TW201829412A - 抗病毒之替諾福韋（tenofovir）之脂系酯前藥 - Google Patents
抗病毒之替諾福韋（tenofovir）之脂系酯前藥 Download PDFInfo
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- TW201829412A TW201829412A TW106144739A TW106144739A TW201829412A TW 201829412 A TW201829412 A TW 201829412A TW 106144739 A TW106144739 A TW 106144739A TW 106144739 A TW106144739 A TW 106144739A TW 201829412 A TW201829412 A TW 201829412A
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- alkyl
- methyl
- oxy
- amino
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- -1 lipid ester Chemical class 0.000 title claims description 169
- 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 title description 20
- 229940002612 prodrug Drugs 0.000 title description 19
- 239000000651 prodrug Substances 0.000 title description 19
- 229960004556 tenofovir Drugs 0.000 title description 12
- 230000000840 anti-viral effect Effects 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 214
- 150000003839 salts Chemical class 0.000 claims abstract description 95
- 208000030507 AIDS Diseases 0.000 claims abstract description 34
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 claims abstract description 26
- 208000031886 HIV Infections Diseases 0.000 claims abstract description 25
- 208000037357 HIV infectious disease Diseases 0.000 claims abstract description 24
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims abstract description 24
- 239000003443 antiviral agent Substances 0.000 claims abstract description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 22
- 238000011282 treatment Methods 0.000 claims abstract description 17
- 230000002265 prevention Effects 0.000 claims abstract description 7
- 125000001424 substituent group Chemical group 0.000 claims description 103
- 125000000217 alkyl group Chemical group 0.000 claims description 75
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 65
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 56
- 125000001153 fluoro group Chemical group F* 0.000 claims description 55
- 125000001246 bromo group Chemical group Br* 0.000 claims description 54
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 claims description 37
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 36
- 239000003814 drug Substances 0.000 claims description 22
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 claims description 22
- 229910052799 carbon Inorganic materials 0.000 claims description 21
- 239000003112 inhibitor Substances 0.000 claims description 20
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
- 229940079593 drug Drugs 0.000 claims description 17
- 239000002835 hiv fusion inhibitor Substances 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 239000002777 nucleoside Substances 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 239000004030 hiv protease inhibitor Substances 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 229940099797 HIV integrase inhibitor Drugs 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 239000003084 hiv integrase inhibitor Substances 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 125000003386 piperidinyl group Chemical group 0.000 claims description 7
- QEYGAMYURHNUMI-UHFFFAOYSA-N propan-2-yl cyclopropanecarboxylate Chemical compound CC(C)OC(=O)C1CC1 QEYGAMYURHNUMI-UHFFFAOYSA-N 0.000 claims description 7
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 7
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 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
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
