JP5044854B2 - ヌクレオチドプロドラッグおよびオリゴヌクレオチドプロドラッグ - Google Patents
ヌクレオチドプロドラッグおよびオリゴヌクレオチドプロドラッグ Download PDFInfo
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- JP5044854B2 JP5044854B2 JP2008545782A JP2008545782A JP5044854B2 JP 5044854 B2 JP5044854 B2 JP 5044854B2 JP 2008545782 A JP2008545782 A JP 2008545782A JP 2008545782 A JP2008545782 A JP 2008545782A JP 5044854 B2 JP5044854 B2 JP 5044854B2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
-
- 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
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- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Virology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Steroid Compounds (AREA)
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
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| US75003605P | 2005-12-13 | 2005-12-13 | |
| US60/750,036 | 2005-12-13 | ||
| US80029406P | 2006-05-15 | 2006-05-15 | |
| US60/800,294 | 2006-05-15 | ||
| US11/637,520 | 2006-12-12 | ||
| US11/637,520 US8076303B2 (en) | 2005-12-13 | 2006-12-12 | Nucleotide and oligonucleotide prodrugs |
| PCT/US2006/047617 WO2007070598A2 (en) | 2005-12-13 | 2006-12-13 | Nucleotide and oligonucleotide prodrugs |
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| JP2009519345A JP2009519345A (ja) | 2009-05-14 |
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| EP (3) | EP3090748B1 (https=) |
| JP (1) | JP5044854B2 (https=) |
| KR (2) | KR101123534B1 (https=) |
| CN (2) | CN101437397B (https=) |
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| DK (2) | DK3090748T3 (https=) |
| ES (2) | ES2573928T3 (https=) |
| HR (1) | HRP20160531T1 (https=) |
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| IN (1) | IN2015DN01786A (https=) |
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| PT (1) | PT3090748T (https=) |
| RS (1) | RS54867B1 (https=) |
| SI (2) | SI3090748T1 (https=) |
| WO (1) | WO2007070598A2 (https=) |
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| JP4012070B2 (ja) * | 2001-01-16 | 2007-11-21 | カン−フィテ・バイオファーマ・リミテッド | ウイルスの複製を阻害するためのアデノシンａ３受容体アゴニストの使用 |
| US8076303B2 (en) * | 2005-12-13 | 2011-12-13 | Spring Bank Pharmaceuticals, Inc. | Nucleotide and oligonucleotide prodrugs |
| GB2471806B (en) | 2008-04-03 | 2012-12-19 | Spring Bank Pharmaceuticals Inc | Compositions and methods for treating viral infections |
| US8691971B2 (en) * | 2008-09-23 | 2014-04-08 | Scott G. Petersen | Self delivering bio-labile phosphate protected pro-oligos for oligonucleotide based therapeutics and mediating RNA interference |
| RU2572826C2 (ru) | 2008-12-02 | 2016-01-20 | Чиралджен, Лтд. | Способ синтеза модифицированных по атому фосфора нуклеиновых кислот |
| CN102307889A (zh) * | 2008-12-23 | 2012-01-04 | 集润德斯股份公司 | 硫化剂及其用于寡核苷酸合成的用途 |
| AU2015255202B2 (en) * | 2009-07-06 | 2017-07-27 | Wave Life Sciences Ltd. | Novel nucleic acid prodrugs and methods of use thereof |
| CA2767253A1 (en) | 2009-07-06 | 2011-01-13 | Ontorii, Inc. | Novel nucleic acid prodrugs and methods of use thereof |
| CN101659612B (zh) * | 2009-09-24 | 2013-01-09 | 华润赛科药业有限责任公司 | 一种选择性酯化的方法 |
| KR101926419B1 (ko) * | 2010-08-30 | 2018-12-10 | 스프링 뱅크 파마슈티칼스, 인크. | 치료제로서 올리고뉴클레오타이드 유사체의 설계 |
| JP5868324B2 (ja) | 2010-09-24 | 2016-02-24 | 株式会社Wave Life Sciences Japan | 不斉補助基 |
| AU2012284265B2 (en) | 2011-07-19 | 2017-08-17 | Wave Life Sciences Ltd. | Methods for the synthesis of functionalized nucleic acids |
