KR102704620B1 - 프로드러그 및 이의 용도 - Google Patents
프로드러그 및 이의 용도 Download PDFInfo
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- KR102704620B1 KR102704620B1 KR1020230008488A KR20230008488A KR102704620B1 KR 102704620 B1 KR102704620 B1 KR 102704620B1 KR 1020230008488 A KR1020230008488 A KR 1020230008488A KR 20230008488 A KR20230008488 A KR 20230008488A KR 102704620 B1 KR102704620 B1 KR 102704620B1
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Classifications
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/605—Glucagons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
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- Toxicology (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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| US202263301311P | 2022-01-20 | 2022-01-20 | |
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| EP22154309 | 2022-01-31 | ||
| EP22154309.3 | 2022-01-31 |
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| KR20230112568A KR20230112568A (ko) | 2023-07-27 |
| KR102704620B1 true KR102704620B1 (ko) | 2024-09-12 |
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| KR1020230153466A Pending KR20230159805A (ko) | 2022-01-20 | 2023-11-08 | 프로드러그 및 이의 용도 |
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| JP (2) | JP7434616B2 (https=) |
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| AR (1) | AR128315A1 (https=) |
| TW (1) | TW202330584A (https=) |
| WO (1) | WO2023139187A1 (https=) |
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| TW202511291A (zh) | 2023-09-11 | 2025-03-16 | 丹麥商諾佛 儂迪克股份有限公司 | 抗ｉｌ－６結構域之抗體 |
| JP7755031B2 (ja) * | 2023-11-30 | 2025-10-15 | ノヴォ ノルディスク アー／エス | Ｇｌｐ－１、ｇｉｐ、およびアミリン受容体の三重作動薬 |
| WO2025252197A1 (zh) * | 2024-06-07 | 2025-12-11 | 江苏恒瑞医药股份有限公司 | 药物组合物 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016111971A1 (en) * | 2015-01-09 | 2016-07-14 | Eli Lilly And Company | Gip and glp-1 co-agonist compounds |
Family Cites Families (45)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04218000A (ja) * | 1990-02-13 | 1992-08-07 | Kirin Amgen Inc | 修飾ポリペプチド |
| DK2300035T3 (en) | 2008-06-17 | 2015-11-16 | Univ Indiana Res & Tech Corp | Mixed GIP-based agonists for the treatment of metabolic diseases and obesity |
| CN102325539A (zh) | 2008-12-19 | 2012-01-18 | 印第安纳大学研究及科技有限公司 | 基于酰胺的胰高血糖素超家族肽前药 |
| CN102300580A (zh) | 2008-12-19 | 2011-12-28 | 印第安纳大学研究及科技有限公司 | 二肽连接的药剂 |
| WO2010148089A1 (en) | 2009-06-16 | 2010-12-23 | Indiana University Research And Technology Corporation | Gip receptor-active glucagon compounds |
| EP2512518A1 (en) | 2009-12-16 | 2012-10-24 | Novo Nordisk A/S | Glp-1 receptor agonist compounds with a modified n-terminus |
| EP2588127A4 (en) | 2010-06-24 | 2014-06-11 | Univ Indiana Res & Tech Corp | DIPEPTIDE-NETWORKED MEDICAL ACTIVE SUBSTANCES |
| RU2580317C2 (ru) | 2010-06-24 | 2016-04-10 | Индиана Юниверсити Рисерч Энд Текнолоджи Корпорейшн | Пептидные пролекарства, принадлежащие к суперсемейству амид-содержащих глюкагонов |
