KR20190057277A - B형 간염 바이러스 치료용 포스포아미데이트 - Google Patents
B형 간염 바이러스 치료용 포스포아미데이트 Download PDFInfo
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- KR20190057277A KR20190057277A KR1020197002039A KR20197002039A KR20190057277A KR 20190057277 A KR20190057277 A KR 20190057277A KR 1020197002039 A KR1020197002039 A KR 1020197002039A KR 20197002039 A KR20197002039 A KR 20197002039A KR 20190057277 A KR20190057277 A KR 20190057277A
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- South Korea
- Prior art keywords
- substituted
- alkyl
- amino
- aryl
- methyl
- Prior art date
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- Ceased
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- 238000011282 treatment Methods 0.000 title claims abstract description 23
- 241000700721 Hepatitis B virus Species 0.000 title description 30
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 146
- 239000000203 mixture Substances 0.000 claims abstract description 116
- 238000000034 method Methods 0.000 claims abstract description 69
- 239000003443 antiviral agent Substances 0.000 claims abstract description 41
- 229960004556 tenofovir Drugs 0.000 claims abstract description 17
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 claims abstract description 17
- 229960001997 adefovir Drugs 0.000 claims abstract description 16
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 claims abstract description 16
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229960001627 lamivudine Drugs 0.000 claims abstract description 14
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 claims abstract description 14
- 229960005311 telbivudine Drugs 0.000 claims abstract description 14
- IQFYYKKMVGJFEH-CSMHCCOUSA-N telbivudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1O[C@@H](CO)[C@H](O)C1 IQFYYKKMVGJFEH-CSMHCCOUSA-N 0.000 claims abstract description 14
- 229960000980 entecavir Drugs 0.000 claims abstract description 12
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 claims abstract description 12
- -1 4-substituted phenyl Chemical group 0.000 claims description 231
- 125000000217 alkyl group Chemical group 0.000 claims description 215
- 125000003118 aryl group Chemical group 0.000 claims description 142
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 125
- 229910052739 hydrogen Inorganic materials 0.000 claims description 105
- 125000003342 alkenyl group Chemical group 0.000 claims description 99
- 125000003545 alkoxy group Chemical group 0.000 claims description 98
- 239000001257 hydrogen Substances 0.000 claims description 87
- 125000000304 alkynyl group Chemical group 0.000 claims description 85
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 85
- 150000003839 salts Chemical class 0.000 claims description 82
- 125000001072 heteroaryl group Chemical group 0.000 claims description 79
- 125000002252 acyl group Chemical group 0.000 claims description 65
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 65
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 63
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 62
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 62
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 58
- 229910052805 deuterium Inorganic materials 0.000 claims description 55
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 54
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 53
- 241000700605 Viruses Species 0.000 claims description 48
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 45
- 239000002777 nucleoside Substances 0.000 claims description 44
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 43
- 150000002632 lipids Chemical class 0.000 claims description 42
- 229910052760 oxygen Inorganic materials 0.000 claims description 42
- 125000003107 substituted aryl group Chemical group 0.000 claims description 42
- 229910052717 sulfur Inorganic materials 0.000 claims description 40
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 39
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 39
- 150000003573 thiols Chemical class 0.000 claims description 37
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 36
- 229910052757 nitrogen Inorganic materials 0.000 claims description 34
- 230000015572 biosynthetic process Effects 0.000 claims description 33
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- 108020004414 DNA Proteins 0.000 claims description 31
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 30
- 239000003112 inhibitor Substances 0.000 claims description 29
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 28
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- 125000001153 fluoro group Chemical group F* 0.000 claims description 24
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 23
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 23
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 23
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 23
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 23
- 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 22
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 22
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 21
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 21
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 19
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
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- 239000000651 prodrug Substances 0.000 claims description 14
- 229940002612 prodrug Drugs 0.000 claims description 14
- 108010014726 Interferon Type I Proteins 0.000 claims description 13