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- YSIBYEBNVMDAPN-CMDGGOBGSA-N (e)-4-oxo-4-(3-triethoxysilylpropylamino)but-2-enoic acid Chemical compound CCO[Si](OCC)(OCC)CCCNC(=O)\C=C\C(O)=O YSIBYEBNVMDAPN-CMDGGOBGSA-N 0.000 claims description 3
- NUBQKPWHXMGDLP-UHFFFAOYSA-N 1-[4-benzyl-2-hydroxy-5-[(2-hydroxy-2,3-dihydro-1h-inden-1-yl)amino]-5-oxopentyl]-n-tert-butyl-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide;sulfuric acid Chemical compound OS(O)(=O)=O.C1CN(CC(O)CC(CC=2C=CC=CC=2)C(=O)NC2C3=CC=CC=C3CC2O)C(C(=O)NC(C)(C)C)CN1CC1=CC=CN=C1 NUBQKPWHXMGDLP-UHFFFAOYSA-N 0.000 claims description 3
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- YIBOMRUWOWDFLG-ONEGZZNKSA-N rilpivirine Chemical compound CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 YIBOMRUWOWDFLG-ONEGZZNKSA-N 0.000 claims description 3
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- KHASNRBNVBIREH-IZEXYCQBSA-N methyl n-[(2s)-1-[[(5s)-5-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-6-phosphonooxyhexyl]amino]-1-oxo-3,3-diphenylpropan-2-yl]carbamate Chemical compound C=1C=CC=CC=1C([C@H](NC(=O)OC)C(=O)NCCCC[C@@H](COP(O)(O)=O)N(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)C1=CC=CC=C1 KHASNRBNVBIREH-IZEXYCQBSA-N 0.000 claims 2
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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| US10450335B2 (en) | 2015-12-15 | 2019-10-22 | Merck Sharp & Dohme Corp. | Antiviral oxime phosphoramide compounds |
| EP3503895B1 (en) * | 2016-08-25 | 2021-09-15 | Merck Sharp & Dohme Corp. | Antiviral prodrugs of tenofovir |
| KR20230010826A (ko) | 2016-10-14 | 2023-01-19 | 프리시젼 바이오사이언시스 인코포레이티드 | B형 간염 바이러스 게놈 내의 인식 서열에 대해 특이적인 조작된 메가뉴클레아제 |
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| US11447512B2 (en) | 2017-12-21 | 2022-09-20 | Shenzhen Targetrx, Inc. | Antiviral nucleoside reverse transcriptase inhibitor |
| JP7050165B2 (ja) | 2018-02-26 | 2022-04-07 | ギリアード サイエンシーズ， インコーポレイテッド | Ｈｂｖ複製阻害剤としての置換ピロリジン化合物 |
| US10870691B2 (en) | 2018-04-05 | 2020-12-22 | Gilead Sciences, Inc. | Antibodies and fragments thereof that bind hepatitis B virus protein X |
| TW202005654A (zh) | 2018-04-06 | 2020-02-01 | 捷克科學院有機化學與生物化學研究所 | ２，２，─環二核苷酸 |
| TWI818007B (zh) | 2018-04-06 | 2023-10-11 | 捷克科學院有機化學與生物化學研究所 | 2'3'-環二核苷酸 |
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| CN108586239B (zh) * | 2018-04-11 | 2020-12-29 | 深圳市前海博扬研究院有限公司 | 一种3-羟基丙酸甲酯的制备方法 |
| US11142750B2 (en) | 2018-04-12 | 2021-10-12 | Precision Biosciences, Inc. | Optimized engineered meganucleases having specificity for a recognition sequence in the Hepatitis B virus genome |
| US20190359645A1 (en) | 2018-05-03 | 2019-11-28 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2'3'-cyclic dinucleotides comprising carbocyclic nucleotide |
| WO2020018399A1 (en) | 2018-07-19 | 2020-01-23 | Merck Sharp & Dohme Corp. | Phosphinic amide prodrugs of tenofovir |
| WO2020028097A1 (en) | 2018-08-01 | 2020-02-06 | Gilead Sciences, Inc. | Solid forms of (r)-11-(methoxymethyl)-12-(3-methoxypropoxy)-3,3-dimethyl-8-0x0-2,3,8,13b-tetrahydro-1h-pyrido[2,1-a]pyrrolo[1,2-c] phthalazine-7-c arboxylic acid |
| WO2020092528A1 (en) | 2018-10-31 | 2020-05-07 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds having hpk1 inhibitory activity |
| US11203591B2 (en) | 2018-10-31 | 2021-12-21 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds |
| EP3914604B1 (en) | 2019-01-25 | 2026-03-04 | Brown University | Compositions comprising censavudine or elvucitabine for treating age-associated inflammation and disorders |