| KR101327026B1 (ko) | 2011-11-29 | 2013-11-13 | 현대자동차주식회사 | 운전자 보호장치 |
| SG11201500239VA (en) | 2012-07-13 | 2015-03-30 | Wave Life Sciences Japan | Asymmetric auxiliary group |
| CN104684923B (zh) | 2012-07-13 | 2018-09-28 | 株式会社新日本科学 | 手性核酸佐剂 |
| JP6453212B2 (ja) * | 2012-07-13 | 2019-01-16 | ウェイブ ライフ サイエンシズ リミテッドＷａｖｅ Ｌｉｆｅ Ｓｃｉｅｎｃｅｓ Ｌｔｄ． | キラル制御 |
| EP2956145A4 (en) * | 2013-02-18 | 2016-08-17 | Spring Bank Pharmaceuticals Inc | DESIGN OF SHORT OLIGONUCLEOTIDES AS VACCINATE ADJUVANTIES AND THERAPEUTICS |
| JPWO2015108046A1 (ja) | 2014-01-15 | 2017-03-23 | 株式会社新日本科学 | 抗アレルギー作用を有するキラル核酸アジュバンド及び抗アレルギー剤 |
| WO2015108047A1 (ja) | 2014-01-15 | 2015-07-23 | 株式会社新日本科学 | 免疫誘導活性を有するキラル核酸アジュバンド及び免疫誘導活性剤 |
| WO2015108048A1 (ja) | 2014-01-15 | 2015-07-23 | 株式会社新日本科学 | 抗腫瘍作用を有するキラル核酸アジュバンド及び抗腫瘍剤 |
| ES2917473T3 (es) | 2014-01-16 | 2022-07-08 | Wave Life Sciences Ltd | Diseño quiral |
| GB201403697D0 (en) * | 2014-03-03 | 2014-04-16 | Link Technologies Ltd | Compounds and methods of use |
| WO2016045642A1 (en) * | 2014-09-28 | 2016-03-31 | National Institute Of Biological Sciences, Beijing | Polymeric bile acid derivatives inhibit hepatitis b and d virus and ntcp transport |
| WO2016164625A1 (en) * | 2015-04-07 | 2016-10-13 | Spring Bank Pharmaceuticals, Inc. | Compositions and methods for the treatment of hcv infection |
| EP3317290A4 (en) * | 2015-07-02 | 2019-04-10 | Spring Bank Pharmaceuticals, Inc. | COMPOSITIONS AND METHOD FOR TREATING VIRUS INFECTION |
| US20190070212A1 (en) * | 2016-03-11 | 2019-03-07 | Spring Bank Pharmaceuticals, Inc. | Compounds and compositions for the treatment of infections |
| MX2019000660A (es) * | 2016-07-15 | 2019-10-02 | Sperovie Biosciences Inc | Compuestos, composiciones y métodos para el tratamiento de enfermedades. |
| WO2018100558A2 (en) | 2016-12-01 | 2018-06-07 | Takeda Pharmaceutical Company Limited | Cyclic dinucleotide |
| US20200055883A1 (en) | 2017-02-17 | 2020-02-20 | Eisai R&D Management Co., Ltd. | Cyclic di-nucleotides derivative for the treatment of cancer |
| AR113224A1 (es) | 2017-04-28 | 2020-02-19 | Novartis Ag | Conjugados de anticuerpo que comprenden un agonista de sting |
| WO2019051489A1 (en) * | 2017-09-11 | 2019-03-14 | Sperovie Biosciences, Inc. | COMPOUNDS, COMPOSITIONS AND METHODS OF TREATING DISEASE |
| WO2019051488A1 (en) | 2017-09-11 | 2019-03-14 | Sperovie Biosciences, Inc. | COMPOUNDS, COMPOSITIONS AND METHODS OF TREATING DISEASE |
| CN110467647B (zh) * | 2018-05-09 | 2022-08-30 | 博瑞生物医药（苏州）股份有限公司 | 双核苷酸前体药物的制备方法 |
| CN110467646A (zh) * | 2018-05-09 | 2019-11-19 | 博瑞生物医药（苏州）股份有限公司 | 双核苷酸前体药物 |
| CN111918870B (zh) * | 2018-05-18 | 2022-07-08 | 正大天晴药业集团股份有限公司 | 氘代的低聚核苷酸及前体药物 |
| MX2020012964A (es) | 2018-06-01 | 2021-02-16 | Eisai R&D Man Co Ltd | Metodos para el tratamiento de cancer de vejiga. |
| FR3082434B1 (fr) | 2018-06-14 | 2021-04-30 | Cairdac | Implant cardiaque autonome de type "capsule leadless", comprenant un recuperateur d'energie a lame piezoelectrique |
| MX2020013322A (es) | 2018-08-16 | 2021-02-22 | Eisai R&D Man Co Ltd | Sales de compuestos y cristales de los mismos. |
| WO2020092617A1 (en) | 2018-10-31 | 2020-05-07 | Novartis Ag | Dc-sign antibody conjugates comprising sting agonists |
| WO2020089815A1 (en) | 2018-10-31 | 2020-05-07 | Novartis Ag | Antibody conjugates comprising sting agonist |
| CN113164506B (zh) * | 2018-12-06 | 2023-12-08 | 正大天晴药业集团股份有限公司 | 二核苷酸化合物及其前体药物 |
