JP6231386B2 - リンカーを有する二重アシル化されたｇｌｐ−１誘導体 - Google Patents
リンカーを有する二重アシル化されたｇｌｐ−１誘導体 Download PDFInfo
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
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Classifications
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
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- A—HUMAN NECESSITIES
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- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
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- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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-
- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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- 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
-
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- 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)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
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- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Reproductive Health (AREA)
- Emergency Medicine (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Nutrition Science (AREA)
- Cardiology (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Child & Adolescent Psychology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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| EP10190515 | 2010-11-09 | ||
| US41422110P | 2010-11-16 | 2010-11-16 | |
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| US201161497123P | 2011-06-15 | 2011-06-15 | |
| US61/497,123 | 2011-06-15 | ||
| PCT/EP2011/069743 WO2012062804A1 (en) | 2010-11-09 | 2011-11-09 | Double-acylated glp-1 derivatives with a linker |
Related Child Applications (1)
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| JP2016151098A Division JP2016188246A (ja) | 2010-11-09 | 2016-08-01 | リンカーを有する二重アシル化されたｇｌｐ−１誘導体 |
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| JP2014501712A JP2014501712A (ja) | 2014-01-23 |
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| JP2016151098A Withdrawn JP2016188246A (ja) | 2010-11-09 | 2016-08-01 | リンカーを有する二重アシル化されたｇｌｐ−１誘導体 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022244757A1 (ja) | 2021-05-18 | 2022-11-24 | 株式会社Ｌｔｔバイオファーマ | 抗癌剤の投与に伴う障害を治療又は予防するための医薬組成物 |
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| US5750341A (en) | 1995-04-17 | 1998-05-12 | Lynx Therapeutics, Inc. | DNA sequencing by parallel oligonucleotide extensions |
| JP6054742B2 (ja) | 2009-07-13 | 2016-12-27 | ジーランド ファーマ アクティーゼルスカブ | アシル化グルカゴン類似体 |
| JP6231386B2 (ja) * | 2010-11-09 | 2017-11-15 | ノヴォ ノルディスク アー／エス | リンカーを有する二重アシル化されたｇｌｐ−１誘導体 |
| JP6126097B2 (ja) | 2011-09-06 | 2017-05-10 | ノヴォ ノルディスク アー／エス | Ｇｌｐ−１誘導体 |
| CA2872314C (en) | 2012-05-03 | 2021-08-31 | Zealand Pharma A/S | Gip-glp-1 dual agonist compounds and methods |
| CN104411322B (zh) * | 2012-05-08 | 2017-05-24 | 诺和诺德股份有限公司 | 双酰化glp‑1衍生物 |
| EP2846823B1 (en) * | 2012-05-08 | 2019-12-04 | Novo Nordisk A/S | Double-acylated glp-1 derivatives |
| NZ704043A (en) | 2012-07-23 | 2017-07-28 | Zealand Pharma As | Glucagon analogues |
| TWI608013B (zh) | 2012-09-17 | 2017-12-11 | 西蘭製藥公司 | 升糖素類似物 |
| WO2014199397A2 (en) * | 2013-06-11 | 2014-12-18 | Mylan Laboratories Ltd | Process for the preparation of liraglutide |
| AU2014283221A1 (en) | 2013-06-20 | 2015-12-03 | Novo Nordisk A/S | GLP-1 derivatives and uses thereof |
| JP6139712B2 (ja) | 2013-07-04 | 2017-05-31 | ノヴォ ノルディスク アー／エス | Ｇｌｐ−１様ペプチドの誘導体及びその使用 |