| MX377589B (es) | 2010-12-16 | 2025-03-10 | Novo Nordisk As | Composiciones sólidas que comprenden agonista de glp-1 y sal del ácido n-(8-(2-hidroxibenzoil)amino)caprílico. |
| US8507428B2 (en) | 2010-12-22 | 2013-08-13 | Indiana University Research And Technology Corporation | Glucagon analogs exhibiting GIP receptor activity |
| SG191252A1 (en) | 2010-12-22 | 2013-07-31 | Marcadia Biotech Inc | Methods for treating metabolic disorders and obesity with gip and glp-1 receptor-active glucagon-based peptides |
| WO2012167744A1 (en) | 2011-06-10 | 2012-12-13 | Beijing Hanmi Pharmaceutical Co., Ltd. | Glucose dependent insulinotropic polypeptide analogs, pharmaceutical compositions and use thereof |
| RU2014117678A (ru) * | 2011-11-17 | 2015-12-27 | Индиана Юниверсити Рисерч Энд Текнолоджи Корпорейшн | Пептиды глюкагонового суперсемейства, обладающие глюкокортикоидной рецепторной активностью |
| EP3542790B1 (en) | 2012-03-22 | 2023-09-13 | Novo Nordisk A/S | Compositions comprising a delivery agent and preparation thereof |
| JP6228187B2 (ja) | 2012-05-03 | 2017-11-08 | ジーランド ファーマ アクティーゼルスカブ | Ｇｉｐ−ｇｌｐ−１デュアルアゴニスト化合物及び方法 |
| JP6517690B2 (ja) | 2012-06-20 | 2019-05-22 | ノヴォ ノルディスク アー／エス | ペプチド及び送達剤を含む錠剤製剤 |
| HRP20180936T1 (hr) | 2012-06-21 | 2018-12-14 | Indiana University Research And Technology Corporation | Analozi glukagona koji pokazuju aktivnost prema receptoru za gip |
| HK1211232A1 (en) | 2012-12-21 | 2016-05-20 | Sanofi | Exendin-4 derivatives as dual glp1/gip or trigonal glp1/gip/glucagon agonists |
| CN105324125A (zh) | 2013-03-15 | 2016-02-10 | 印第安纳大学研究及科技有限公司 | 具有长效的前体药物 |
| JP6672140B2 (ja) | 2013-05-02 | 2020-03-25 | ノヴォ ノルディスク アー／エス | Ｇｌｐ−１化合物の経口投薬 |
| LT3004155T (lt) | 2013-05-28 | 2021-12-27 | Takeda Pharmaceutical Company Limited | Peptidų junginys |
| HK1226084A1 (zh) | 2013-08-16 | 2017-09-22 | Medimmune Limited | 用於治疗糖尿病的gip和glp-1受体双重激动剂 |
| WO2015035419A1 (en) | 2013-09-09 | 2015-03-12 | Hoffmann-La Roche Inc. | Dosages of gip/glp-1 co-agonist peptides for human administration |
| MX2016005556A (es) | 2013-11-06 | 2016-07-15 | Zealand Pharma As | Compuestos agonistas duales de gip-glp-1 y procedimientos. |
| WO2015086728A1 (en) | 2013-12-13 | 2015-06-18 | Sanofi | Exendin-4 peptide analogues as dual glp-1/gip receptor agonists |
| TW201609799A (zh) | 2013-12-13 | 2016-03-16 | 賽諾菲公司 | 雙重ｇｌｐ－１／ｇｉｐ受體促效劑 |
| TW201625670A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 衍生自ｅｘｅｎｄｉｎ－４之雙重ｇｌｐ－１／升糖素受體促效劑 |
| GB2528436A (en) | 2014-07-15 | 2016-01-27 | Lancaster Univ Business Entpr Ltd | Treatment of neurological diseases |
| WO2016049174A1 (en) | 2014-09-24 | 2016-03-31 | Indiana University Research And Technology Corporation | Lipidated amide-based insulin prodrugs |
| WO2016077220A1 (en) | 2014-11-10 | 2016-05-19 | Mb2 Llc | Gip/glp-1 co-agonist peptides for human administration |
| JP2018012644A (ja) | 2014-11-26 | 2018-01-25 | 武田薬品工業株式会社 | ペプチド化合物 |