| CN111484540B (zh) * | 2019-01-25 | 2023-09-08 | 博瑞生物医药（苏州）股份有限公司 | 含双核苷酸结构的化合物 |
| CN111484541B (zh) * | 2019-01-25 | 2023-06-02 | 博瑞生物医药（苏州）股份有限公司 | 双核苷酸前体药物及其制备方法 |
Family Cites Families (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US688183A (en) | 1900-12-17 | 1901-12-03 | Carl C Lantz | Adjusting-clip for garment-supporters. |
| DE2817041C2 (de) | 1978-04-19 | 1987-02-19 | Reich Spezialmaschinen GmbH, 7440 Nürtingen | Vorrichtung zum Aufteilen von Platten |
| CS264222B1 (en) * | 1986-07-18 | 1989-06-13 | Holy Antonin | N-phosphonylmethoxyalkylderivatives of bases of pytimidine and purine and method of use them |
| US5204466A (en) | 1990-02-01 | 1993-04-20 | Emory University | Method and compositions for the synthesis of bch-189 and related compounds |
| US5914331A (en) | 1990-02-01 | 1999-06-22 | Emory University | Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane |
| KR100204987B1 (ko) | 1990-04-18 | 1999-06-15 | 제이코버스 코넬리스 레이서 | 항미생물성 퀴놀로닐 락탐 |
| US5444063A (en) | 1990-12-05 | 1995-08-22 | Emory University | Enantiomerically pure β-D-dioxolane nucleosides with selective anti-Hepatitis B virus activity |
| US5432165A (en) | 1992-04-06 | 1995-07-11 | Oclassen Pharmaceuticals, Inc. | Methods for the treatment of infection caused by Hepatitis B virus (HBV) |
| FR2705099B1 (fr) | 1993-05-12 | 1995-08-04 | Centre Nat Rech Scient | Oligonucléotides phosphorothioates triesters et procédé de préparation. |
| US5955591A (en) | 1993-05-12 | 1999-09-21 | Imbach; Jean-Louis | Phosphotriester oligonucleotides, amidites and method of preparation |
| FR2709754B1 (fr) * | 1993-09-10 | 1995-12-01 | Centre Nat Rech Scient | Composés 2' ou 3'-déoxy- et 2', 3'-didéoxy-beta-L-pentofuranonucléosides, procédé de préparation et application thérapeutique, notamment anti-virale. |
| US5587362A (en) | 1994-01-28 | 1996-12-24 | Univ. Of Ga Research Foundation | L-nucleosides |
| US5581639A (en) | 1995-05-04 | 1996-12-03 | National Research Council Of Canada | Raman-nath diffraction grating |
| WO1998007734A1 (en) | 1996-08-21 | 1998-02-26 | Hybridon, Inc. | Oligonucleotide prodrugs |
| AU4988697A (en) | 1996-10-24 | 1998-05-15 | Vion Pharmaceuticals, Inc. | Monophosphate prodrugs of beta-l-fd4c and beta-l-fddc as potent antiviral agents |
| US6444652B1 (en) | 1998-08-10 | 2002-09-03 | Novirio Pharmaceuticals Limited | β-L-2'-deoxy-nucleosides for the treatment of hepatitis B |
| ES2255295T3 (es) | 1998-08-10 | 2006-06-16 | Idenix (Cayman) Limited | 2'-deoxi-beta-l-nucleosidos para el tratamiento de la hepatitis b. |
| CA2599597A1 (en) | 1998-08-10 | 2000-02-24 | Idenix (Cayman) Limited | .beta.-l-2'-deoxy-nucleosides for the treatment of hepatitis b |
| US6875751B2 (en) | 2000-06-15 | 2005-04-05 | Idenix Pharmaceuticals, Inc. | 3′-prodrugs of 2′-deoxy-β-L-nucleosides |
| CZ304734B6 (cs) | 2000-07-21 | 2014-09-10 | Gilead Sciences, Inc. | Způsob přípravy 9-[2-(fosfonomethoxy)propyl]adeninu a 9-[2-(fosfonomethoxy)ethyl]adeninu |
| CN101113160A (zh) * | 2001-05-16 | 2008-01-30 | 米珍尼克斯公司 | 基于核酸的化合物及其使用方法 |
| US8076303B2 (en) * | 2005-12-13 | 2011-12-13 | Spring Bank Pharmaceuticals, Inc. | Nucleotide and oligonucleotide prodrugs |
| CN101146337B (zh) | 2006-09-15 | 2011-04-20 | 华为技术有限公司 | 新接入节点随机接入的方法及其系统 |
| GB2471806B (en) * | 2008-04-03 | 2012-12-19 | Spring Bank Pharmaceuticals Inc | Compositions and methods for treating viral infections |
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