| CN105451776B (zh) * | 2013-08-15 | 2020-04-17 | 诺和诺德股份有限公司 | Glp-1衍生物及其用途 |
| AR098065A1 (es) | 2013-10-17 | 2016-04-27 | Zealand Pharma As | Análogos de glucagón acilados |
| US9988429B2 (en) | 2013-10-17 | 2018-06-05 | Zealand Pharma A/S | Glucagon analogues |
| AU2014345570B2 (en) | 2013-11-06 | 2019-01-24 | Zealand Pharma A/S | Glucagon-GLP-1-GIP triple agonist compounds |
| CA2929459C (en) | 2013-11-06 | 2022-05-03 | Zealand Pharma A/S | Gip-glp-1 dual agonist compounds and methods |
| US10221315B2 (en) * | 2013-11-08 | 2019-03-05 | Ppg Industries Ohio, Inc. | Curable film-forming composition comprising catalyst associated with a carrier |
| WO2015155151A1 (en) * | 2014-04-07 | 2015-10-15 | Novo Nordisk A/S | Double-acylated glp-1 compounds |
| EP3212218B1 (en) | 2014-10-29 | 2021-06-30 | Zealand Pharma A/S | Gip agonist compounds and methods |
| JP6730278B2 (ja) * | 2014-11-27 | 2020-07-29 | ノヴォ ノルディスク アー／エス | Ｇｌｐ−１誘導体及びその使用 |
| EP3233898A1 (en) | 2014-12-17 | 2017-10-25 | Novo Nordisk A/S | Glp-1 derivatives and uses thereof |
| PL3283507T3 (pl) | 2015-04-16 | 2020-05-18 | Zealand Pharma A/S | Acylowany analog glukagonu |
| US10118904B2 (en) | 2015-06-05 | 2018-11-06 | Vertex Pharmaceuticals Incorporated | Triazoles for the treatment of Demyelinating Diseases |
| WO2018106646A1 (en) | 2016-12-06 | 2018-06-14 | Vertex Pharmaceuticals Incorporated | Aminotriazoles for the treatment of demyelinating diseases |
| WO2018106643A1 (en) | 2016-12-06 | 2018-06-14 | Vertex Pharmaceuticals Incorporated | Heterocyclic azoles for the treatment of demyelinating diseases |
| WO2018106641A1 (en) | 2016-12-06 | 2018-06-14 | Vertex Pharmaceuticals Incorporated | Pyrazoles for the treatment of demyelinating diseases |
| WO2019023295A1 (en) * | 2017-07-27 | 2019-01-31 | Saint Louis University | Fatty acid modified human epidermal growth factor |
| BR112020002804A2 (pt) | 2017-08-24 | 2020-07-28 | Novo Nordisk A/S | composição farmacêutica líquida, e, kit |
| SMT202200352T1 (it) | 2018-04-05 | 2022-09-14 | Sun Pharmaceutical Ind Ltd | Analoghi del glp-1 innovativi |
| CN113214382B (zh) * | 2018-04-19 | 2024-01-19 | 杭州先为达生物科技股份有限公司 | 酰化的glp-1衍生物 |
| WO2019200594A1 (zh) | 2018-04-19 | 2019-10-24 | 杭州先为达生物科技有限公司 | 酰化的glp-1衍生物 |
| TWI829687B (zh) | 2018-05-07 | 2024-01-21 | 丹麥商諾佛 儂迪克股份有限公司 | 包含glp-1促效劑與n-(8-(2-羥基苯甲醯基)胺基)辛酸之鹽的固體組成物 |
| GB201813678D0 (en) * | 2018-08-22 | 2018-10-03 | Keybioscience Ag | Acylated calcitonin mimetics |
| WO2021136223A1 (en) | 2019-12-31 | 2021-07-08 | Beijing Ql Biopharmaceutical Co., Ltd. | Fusion proteins of glp-1 and gdf15 and conjugates thereof |
| IL294521A (en) | 2020-02-18 | 2022-09-01 | Novo Nordisk As | glp-1 compounds and their uses |
| CA3193453A1 (en) | 2020-09-30 | 2022-04-07 | Beijing Ql Biopharmaceutical Co., Ltd. | Polypeptide conjugates and methods of uses |
| CN116490212A (zh) * | 2020-11-06 | 2023-07-25 | 诺和诺德股份有限公司 | Glp-1前药及其用途 |
| JP7484018B2 (ja) | 2020-11-06 | 2024-05-15 | ノヴォ ノルディスク アー／エス | Ｇｌｐ－１プロドラッグおよびその使用 |
| WO2022266927A1 (zh) * | 2021-06-24 | 2022-12-29 | 深圳翰宇药业股份有限公司 | 一种利拉鲁肽变构体及其制备方法、应用 |
| EP4323413A4 (en) | 2022-03-30 | 2025-10-15 | Beijing Ql Biopharmaceutical Co Ltd | LIQUID PHARMACEUTICAL COMPOSITIONS OF POLYPEPTIDE CONJUGATES AND METHODS OF USE THEREOF |
| US20250304645A1 (en) | 2022-05-10 | 2025-10-02 | Novo Nordisk A/S | Prodrugs of GLP-1 Polypeptide and Uses Thereof |
| CN121001710A (zh) | 2022-12-30 | 2025-11-21 | 阿尔吉法玛公司 | 提高口服多肽治疗剂的全身生物利用度的组合物和方法 |
| WO2025098422A1 (zh) * | 2023-11-07 | 2025-05-15 | 深圳信立泰药业股份有限公司 | 多重受体共激动剂化合物及其制备方法与应用 |
