구성원 19(slc6a19)의 억제제 및 이의 사용 방법 |
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| EP1730146B1 (en) | 2004-03-30 | 2011-05-04 | Vertex Pharmaceuticals Incorporated | Azaindoles useful as inhibitors of jak and other protein kinases |
| AU2007207533B8 (en) | 2006-01-17 | 2012-06-28 | Vertex Pharmaceuticals Incorporated | Azaindoles useful as inhibitors of Janus kinases |
| CN104151312B (zh) * | 2009-06-17 | 2016-06-15 | 沃泰克斯药物股份有限公司 | 流感病毒复制抑制剂 |
| ES2602972T3 (es) * | 2010-09-08 | 2017-02-23 | Glaxosmithkline Intellectual Property Development Limited | Derivados de indazol para su uso en el tratamiento de infección por virus de la gripe |
| MX2013006840A (es) | 2010-12-16 | 2014-01-31 | Vertex Pharma | Inhibidores de la replicacion de los virus de la influenza. |
| MX2013006836A (es) | 2010-12-16 | 2013-09-26 | Vertex Pharma | Inhibidores de la replicacion de los virus de la influenza. |
| UA118010C2 (uk) * | 2011-08-01 | 2018-11-12 | Вертекс Фармасьютікалз Інкорпорейтед | Інгібітори реплікації вірусів грипу |
| BR112014004569A2 (pt) | 2011-09-01 | 2017-06-13 | F. Hoffmann-La Roche Ag | composto da fórmula i, métodos para tratar condição inflamatória, artrite reumatoide, asma e distúrbio imune, composição farmacêutica e uso do composto |
| EP2858984A1 (en) * | 2012-06-08 | 2015-04-15 | Vertex Pharmaceuticals Inc. | Inhibitors of influenza viruses replication |
| HUE044667T2 (hu) | 2013-11-13 | 2019-11-28 | Vertex Pharma | Influenza vírus replikáció inhibitorok |
| UY36249A (es) | 2014-08-08 | 2016-01-29 | Bayer Cropscience Ag | Compuestos sustituidos con halógeno novedosos |
| AU2015298876B2 (en) | 2014-08-08 | 2020-02-13 | Janssen Sciences Ireland Uc | Indoles for use in influenza virus infection |
| AR101448A1 (es) | 2014-08-08 | 2016-12-21 | Bayer Cropscience Ag | Compuestos sustituidos por halógeno |
| CN104592038A (zh) | 2015-01-12 | 2015-05-06 | 烟台万润精细化工股份有限公司 | 一种5,5-二甲基-1,3-环己二胺的制备方法 |
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2015
- 2015-08-07 AU AU2015298876A patent/AU2015298876B2/en not_active Ceased
- 2015-08-07 MA MA040547A patent/MA40547A/fr unknown
- 2015-08-07 CN CN201580042406.9A patent/CN106573920B/zh not_active Expired - Fee Related
- 2015-08-07 US US15/501,730 patent/US10597390B2/en not_active Expired - Fee Related
- 2015-08-07 EP EP15750365.7A patent/EP3177609A1/en not_active Withdrawn
- 2015-08-07 EA EA201790266A patent/EA201790266A1/ru unknown
- 2015-08-07 WO PCT/EP2015/068257 patent/WO2016020526A1/en not_active Ceased
- 2015-08-07 KR KR1020177005979A patent/KR102488479B1/ko active Active
- 2015-08-07 UA UAA201702154A patent/UA124609C2/uk unknown
- 2015-08-07 SG SG11201700956VA patent/SG11201700956VA/en unknown
- 2015-08-07 JP JP2017506964A patent/JP6577570B2/ja not_active Expired - Fee Related
- 2015-08-07 BR BR112017002370-9A patent/BR112017002370B1/pt not_active IP Right Cessation
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2017
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- 2017-02-02 PH PH12017500207A patent/PH12017500207A1/en unknown
- 2017-02-07 ZA ZA2017/00952A patent/ZA201700952B/en unknown
- 2017-02-07 CL CL2017000309A patent/CL2017000309A1/es unknown
Also Published As
| Publication number | Publication date |
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| BR112017002370A2 (pt) | 2017-12-05 |
| KR102488479B1 (ko) | 2023-01-12 |
| CN106573920A (zh) | 2017-04-19 |
| ZA201700952B (en) | 2018-12-19 |
| AU2015298876B2 (en) | 2020-02-13 |
| US20170226102A1 (en) | 2017-08-10 |
| MA40547A (fr) | 2017-06-14 |
| UA124609C2 (uk) | 2021-10-20 |
| EA201790266A1 (ru) | 2017-06-30 |
| CN106573920B (zh) | 2020-11-10 |
| SG11201700956VA (en) | 2017-03-30 |
| EP3177609A1 (en) | 2017-06-14 |
| CL2017000309A1 (es) | 2017-08-18 |
| IL250408A0 (en) | 2017-03-30 |
| IL250408B (en) | 2020-08-31 |
| KR20170039275A (ko) | 2017-04-10 |
| US10597390B2 (en) | 2020-03-24 |
| WO2016020526A1 (en) | 2016-02-11 |
| MX381488B (es) | 2025-03-12 |
| MX2017001752A (es) | 2018-02-08 |
| PH12017500207B1 (en) | 2017-07-10 |
| CA2954751A1 (en) | 2016-02-11 |
| BR112017002370B1 (pt) | 2022-11-22 |
| JP2017523225A (ja) | 2017-08-17 |
| JP6577570B2 (ja) | 2019-09-18 |
| PH12017500207A1 (en) | 2017-07-10 |
| AU2015298876A1 (en) | 2017-02-02 |
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