- 102000002227 Interferon Type I Human genes 0.000 claims description 13
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 claims description 12
- 239000000427 antigen Substances 0.000 claims description 11
- 102000036639 antigens Human genes 0.000 claims description 11
- 108091007433 antigens Proteins 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 11
- 229940123066 Polymerase inhibitor Drugs 0.000 claims description 10
- 229960004150 aciclovir Drugs 0.000 claims description 10
- 102000014150 Interferons Human genes 0.000 claims description 9
- 108010050904 Interferons Proteins 0.000 claims description 9
- 229940079322 interferon Drugs 0.000 claims description 9
- 108091033409 CRISPR Proteins 0.000 claims description 8
- 238000010362 genome editing Methods 0.000 claims description 8
- 229940101771 nexavir Drugs 0.000 claims description 8
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 108010092853 peginterferon alfa-2a Proteins 0.000 claims description 7
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 6
- AXRYRYVKAWYZBR-UHFFFAOYSA-N Atazanavir Natural products C=1C=C(C=2N=CC=CC=2)C=CC=1CN(NC(=O)C(NC(=O)OC)C(C)(C)C)CC(O)C(NC(=O)C(NC(=O)OC)C(C)(C)C)CC1=CC=CC=C1 AXRYRYVKAWYZBR-UHFFFAOYSA-N 0.000 claims description 6
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- 102100034343 Integrase Human genes 0.000 claims description 6
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 claims description 6
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- 229960003805 amantadine Drugs 0.000 claims description 6
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 6
- 229960001830 amprenavir Drugs 0.000 claims description 6
- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 claims description 6
- 229960003277 atazanavir Drugs 0.000 claims description 6
- AXRYRYVKAWYZBR-GASGPIRDSA-N atazanavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@@H](O)CN(CC=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C1=CC=CC=C1 AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 claims description 6
- 210000000234 capsid Anatomy 0.000 claims description 6
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 claims description 6
- NOPFSRXAKWQILS-UHFFFAOYSA-N docosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCO NOPFSRXAKWQILS-UHFFFAOYSA-N 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 claims description 6
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- VSZGPKBBMSAYNT-RRFJBIMHSA-N oseltamivir Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 claims description 6
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- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 6
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- 241000255777 Lepidoptera Species 0.000 claims description 5
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 5
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 claims description 5
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| US8871737B2 (en) | 2010-09-22 | 2014-10-28 | Alios Biopharma, Inc. | Substituted nucleotide analogs |
| US20120142627A1 (en) * | 2010-12-06 | 2012-06-07 | Emory University | Monophosphate prodrugs of dapd and analogs thereof |
| CN103987712B (zh) | 2011-07-19 | 2016-05-04 | 河南美泰宝生物制药有限公司 | 2’，3’-二脱氧-2’-α-氟-2’-β-C-甲基核苷和其前药 |
| BR112015009636A8 (pt) * | 2012-10-29 | 2018-04-17 | Cocrystal Pharma Inc | composto, métodos para o tratamento de um hospedeiro infectado, métodos para a prevenção de uma infecção, métodos para a redução da atividade biológica de uma infecção e uso de um composto |
| WO2014078427A1 (en) | 2012-11-14 | 2014-05-22 | Idenix Pharmaceuticals, Inc. | D-alanine ester of rp-nucleoside analog |
| EP2970357B1 (en) | 2013-03-13 | 2025-01-01 | Idenix Pharmaceuticals LLC | Amino acid phosphoramidate pronucleotides of 2'-cyano, azido and amino nucleosides for the treatment of hcv |
| RU2015148006A (ru) | 2013-04-12 | 2017-05-18 | Ачиллион Фармасютикалз, Инк. | Дейтерированные нуклеозидные пролекарства, применимые для лечения hcv |
| BR112017012859A2 (pt) * | 2014-12-15 | 2017-12-26 | Univ Emory | fosforamidatos para o tratamento do vírus da hepatite b |
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2017
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- 2017-06-23 WO PCT/US2017/038963 patent/WO2017223421A1/en not_active Ceased
- 2017-06-23 AU AU2017281531A patent/AU2017281531A1/en not_active Abandoned
- 2017-06-23 KR KR1020197002039A patent/KR20190057277A/ko not_active Ceased
- 2017-06-23 SG SG11201811316YA patent/SG11201811316YA/en unknown
- 2017-06-23 US US16/312,756 patent/US11364257B2/en active Active
- 2017-06-23 CA CA3029315A patent/CA3029315A1/en active Pending
- 2017-06-23 EA EA201990059A patent/EA201990059A1/ru unknown
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2019
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2022
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| US11364257B2 (en) | 2022-06-21 |
| US20220280542A1 (en) | 2022-09-08 |
| PH12018550207A1 (en) | 2019-04-15 |
| BR112018076913A2 (pt) | 2019-04-02 |
| ZA201900156B (en) | 2019-08-28 |
| IL263859A (en) | 2019-01-31 |
| IL263859B1 (en) | 2023-03-01 |
| CN109689065A (zh) | 2019-04-26 |
| CA3029315A1 (en) | 2017-12-28 |
| US20190350954A1 (en) | 2019-11-21 |
| SG11201811316YA (en) | 2019-01-30 |
| JP2019525905A (ja) | 2019-09-12 |
| JP2022116024A (ja) | 2022-08-09 |
| EP3474863A1 (en) | 2019-05-01 |
| EP3474863A4 (en) | 2020-03-25 |
| EA201990059A1 (ru) | 2019-07-31 |
| AU2017281531A1 (en) | 2019-01-17 |
| WO2017223421A1 (en) | 2017-12-28 |
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