KR102575605B1 - B형 간염 코어 단백질 조정제의 제조 방법 - Google Patents
B형 간염 코어 단백질 조정제의 제조 방법 Download PDFInfo
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- KR102575605B1 KR102575605B1 KR1020197029525A KR20197029525A KR102575605B1 KR 102575605 B1 KR102575605 B1 KR 102575605B1 KR 1020197029525 A KR1020197029525 A KR 1020197029525A KR 20197029525 A KR20197029525 A KR 20197029525A KR 102575605 B1 KR102575605 B1 KR 102575605B1
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- South Korea
- Prior art keywords
- compound
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- alkyl
- alkoxy
- give
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- 101710132601 Capsid protein Proteins 0.000 title description 7
- 208000002672 hepatitis B Diseases 0.000 title description 6
- 229940076155 protein modulator Drugs 0.000 title description 3
- 238000004519 manufacturing process Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 210
- 238000000034 method Methods 0.000 claims abstract description 80
- -1 thiazole compound Chemical class 0.000 claims description 35
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- 125000003545 alkoxy group Chemical group 0.000 claims description 28
- 125000001424 substituent group Chemical group 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 150000001412 amines Chemical class 0.000 claims description 15
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 15
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 230000001590 oxidative effect Effects 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- 230000008878 coupling Effects 0.000 claims description 12
- 238000010168 coupling process Methods 0.000 claims description 12
- 238000005859 coupling reaction Methods 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 239000007822 coupling agent Substances 0.000 claims description 8
- 230000003301 hydrolyzing effect Effects 0.000 claims description 8
- 230000002862 amidating effect Effects 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 150000003141 primary amines Chemical class 0.000 claims description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 6
- 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 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical group FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical group [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- 238000007363 ring formation reaction Methods 0.000 claims description 5
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 4
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical group OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 claims description 4
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- 229910052804 chromium Inorganic materials 0.000 claims description 4
- 239000011651 chromium Substances 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 238000006177 thiolation reaction Methods 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical group S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 claims description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 2
- 239000003810 Jones reagent Substances 0.000 claims description 2
- 150000008065 acid anhydrides Chemical group 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 241000700721 Hepatitis B virus Species 0.000 abstract description 2
- 239000012637 allosteric effector Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 103
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 75
- 238000006243 chemical reaction Methods 0.000 description 68
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 62
- 235000019439 ethyl acetate Nutrition 0.000 description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 239000011541 reaction mixture Substances 0.000 description 42
- 239000000243 solution Substances 0.000 description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- 238000003786 synthesis reaction Methods 0.000 description 40
- 230000015572 biosynthetic process Effects 0.000 description 39
- 239000007787 solid Substances 0.000 description 39
- 238000005481 NMR spectroscopy Methods 0.000 description 31
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 26
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
- 239000000460 chlorine Substances 0.000 description 19
- 239000013058 crude material Substances 0.000 description 18
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 18
