TWI714661B - 新穎念珠藻素化合物及接合物、其製備與其治療用途 - Google Patents
新穎念珠藻素化合物及接合物、其製備與其治療用途 Download PDFInfo
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- TWI714661B TWI714661B TW105135522A TW105135522A TWI714661B TW I714661 B TWI714661 B TW I714661B TW 105135522 A TW105135522 A TW 105135522A TW 105135522 A TW105135522 A TW 105135522A TW I714661 B TWI714661 B TW I714661B
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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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
-
- 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
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
- Plural Heterocyclic Compounds (AREA)
- Bedding Items (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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| TWI714661B (zh) | 2015-11-05 | 2021-01-01 | 法商賽諾菲公司 | 新穎念珠藻素化合物及接合物、其製備與其治療用途 |
| CN107043380A (zh) | 2016-02-05 | 2017-08-15 | 正大天晴药业集团股份有限公司 | 一种tlr7激动剂的马来酸盐、其晶型c、晶型d、晶型e、制备方法和用途 |
| WO2018206635A1 (en) * | 2017-05-10 | 2018-11-15 | Sanofi | Peptidic linkers and cryptophycin conjugates, useful in therapy, and their preparation |
| CN108107103B (zh) * | 2017-12-14 | 2020-10-16 | 华中师范大学 | 谷氨酸受体的质谱探针及其在脑组织中的空间分布规律检测方法 |
| AU2020231396B2 (en) | 2019-03-07 | 2025-03-20 | Nobo Medicine Inc. | Caspase inhibitors and methods of use thereof |
| US11530204B2 (en) | 2019-09-30 | 2022-12-20 | The Regents Of The University Of Michigan | Biocatalytic synthesis of cryptophycin anticancer agents |
| EP4046996A1 (en) | 2021-02-19 | 2022-08-24 | Universität Bielefeld | Cryptophycin compounds and conjugates thereof |
| KR20240150807A (ko) | 2022-02-22 | 2024-10-16 | 아라리스 바이오테크 아게 | 2개 이상의 페이로드를 포함하는 펩티드 링커 |
| EP4495105A1 (en) | 2023-07-17 | 2025-01-22 | Basf Se | 3-(4-hydroxybut-2-ynoxy)propanoic acid ester, amide and nitrile derivatives as corrosion protection agents |
| EP4495108A1 (en) | 2023-07-17 | 2025-01-22 | Basf Se | 3-[2-(2-oxo-1,3-dioxolan-4-ylidene)ethoxy]propanoic acid derivatives as precursors of monomers in polymerisations |
| WO2025082990A1 (en) | 2023-10-15 | 2025-04-24 | Araris Biotech Ag | Antibody-drug conjugates using two different types of topoisomerase i inhibitors |
| WO2026013234A1 (en) | 2024-07-10 | 2026-01-15 | Araris Biotech Ag | Triple-payload antibody-drug conjugates (adcs) |
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| WO2011001052A1 (fr) * | 2009-06-29 | 2011-01-06 | Sanofi-Aventis | Nouveaux conjugues, leur preparation et leur application en therapeutique |
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| US20020128185A1 (en) * | 1998-02-25 | 2002-09-12 | Chuan Shih | Pharmaceutical compounds |
| US7230101B1 (en) | 2002-08-28 | 2007-06-12 | Gpc Biotech, Inc. | Synthesis of methotrexate-containing heterodimeric molecules |
| US20050175619A1 (en) | 2004-02-05 | 2005-08-11 | Robert Duffy | Methods of producing antibody conjugates |
| US8212083B2 (en) | 2006-04-27 | 2012-07-03 | Intezyne Technologies, Inc. | Heterobifunctional poly(ethylene glycol) containing acid-labile amino protecting groups and uses thereof |
| ZA200900545B (en) | 2006-07-18 | 2010-03-31 | Sanofi Aventis | Antagonist antibody against EPHA2 for the treatment of cancer |
| UY32914A (es) | 2009-10-02 | 2011-04-29 | Sanofi Aventis | Anticuerpos que se usan específicamente al receptor epha2 |
| TWI714661B (zh) | 2015-11-05 | 2021-01-01 | 法商賽諾菲公司 | 新穎念珠藻素化合物及接合物、其製備與其治療用途 |
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Non-Patent Citations (1)
| Title |
|---|
| Naoyuki Kotoku et al., "Synthesis of 15,20-triamide analogue with polar substituent on the phenyl ring of arenastatin A, an extremely potent cytotoxic spongean depsipeptide", Bioorganic & Medicinal Chemistry, Volume 14, Issue 22, 15 November 2006, Pages 7446-7457. * |
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