| EP3934757B1 (en) | 2019-03-07 | 2023-02-22 | Institute of Organic Chemistry and Biochemistry ASCR, V.V.I. | 2'3'-cyclic dinucleotides and prodrugs thereof |
| WO2020178770A1 (en) | 2019-03-07 | 2020-09-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 3'3'-cyclic dinucleotides and prodrugs thereof |
| WO2020178768A1 (en) | 2019-03-07 | 2020-09-10 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 3'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator |
| TWI751516B (zh) | 2019-04-17 | 2022-01-01 | 美商基利科學股份有限公司 | 類鐸受體調節劑之固體形式 |
| TW202212339A (zh) | 2019-04-17 | 2022-04-01 | 美商基利科學股份有限公司 | 類鐸受體調節劑之固體形式 |
| KR102054104B1 (ko) * | 2019-04-30 | 2019-12-09 | 유니셀랩 주식회사 | 신규한 테노포비어 알라펜아미드 염 및 이의 제조방법 |
| EP3972695A1 (en) | 2019-05-23 | 2022-03-30 | Gilead Sciences, Inc. | Substituted exo-methylene-oxindoles which are hpk1/map4k1 inhibitors |
| WO2020263830A1 (en) | 2019-06-25 | 2020-12-30 | Gilead Sciences, Inc. | Flt3l-fc fusion proteins and methods of use |
| WO2021034804A1 (en) | 2019-08-19 | 2021-02-25 | Gilead Sciences, Inc. | Pharmaceutical formulations of tenofovir alafenamide |
| DK4037708T3 (da) | 2019-09-30 | 2024-09-30 | Gilead Sciences Inc | HBV-vacciner og fremgangsmåder til at behandle HBV |
| DK4069729T3 (da) | 2019-12-06 | 2025-04-07 | Prec Biosciences Inc | Optimerede, modificerede meganukleaser med specificitet for en genkendelsessekvens i hepatitis b-virusgenomet |
| CN111018916B (zh) * | 2019-12-30 | 2022-04-29 | 天津天士力圣特制药有限公司 | 一种替诺福韦苯基烷基酯膦酰胺前体的合成方法 |
| WO2021188959A1 (en) | 2020-03-20 | 2021-09-23 | Gilead Sciences, Inc. | Prodrugs of 4'-c-substituted-2-halo-2'-deoxyadenosine nucleosides and methods of making and using the same |
| EP4192474B1 (en) * | 2020-08-07 | 2025-09-10 | Gilead Sciences, Inc. | Prodrugs of phosphonamide nucleotide analogues and their pharmaceutical use |
| TW202228724A (zh) * | 2020-09-23 | 2022-08-01 | 美商昂克萊亞製藥公司 | 以反轉錄酶抑制劑治療癌症之方法 |
| TW202406932A (zh) | 2020-10-22 | 2024-02-16 | 美商基利科學股份有限公司 | 介白素2-Fc融合蛋白及使用方法 |
| WO2022241134A1 (en) | 2021-05-13 | 2022-11-17 | Gilead Sciences, Inc. | COMBINATION OF A TLR8 MODULATING COMPOUND AND ANTI-HBV siRNA THERAPEUTICS |
| JP7651018B2 (ja) | 2021-06-23 | 2025-03-25 | ギリアード サイエンシーズ， インコーポレイテッド | ジアシルグリセロールキナーゼ調節化合物 |
| AU2022299051B2 (en) | 2021-06-23 | 2025-03-13 | Gilead Sciences, Inc. | Diacylglyercol kinase modulating compounds |
| JP7686091B2 (ja) | 2021-06-23 | 2025-05-30 | ギリアード サイエンシーズ， インコーポレイテッド | ジアシルグリセロールキナーゼ調節化合物 |
| MX2023014762A (es) | 2021-06-23 | 2024-01-15 | Gilead Sciences Inc | Compuestos moduladores de diacilglicerol quinasa. |
| WO2025240243A1 (en) | 2024-05-13 | 2025-11-20 | Gilead Sciences, Inc. | Combination therapies with bulevirtide and an inhibitory nucleic acid targeting hepatitis b virus |
| WO2025240242A1 (en) | 2024-05-13 | 2025-11-20 | Gilead Sciences, Inc. | Combination therapies with ribavirin |
| WO2025240244A1 (en) | 2024-05-13 | 2025-11-20 | Gilead Sciences, Inc. | Combination therapies comprising bulevirtide and lonafarnib for use in the treatment of hepatitis d virus infection |
| WO2025240246A1 (en) | 2024-05-13 | 2025-11-20 | Gilead Sciences, Inc. | Combination therapies with ribavirin |
Family Cites Families (28)
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|---|---|---|---|---|
| US5922695A (en) | 1996-07-26 | 1999-07-13 | Gilead Sciences, Inc. | Antiviral phosphonomethyoxy nucleotide analogs having increased oral bioavarilability |