- 239000012065 filter cake Substances 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 239000012298 atmosphere Substances 0.000 description 15
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 15
- 239000010410 layer Substances 0.000 description 15
- 239000000203 mixture Substances 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 14
- 239000003039 volatile agent Substances 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 229910052938 sodium sulfate Inorganic materials 0.000 description 13
- 235000011152 sodium sulphate Nutrition 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 150000003839 salts Chemical class 0.000 description 11
- 239000000284 extract Substances 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000000623 heterocyclic group Chemical group 0.000 description 9
- 229940002612 prodrug Drugs 0.000 description 9
- 239000000651 prodrug Substances 0.000 description 9
- 230000003612 virological effect Effects 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- UEKIEJNYSPXCAW-UHFFFAOYSA-N 6,11,11-trioxo-5h-benzo[b][1,4]benzothiazepine-3-carboxylic acid Chemical compound N1C(=O)C2=CC=CC=C2S(=O)(=O)C2=CC=C(C(=O)O)C=C12 UEKIEJNYSPXCAW-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 150000003833 nucleoside derivatives Chemical class 0.000 description 8
- 238000011282 treatment Methods 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 210000000234 capsid Anatomy 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OUBKMWYXTAZEER-UHFFFAOYSA-N Cl.C(C)C=1SC(=CN1)CN Chemical compound Cl.C(C)C=1SC(=CN1)CN OUBKMWYXTAZEER-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- UWIFKJLMIUEHQC-UHFFFAOYSA-N [2-(trifluoromethyl)-1,3-thiazol-5-yl]methanamine Chemical compound NCC1=CN=C(C(F)(F)F)S1 UWIFKJLMIUEHQC-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 6
- 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
- SFKYHKPVINNAGJ-UHFFFAOYSA-N CC1=C(C=CC=2S(C3=C(C(NC=21)=O)C=CC=C3)(=O)=O)C(=O)O Chemical compound CC1=C(C=CC=2S(C3=C(C(NC=21)=O)C=CC=C3)(=O)=O)C(=O)O SFKYHKPVINNAGJ-UHFFFAOYSA-N 0.000 description 5
- GIUQNPIOTZMGHH-UHFFFAOYSA-N COC(=O)c1ccc2Sc3ccccc3C(=O)Nc2c1C Chemical compound COC(=O)c1ccc2Sc3ccccc3C(=O)Nc2c1C GIUQNPIOTZMGHH-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- ZSCDINYDKRECNJ-UHFFFAOYSA-N FC1=CC=CC2=C1C(NC1=C(S2)C=CC(=C1)C(=O)O)=O Chemical compound FC1=CC=CC2=C1C(NC1=C(S2)C=CC(=C1)C(=O)O)=O ZSCDINYDKRECNJ-UHFFFAOYSA-N 0.000 description 5
- WSVIMOBMIXUBHH-UHFFFAOYSA-N OC(=O)c1ccc2c(NC(=O)c3ccccc3S2(=O)=O)c1Cl Chemical compound OC(=O)c1ccc2c(NC(=O)c3ccccc3S2(=O)=O)c1Cl WSVIMOBMIXUBHH-UHFFFAOYSA-N 0.000 description 5
- 125000002837 carbocyclic group Chemical group 0.000 description 5
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 150000002430 hydrocarbons Chemical class 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000006188 syrup Substances 0.000 description 5
- 235000020357 syrup Nutrition 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- FJRFBJJNVQHNBM-UHFFFAOYSA-N (2-ethyl-1,3-thiazol-5-yl)methanol Chemical compound CCC1=NC=C(CO)S1 FJRFBJJNVQHNBM-UHFFFAOYSA-N 0.000 description 4
- AIBRJIYOSLKVFL-UHFFFAOYSA-N 1-bromo-4-fluoro-2-methyl-3-nitrobenzene Chemical compound CC1=C(Br)C=CC(F)=C1[N+]([O-])=O AIBRJIYOSLKVFL-UHFFFAOYSA-N 0.000 description 4
- PMQYXJZNUYBCFT-UHFFFAOYSA-N 3-amino-4-(2-carboxyphenyl)sulfanyl-2-chlorobenzoic acid Chemical compound NC=1C(=C(C(=O)O)C=CC=1SC1=C(C=CC=C1)C(=O)O)Cl PMQYXJZNUYBCFT-UHFFFAOYSA-N 0.000 description 4
- OSMNJSLUFGQCRO-UHFFFAOYSA-N 5-(chloromethyl)-2-ethyl-1,3-thiazole Chemical compound CCC1=NC=C(CCl)S1 OSMNJSLUFGQCRO-UHFFFAOYSA-N 0.000 description 4
- NLBIZCARYPAMPK-UHFFFAOYSA-N COC(=O)c1ccc2c(NC(=O)c3ccccc3S2(=O)=O)c1C Chemical compound COC(=O)c1ccc2c(NC(=O)c3ccccc3S2(=O)=O)c1C NLBIZCARYPAMPK-UHFFFAOYSA-N 0.000 description 4
- YTUMBMMRQQQLOG-UHFFFAOYSA-N Cc1c(Br)ccc2Sc3ccccc3C(=O)Nc12 Chemical compound Cc1c(Br)ccc2Sc3ccccc3C(=O)Nc12 YTUMBMMRQQQLOG-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- 102000014150 Interferons Human genes 0.000 description 4
- 108010050904 Interferons Proteins 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- FTECDEMQHBOMFK-UHFFFAOYSA-N N(=[N+]=[N-])CC1=CN=C(S1)CC Chemical compound N(=[N+]=[N-])CC1=CN=C(S1)CC FTECDEMQHBOMFK-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- VWZBAGQKNBGRMK-UHFFFAOYSA-N NC1=C(C=CC(=C1C)Br)SC1=C(C(=O)O)C=CC=C1 Chemical compound NC1=C(C=CC(=C1C)Br)SC1=C(C(=O)O)C=CC=C1 VWZBAGQKNBGRMK-UHFFFAOYSA-N 0.000 description 4