| GB202418179D0 (en) | 2024-12-11 | 2025-01-22 | Algipharma As | Compositions and methods |
| GB202418172D0 (en) | 2024-12-11 | 2025-01-22 | Algipharma As | Compositions and methods |
Family Cites Families (17)
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| US5336782A (en) | 1991-04-24 | 1994-08-09 | Kuraray Co., Ltd. | Long chain carboxylic acid imide ester |
| SE9102652D0 (sv) * | 1991-09-13 | 1991-09-13 | Kabi Pharmacia Ab | Injection needle arrangement |
| US5512549A (en) * | 1994-10-18 | 1996-04-30 | Eli Lilly And Company | Glucagon-like insulinotropic peptide analogs, compositions, and methods of use |
| DE122009000079I2 (de) | 1996-08-30 | 2011-06-16 | Novo Nordisk As Novo Alle | Glp-1 derivate |
| EP1060191B1 (en) | 1998-02-27 | 2010-04-28 | Novo Nordisk A/S | Derivatives of glp-1 analogs |
| MY155270A (en) * | 1998-09-24 | 2015-09-30 | Lilly Co Eli | Use of glp-1 or analogs in treatment of stroke |
| EP1670515A2 (en) | 2003-09-19 | 2006-06-21 | Novo Nordisk A/S | Albumin-binding derivatives of therapeutic peptides |
| WO2006082204A1 (en) | 2005-02-02 | 2006-08-10 | Novo Nordisk A/S | Insulin derivatives |
| TWI362392B (en) | 2005-03-18 | 2012-04-21 | Novo Nordisk As | Acylated glp-1 compounds |
| EP2514406A1 (en) | 2007-06-01 | 2012-10-24 | Novo Nordisk A/S | Spontaneously dispersible preconcentrates including a peptide drug in a solid or semisolid carrier |
| EP2190872B1 (en) | 2007-09-05 | 2018-03-14 | Novo Nordisk A/S | Glucagon-like peptide-1 derivatives and their pharmaceutical use |
| US20100261637A1 (en) * | 2007-09-05 | 2010-10-14 | Novo Nordisk A/S | Peptides derivatized with a-b-c-d- and their therapeutical use |
| US8598314B2 (en) * | 2007-09-27 | 2013-12-03 | Amylin Pharmaceuticals, Llc | Peptide-peptidase-inhibitor conjugates and methods of making and using same |
| US20100317057A1 (en) * | 2007-12-28 | 2010-12-16 | Novo Nordisk A/S | Semi-recombinant preparation of glp-1 analogues |
| CN102149411A (zh) | 2008-09-12 | 2011-08-10 | 诺沃—诺迪斯克有限公司 | 酰化肽或蛋白的方法 |
| US20120329711A1 (en) | 2009-12-16 | 2012-12-27 | Nordisk A/S | Glp-1 receptor agonist compounds with a modified n-terminus |
| JP6231386B2 (ja) * | 2010-11-09 | 2017-11-15 | ノヴォ ノルディスク アー／エス | リンカーを有する二重アシル化されたｇｌｐ−１誘導体 |
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2011
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- 2011-11-09 WO PCT/EP2011/069738 patent/WO2012062803A1/en not_active Ceased
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022244757A1 (ja) | 2021-05-18 | 2022-11-24 | 株式会社Ｌｔｔバイオファーマ | 抗癌剤の投与に伴う障害を治療又は予防するための医薬組成物 |
| KR20240008844A (ko) | 2021-05-18 | 2024-01-19 | 가부시키가이샤 엘티티 바이오파마 | 항암제의 투여에 수반되는 장애를 치료 또는 예방하기 위한 의약 조성물 |
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| EP2637699B1 (en) | 2018-05-16 |
| US9006178B2 (en) | 2015-04-14 |
| JP2014501712A (ja) | 2014-01-23 |
| CN103209711B (zh) | 2016-04-13 |
| US20130288960A1 (en) | 2013-10-31 |
| CN105601729A (zh) | 2016-05-25 |
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| US20150210745A1 (en) | 2015-07-30 |
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| JP2016188246A (ja) | 2016-11-04 |
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| EP2637698A1 (en) | 2013-09-18 |
| US9708383B2 (en) | 2017-07-18 |
| WO2012062803A1 (en) | 2012-05-18 |
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| ES2683372T3 (es) | 2018-09-26 |
| EP2637699A1 (en) | 2013-09-18 |
| WO2012062804A1 (en) | 2012-05-18 |
| EP2637698B1 (en) | 2022-04-20 |
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