| US5935946A (en) | 1997-07-25 | 1999-08-10 | Gilead Sciences, Inc. | Nucleotide analog composition and synthesis method |
| US20020119443A1 (en) | 2000-07-21 | 2002-08-29 | Gilead Sciences, Inc. | Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same |
| ATE478082T1 (de) | 2003-12-30 | 2010-09-15 | Gilead Sciences Inc | Phosphonate, monophosphonamidate, bisphosphonamidate zur behandlung von virenerkrankungen |
| WO2006114065A2 (en) | 2005-04-25 | 2006-11-02 | Institute Of Organic Chemistry And Biochemistry A Cademy Of Sciences Of The Czech Republic | Use of compounds to inhibit neoplasia |
| WO2007002912A2 (en) | 2005-06-29 | 2007-01-04 | Gilead Sciences, Inc. | Anti-proliferative compounds, compositions, and methods of use thereof |
| US20080008682A1 (en) | 2006-07-07 | 2008-01-10 | Chong Lee S | Modulators of toll-like receptor 7 |
| US7964580B2 (en) | 2007-03-30 | 2011-06-21 | Pharmasset, Inc. | Nucleoside phosphoramidate prodrugs |
| TWI444384B (zh) | 2008-02-20 | 2014-07-11 | Gilead Sciences Inc | 核苷酸類似物及其在治療惡性腫瘤上的用途 |
| US9095599B2 (en) | 2011-01-03 | 2015-08-04 | Nanjing Molecular Research, Inc. | O-(substituted benzyl) phosphoramidate compounds and therapeutic use |
| US9156874B2 (en) * | 2011-01-03 | 2015-10-13 | Nanjing Molecular Research, Inc. | Double-liver-targeting phosphoramidate and phosphonoamidate prodrugs |
| CN102887901B (zh) | 2011-07-01 | 2015-01-07 | 四川好医生攀西药业有限责任公司 | 无环核苷酸类似物及其制备方法和应用 |
| ES2608871T5 (es) | 2011-08-16 | 2024-04-04 | Gilead Sciences Inc | Alafenamide hemifumarate de tenofovir |
| CN103665043B (zh) * | 2012-08-30 | 2017-11-10 | 江苏豪森药业集团有限公司 | 一种替诺福韦前药及其在医药上的应用 |
| CN103435672A (zh) * | 2013-04-25 | 2013-12-11 | 刘沛 | 含有取代苄基的新型核苷磷酸酯前药的结构与合成 |
| WO2015197006A1 (zh) * | 2014-06-25 | 2015-12-30 | 四川海思科制药有限公司 | 一种取代的氨基酸硫酯类化合物、其组合物及应用 |
| CN111808136B (zh) | 2014-09-15 | 2024-06-11 | 加利福尼亚大学董事会 | 核苷酸类似物 |
| CN106188139B (zh) | 2015-05-29 | 2020-02-18 | 江苏天士力帝益药业有限公司 | 替诺福韦单苄酯磷酸酰胺前药、其制备方法及应用 |
| WO2017007701A1 (en) | 2015-07-07 | 2017-01-12 | Merck Sharp & Dohme Corp. | Antiviral phosphodiamide compounds |
| PE20181016A1 (es) | 2015-08-10 | 2018-06-26 | Merck Sharp & Dohme | Compuestos antivirales de fosfodiamida de ester de beta aminoacido |
| EP3350191B9 (en) | 2015-09-15 | 2021-12-22 | The Regents of the University of California | Nucleotide analogs |
| CN106167504A (zh) | 2015-11-04 | 2016-11-30 | 洛阳聚慧医药科技有限公司 | 非环核苷磷酰胺d‑氨基酸酯衍生物及其盐的制备以及在抗病毒方面的应用 |
| RU2604068C1 (ru) * | 2015-12-10 | 2016-12-10 | Федеральное государственное бюджетное учреждение науки Институт органического синтеза им. И.Я. Постовского Уральского отделения Российской академии наук | N-(2-аминопурин-6-ил)глицил-(s)-глутаминовая кислота, обладающая противотуберкулёзной активностью |
| US10745428B2 (en) | 2015-12-10 | 2020-08-18 | Idenix Pharmaceuticals Llc | Antiviral phosphodiamide prodrugs of tenofovir |
| US10450335B2 (en) | 2015-12-15 | 2019-10-22 | Merck Sharp & Dohme Corp. | Antiviral oxime phosphoramide compounds |
| EP3503895B1 (en) * | 2016-08-25 | 2021-09-15 | Merck Sharp & Dohme Corp. | Antiviral prodrugs of tenofovir |
| EP3532069A4 (en) | 2016-10-26 | 2020-05-13 | Merck Sharp & Dohme Corp. | ANTIVIRAL ARYL AMID PHOSPHODIAMID COMPOUNDS |
| US11123355B2 (en) | 2016-12-22 | 2021-09-21 | Idenix Pharmaceuticals Llc | Antiviral benzyl-amine phosphodiamide compounds |
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| US10519159B2 (en) | 2019-12-31 |
| EP3559011B1 (en) | 2022-04-13 |
| BR112019013017A2 (pt) | 2020-01-14 |
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