- YLZFPGCXBJINGJ-UHFFFAOYSA-N OC(=O)c1ccc2Sc3ccccc3C(=O)Nc2c1Cl Chemical compound OC(=O)c1ccc2Sc3ccccc3C(=O)Nc2c1Cl YLZFPGCXBJINGJ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 208000036142 Viral infection Diseases 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 239000012300 argon atmosphere Substances 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 239000000539 dimer Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- DWXKSCKBUSAOKS-UHFFFAOYSA-N ethyl 2-chloro-3-oxopropanoate Chemical compound CCOC(=O)C(Cl)C=O DWXKSCKBUSAOKS-UHFFFAOYSA-N 0.000 description 4
- NBUMKGUEMVLATG-UHFFFAOYSA-N ethyl 2-ethyl-1,3-thiazole-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(CC)S1 NBUMKGUEMVLATG-UHFFFAOYSA-N 0.000 description 4
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 229940079322 interferon Drugs 0.000 description 4
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 4
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 4
- SYOLBVIJSYGAHR-UHFFFAOYSA-N methyl 2,4-dichloro-3-nitrobenzoate Chemical compound COC(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1Cl SYOLBVIJSYGAHR-UHFFFAOYSA-N 0.000 description 4
- FKUIWHAHFRZTPE-UHFFFAOYSA-N methyl 2-chloro-4-(2-methoxycarbonylphenyl)sulfanyl-3-nitrobenzoate Chemical compound ClC1=C(C(=O)OC)C=CC(=C1[N+](=O)[O-])SC1=C(C=CC=C1)C(=O)OC FKUIWHAHFRZTPE-UHFFFAOYSA-N 0.000 description 4
- YPEMWWHAEVJGIS-UHFFFAOYSA-N methyl 3-amino-2,4-dichlorobenzoate Chemical compound COC(=O)C1=CC=C(Cl)C(N)=C1Cl YPEMWWHAEVJGIS-UHFFFAOYSA-N 0.000 description 4
- DFECCHILCAMQSN-UHFFFAOYSA-N methyl 4-(2-methoxycarbonylphenyl)sulfonyl-3-nitrobenzoate Chemical compound COC(=O)C1=C(C=CC=C1)S(=O)(=O)C1=C(C=C(C(=O)OC)C=C1)[N+](=O)[O-] DFECCHILCAMQSN-UHFFFAOYSA-N 0.000 description 4
- 239000002777 nucleoside Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 230000000707 stereoselective effect Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 230000009385 viral infection Effects 0.000 description 4
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Classifications
-
- 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
- C07D417/12—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 linked by a chain containing hetero atoms as chain links
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
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- Chemical & Material Sciences (AREA)
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- Health & Medical Sciences (AREA)
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- Virology (AREA)
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| US201762470560P | 2017-03-13 | 2017-03-13 | |
| US62/470,560 | 2017-03-13 | ||
| PCT/US2018/022100 WO2018169907A1 (en) | 2017-03-13 | 2018-03-13 | Process for making hepatitis b core protein modulators |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20190128675A KR20190128675A (ko) | 2019-11-18 |
| KR102575605B1 true KR102575605B1 (ko) | 2023-09-05 |
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| Application Number | Title | Priority Date | Filing Date |
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Country Status (9)
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|---|---|
| US (2) | US11040965B2 (https=) |
| EP (1) | EP3596070A1 (https=) |
| JP (1) | JP7179751B2 (https=) |
| KR (1) | KR102575605B1 (https=) |
| CN (1) | CN110612300B (https=) |
| AU (1) | AU2018236188B2 (https=) |
| CA (1) | CA3056696A1 (https=) |
| SG (1) | SG11201908475RA (https=) |
| WO (1) | WO2018169907A1 (https=) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| AU2017326356A1 (en) | 2016-09-15 | 2019-04-11 | Assembly Biosciences, Inc. | Hepatitis B core protein modulators |
| SG11201908012SA (en) | 2017-03-02 | 2019-09-27 | Assembly Biosciences Inc | Cyclic sulfamide compounds and methods of using same |
| SG11202112590WA (en) * | 2019-05-24 | 2021-12-30 | Assembly Biosciences Inc | Pharmaceutical compositions for the treatment of hbv |
| CN111333513B (zh) * | 2020-04-17 | 2021-08-27 | 江苏恒沛药物科技有限公司 | 一种2,4-二氟-3-硝基苯甲酸的制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2015138895A1 (en) | 2014-03-13 | 2015-09-17 | Indiana University Research And Technology Corporation | Hepatitis b core protein allosteric modulators |
