TWI634115B - 普拉二烯內酯吡啶化合物及其使用方法 - Google Patents
普拉二烯內酯吡啶化合物及其使用方法 Download PDFInfo
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- TWI634115B TWI634115B TW104115293A TW104115293A TWI634115B TW I634115 B TWI634115 B TW I634115B TW 104115293 A TW104115293 A TW 104115293A TW 104115293 A TW104115293 A TW 104115293A TW I634115 B TWI634115 B TW I634115B
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Classifications
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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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
- A61K31/33—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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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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
- A61K31/33—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Diaphragms For Electromechanical Transducers (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201461993423P | 2014-05-15 | 2014-05-15 | |
| US61/993,423 | 2014-05-15 |
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| TW201625596A TW201625596A (zh) | 2016-07-16 |
| TWI634115B true TWI634115B (zh) | 2018-09-01 |
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| TW104115293A TWI634115B (zh) | 2014-05-15 | 2015-05-13 | 普拉二烯內酯吡啶化合物及其使用方法 |
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| EP3344780B1 (en) | 2015-09-01 | 2021-06-23 | Eisai R&D Management Co., Ltd. | Splice variants associated with neomorphic sf3b1 mutants |
| IL259198B2 (en) * | 2015-11-18 | 2023-04-01 | Eisai R&D Man Co Ltd | A solid form of paladinolide pyridine compound and methods of its use |
| JP2020514348A (ja) * | 2017-03-15 | 2020-05-21 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | スプライセオソーム変異及びその使用 |
| CN111727059A (zh) | 2017-10-31 | 2020-09-29 | 卫材研究发展管理有限公司 | 包含至少一种剪接体调控剂和至少一种选自BCL2抑制剂、BCL2/BCLxL抑制剂和BCLxL抑制剂的抑制剂的组合及其使用方法 |
| CA3096400A1 (en) * | 2018-04-09 | 2019-10-17 | Eisai R&D Management Co., Ltd. | Certain pladienolide compounds and methods of use |
| CA3096424A1 (en) * | 2018-04-12 | 2019-10-17 | Eisai R&D Management Co., Ltd. | Pladienolide derivatives as spliceosome targeting agents for treating cancer |
| IL278740B2 (en) * | 2018-06-01 | 2024-01-01 | Eisai R&D Man Co Ltd | Methods for using splicing modulators |
| CN119405833A (zh) | 2018-06-01 | 2025-02-11 | 卫材R&D管理有限公司 | 剪接调节抗体-药物缀合物及其使用方法 |
| IL262658A (en) * | 2018-10-28 | 2020-04-30 | Memorial Sloan Kettering Cancer Center | Prevention of age related clonal hematopoiesis and diseases associated therewith |
| EP4161966A1 (en) * | 2020-06-05 | 2023-04-12 | Eisai R&D Management Co., Ltd. | Anti-bcma antibody-drug conjugates and methods of use |
| US20240043928A1 (en) | 2020-11-04 | 2024-02-08 | Eisai R&D Management Co., Ltd. | Biomarkers for myelodysplastic syndrome (mds) and methods of using the same |
| EP4361136A4 (en) * | 2021-06-18 | 2025-08-13 | Univ Cordoba | Compound for the treatment of glioblastoma |
| CN113876771B (zh) * | 2021-11-12 | 2022-09-23 | 中国医学科学院基础医学研究所 | 一种靶向pabpc1的小分子药物及其在慢性髓系白血病中的应用 |
| WO2023131866A1 (en) | 2022-01-05 | 2023-07-13 | Eisai R&D Management Co., Ltd. | Biomarkers for myelodysplastic syndrome (mds) and methods of using the same |
| MA71743A (fr) | 2022-11-07 | 2025-05-30 | Eisai R&D Management Co., Ltd. | Procédé de production d'un composé macrolide |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1380579A1 (en) * | 2001-02-01 | 2004-01-14 | Mercian Corporation | Novel physiologically active substances |
| EP2136209A1 (en) * | 2007-03-05 | 2009-12-23 | Eisai R&D Management Co., Ltd. | Method for examination of action of anti-cancer agent utilizing splicing defect as measure |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI334866B (en) | 2002-05-29 | 2010-12-21 | Mercian Corp | Novel physiologically active substances |
| RU2338741C2 (ru) | 2002-07-31 | 2008-11-20 | Мершан Корпорейшн | Новые физиологически активные вещества |
| US7576204B2 (en) | 2002-07-31 | 2009-08-18 | Mercian Corporation | Heterocyclic macrolide pharmaceutical agent, a method of producing the same and use of the same |
| AU2003285012A1 (en) | 2002-10-24 | 2004-05-13 | Sepracor, Inc. | Compositions comprising zopiclone derivatives and methods of making and using the same |
| RU2330069C2 (ru) | 2002-11-29 | 2008-07-27 | Мершан Корпорейшн | Способ получения макролидного соединения и штаммы streptomyces sp., mortierella sp. и micromonosporaceae |
| CN1886505A (zh) | 2003-11-27 | 2006-12-27 | 美露香株式会社 | 参与大环内酯类化合物的羟化作用的dna |
| CA2552553C (en) | 2003-11-28 | 2015-01-06 | Kanagawa Academy Of Science And Technology | Method of detecting liver cancer, diagnostic for liver cancer and remedy for cancer |
| JPWO2006003706A1 (ja) | 2004-07-02 | 2008-04-17 | 株式会社プラスワンテクノ | 組み合わせ計量技術 |
| CN1977046A (zh) | 2004-07-20 | 2007-06-06 | 卫材R&D管理有限公司 | 编码参与普拉地内酯生物合成的多肽的dna |
| TW200716744A (en) * | 2005-05-26 | 2007-05-01 | Eisai R&D Man Co Ltd | Genetically modified microorganism and process for production of macrolide compound using the microorganism |
| CN101282967B (zh) | 2005-10-13 | 2011-01-26 | 卫材R&D管理有限公司 | 普拉二烯内酯b和普拉二烯内酯d的全合成 |
| US20080312317A1 (en) | 2007-04-12 | 2008-12-18 | Eisai R&D Management Co., Ltd. | 12 membered-ring macrolactam derivatives |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1380579A1 (en) * | 2001-02-01 | 2004-01-14 | Mercian Corporation | Novel physiologically active substances |
| EP2136209A1 (en) * | 2007-03-05 | 2009-12-23 | Eisai R&D Management Co., Ltd. | Method for examination of action of anti-cancer agent utilizing splicing defect as measure |
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