| WO2016131893A1 (en) | 2015-02-18 | 2016-08-25 | Medimmune Limited | Incretin fusion polypeptides |
| US20170112897A1 (en) | 2015-10-23 | 2017-04-27 | Cedars-Sinai Medical Center | Methods for treating brain insulin resistance |
| WO2017204219A1 (ja) | 2016-05-24 | 2017-11-30 | 武田薬品工業株式会社 | ペプチド化合物 |
| GB201620611D0 (en) | 2016-12-05 | 2017-01-18 | Univ Of Lancaster | Treatment of neurological diseases |
| JOP20190211A1 (ar) | 2017-03-31 | 2019-09-15 | Takeda Pharmaceuticals Co | ببتيد منشط لمستقبل gip |
| PL3746111T3 (pl) | 2018-02-02 | 2024-01-15 | Novo Nordisk A/S | Stałe kompozycje zawierające agonistę glp-1 i sól kwasu n-(8-(2- hydroksybenzoilo)amino kaprylowego i substancję poślizgową |
| KR102379958B1 (ko) | 2018-05-04 | 2022-04-01 | 노보 노르디스크 에이/에스 | Gip 유도체 및 이의 용도 |
| CN120754229A (zh) | 2018-07-23 | 2025-10-10 | 伊莱利利公司 | 使用gip/glp1共激动剂用于治疗的方法 |
| CN112469731B (zh) | 2018-07-23 | 2024-11-29 | 伊莱利利公司 | Gip/glp1共激动剂化合物 |
| EP3826662B9 (en) | 2018-07-23 | 2025-02-19 | Eli Lilly and Company | Method of using a gip/glp1 co-agonist for diabetes |
| MX2021012277A (es) * | 2019-04-11 | 2021-11-12 | Jiangsu Hansoh Pharmaceutical Group Co Ltd | Agonista multireceptor y uso medico del mismo. |
| CN110642935A (zh) | 2019-09-25 | 2020-01-03 | 成都奥达生物科技有限公司 | 一种替瑞帕肽类似物 |
| CN110684082B (zh) | 2019-10-08 | 2021-12-10 | 江苏诺泰澳赛诺生物制药股份有限公司 | Gip和glp-1双激动多肽化合物及药学上可接受的盐与用途 |
| MX2023000303A (es) * | 2020-07-22 | 2023-02-09 | Novo Nordisk As | Coagonistas de los receptores del peptido 1 similar al glucagon (glp-1) y del polipeptido insulinotropico dependiente de glucosa (gip) adecuados para el suministro oral. |
-
2023
- 2023-01-19 TW TW112102648A patent/TW202330584A/zh unknown
- 2023-01-20 AR ARP230100137A patent/AR128315A1/es unknown
- 2023-01-20 WO PCT/EP2023/051315 patent/WO2023139187A1/en not_active Ceased
- 2023-01-20 KR KR1020230008488A patent/KR102704620B1/ko active Active
- 2023-01-20 US US18/099,282 patent/US11840560B2/en active Active
- 2023-01-20 EP EP23701440.2A patent/EP4466069A1/en active Pending
- 2023-01-20 JP JP2023007479A patent/JP7434616B2/ja active Active
- 2023-10-27 US US18/384,511 patent/US20240083965A1/en active Pending
- 2023-11-08 KR KR1020230153466A patent/KR20230159805A/ko active Pending
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016111971A1 (en) * | 2015-01-09 | 2016-07-14 | Eli Lilly And Company | Gip and glp-1 co-agonist compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| US11840560B2 (en) | 2023-12-12 |
| WO2023139187A1 (en) | 2023-07-27 |
| EP4466069A1 (en) | 2024-11-27 |
| TW202330584A (zh) | 2023-08-01 |
| KR20230159805A (ko) | 2023-11-22 |
| US20230227521A1 (en) | 2023-07-20 |
| AR128315A1 (es) | 2024-04-17 |
| JP7434616B2 (ja) | 2024-02-20 |
| JP2024015148A (ja) | 2024-02-01 |
| US20240083965A1 (en) | 2024-03-14 |
| KR20230112568A (ko) | 2023-07-27 |
| JP2023106355A (ja) | 2023-08-01 |
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