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| GB1480553A (en) | 1976-06-03 | 1977-07-20 | Pfizer Ltd | Tricyclic sulphonamides |
| JPS58225074A (ja) | 1982-06-25 | 1983-12-27 | Chugai Pharmaceut Co Ltd | ジベンゾオキサゼピン誘導体 |
| GB9109557D0 (en) | 1991-05-02 | 1991-06-26 | Wellcome Found | Chemical compounds |
| US5512563A (en) | 1993-07-29 | 1996-04-30 | American Cyanamid Company | Tricyclic benzazepine vasopressin antagonists |
| GB9707695D0 (en) * | 1996-08-07 | 1997-06-04 | Hoffmann La Roche | Tricyclic dione derivatives |
| US20050192286A1 (en) * | 2003-10-22 | 2005-09-01 | Neurocrine Biosciences, Inc. | Ligands of melanocortin receptors and compositions and methods related thereto |
| DE102004004928A1 (de) | 2004-01-31 | 2005-08-18 | Bayer Healthcare Ag | Dibenzoxazepine II |
| CA2625423A1 (en) | 2005-10-17 | 2007-04-26 | Acadia Pharmaceuticals Inc. | Cb-1 modulating compounds and their use |
| US20070105835A1 (en) | 2005-11-07 | 2007-05-10 | Kazantsev Aleksey G | Compositions and methods for modulating poly(ADP-ribose) polymerase activity |
| JP4042065B1 (ja) | 2006-03-10 | 2008-02-06 | 健治 吉田 | 情報処理装置への入力処理システム |
| WO2008036139A2 (en) | 2006-06-07 | 2008-03-27 | The Regents Of The University Of California | Inhibitors of mshc and homologs thereof, and methods of identifying same |
| WO2008118141A2 (en) | 2006-10-17 | 2008-10-02 | Acadia Pharmaceuticals Inc. | Use of cannabinoid modulating compounds in combination with other therapeutic compounds for adjunctive therapy |
| CN102164605A (zh) | 2008-07-23 | 2011-08-24 | 美国卫生和人力服务部 | 用作抗疟药的疟原虫表面阴离子通道抑制剂 |
| WO2012045194A1 (en) | 2010-10-09 | 2012-04-12 | Abbott Laboratories | Benzodiazepinones as fak inhibitors for treatment of cancer |
| EP3085368A1 (en) | 2011-07-01 | 2016-10-26 | Baruch S. Blumberg Institute | Sulfamoylbenzamide derivatives as antiviral agents against hbv infection |
| US20150141384A1 (en) * | 2012-07-03 | 2015-05-21 | Mahesh Kandula | Compositions and methods for the treatment of neurological degenerative disorders |
| RU2519546C1 (ru) | 2013-01-16 | 2014-06-10 | Общество С Ограниченной Ответственностью "Биоинтегратор" (Ооо "Биоинтегратор") | КОНЪЮГАТЫ И МАЛЫЕ МОЛЕКУЛЫ, ВЗАИМОДЕЙСТВУЮЩИЕ С РЕЦЕПТОРОМ CD16а |
| AR095426A1 (es) | 2013-03-14 | 2015-10-14 | Onyx Therapeutics Inc | Inhibidores tripeptídicos de la epoxicetona proteasa |
| MY181020A (en) | 2013-03-15 | 2020-12-16 | Sanofi Sa | Heteroaryl compounds and uses thereof |
| EA031077B1 (ru) | 2013-06-19 | 2018-11-30 | Серагон Фармасьютикалз, Инк. | Модулятор рецептора эстрогена и его применения |
| WO2015017412A1 (en) | 2013-07-29 | 2015-02-05 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | 11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine s-oxide derivatives and their use as dopamine d2 receptor antagonists |
| CN104803880B (zh) * | 2014-01-23 | 2017-11-21 | 广州喜鹊医药有限公司 | 一种具有神经保护作用的化合物及其制备方法和应用 |
| WO2015189035A1 (en) | 2014-06-10 | 2015-12-17 | Basf Se | Substituted [1,2,4]triazole and imidazole compounds as fungicides |
| TWI730985B (zh) | 2015-09-15 | 2021-06-21 | 美商艾森伯利生物科學公司 | B型肝炎核心蛋白質調節劑 |
| AU2017326356A1 (en) * | 2016-09-15 | 2019-04-11 | Assembly Biosciences, Inc. | Hepatitis B core protein modulators |
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2018
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- 2018-03-13 AU AU2018236188A patent/AU2018236188B2/en not_active Ceased
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- 2018-03-13 WO PCT/US2018/022100 patent/WO2018169907A1/en not_active Ceased
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2021
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015138895A1 (en) | 2014-03-13 | 2015-09-17 | Indiana University Research And Technology Corporation | Hepatitis b core protein allosteric modulators |
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| US11040965B2 (en) | 2021-06-22 |
| AU2018236188B2 (en) | 2022-01-27 |
| CN110612300A (zh) | 2019-12-24 |
| CA3056696A1 (en) | 2019-09-20 |
| WO2018169907A1 (en) | 2018-09-20 |
| AU2018236188A1 (en) | 2019-10-17 |
| US20210380577A1 (en) | 2021-12-09 |
| CN110612300B (zh) | 2023-10-20 |
| KR20190128675A (ko) | 2019-11-18 |
| SG11201908475RA (en) | 2019-10-30 |
| JP7179751B2 (ja) | 2022-11-29 |
| JP2020510059A (ja) | 2020-04-02 |
| EP3596070A1 (en) | 2020-01-22 |
| US20200002325A1 (en) | 2020-01-02 |
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