KR101854249B1 - Cgrp 수용체 길항제 - Google Patents
Cgrp 수용체 길항제 Download PDFInfo
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- KR101854249B1 KR101854249B1 KR1020177015456A KR20177015456A KR101854249B1 KR 101854249 B1 KR101854249 B1 KR 101854249B1 KR 1020177015456 A KR1020177015456 A KR 1020177015456A KR 20177015456 A KR20177015456 A KR 20177015456A KR 101854249 B1 KR101854249 B1 KR 101854249B1
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- cgrp
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Classifications
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
Landscapes
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- Heart & Thoracic Surgery (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (3)
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| GB201519196D0 (en) * | 2015-10-30 | 2015-12-16 | Heptares Therapeutics Ltd | CGRP Receptor Antagonists |
| GB201519194D0 (en) | 2015-10-30 | 2015-12-16 | Heptares Therapeutics Ltd | CGRP receptor antagonists |
| GB201519195D0 (en) | 2015-10-30 | 2015-12-16 | Heptares Therapeutics Ltd | CGRP Receptor Antagonists |
| GB201707938D0 (en) | 2017-05-17 | 2017-06-28 | Univ Sheffield | Compounds |
| US12030868B2 (en) * | 2018-10-13 | 2024-07-09 | Pfizer Ireland Pharmaceuticals | Prodrugs of CGRP antagonists |
| MX2021008191A (es) * | 2019-01-20 | 2021-08-11 | Biohaven Pharm Holding Co Ltd | Antagonistas del péptido relacionado con el gen de calcitonina (cgrp) para el tratamiento de la irrupción de migraña. |
| EA202192793A1 (ru) | 2019-04-11 | 2022-01-12 | Ар.Пи. ШЕРЕР ТЕКНОЛОДЖИЗ, ЭлЭлСи | Композиция для пероральной доставки белков, пептидов и малых молекул со слабой проницаемостью |
| CN114980862A (zh) * | 2019-12-17 | 2022-08-30 | 拜尔哈文制药股份有限公司 | Cgrp抑制剂的鼻内药物组合物 |
| CA3202137A1 (en) * | 2020-11-19 | 2022-05-27 | Pfizer Ireland Pharmaceuticals | Compositions for improved delivery of cgrp inhibitors |
| CN116456981A (zh) * | 2020-11-19 | 2023-07-18 | 辉瑞爱尔兰制药公司 | 用于改善的grp抑制剂递送的组合物 |
| WO2022185224A1 (en) | 2021-03-02 | 2022-09-09 | Mark Hasleton | Treatment and/or reduction of occurrence of migraine |
| EP4320113A1 (en) | 2021-04-09 | 2024-02-14 | Teva Czech Industries s.r.o. | Solid state forms of zavegepant and process for preparation thereof |
| US20250109188A1 (en) | 2021-08-24 | 2025-04-03 | Cgrp Diagnostics Gmbh | Preventative treatment of migraine |
| CN117624191A (zh) * | 2022-08-30 | 2024-03-01 | 熙源安健医药（上海）有限公司 | 吲唑甲酰胺类衍生物及其制备方法和用途 |
| IL320431A (en) | 2022-11-09 | 2025-06-01 | Teva Czech Ind S R O | Crystalline forms of zibagen hydrochloride and process for their preparation |
| CN116003387B (zh) * | 2022-11-20 | 2024-03-26 | 药康众拓(北京)医药科技有限公司 | 一种氘代吲唑丙酰胺类化合物、药物组合物和用途 |
| WO2025003905A1 (en) | 2023-06-29 | 2025-01-02 | Pfizer Inc. | Solid forms of (r)-n-(3-(7-methyl-1h-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide |
| CN119462607B (zh) * | 2023-08-10 | 2025-11-28 | 南京宁丹新药技术股份有限公司 | 一类喹啉酮衍生物及其用途 |
| CN117551081A (zh) * | 2023-11-13 | 2024-02-13 | 北京康立生医药技术开发有限公司 | 一种偏头痛治疗药物新的制备方法 |
| ES3027457A1 (es) * | 2023-12-13 | 2025-06-13 | Moehs Iberica Sl | Metodo de preparacion de zavegepant, intermedios de sintesis de zavegepant y metodos de preparacion de los mismos |
| WO2025238595A1 (en) | 2024-05-16 | 2025-11-20 | Olon S.P.A. | Process for preparing (r)-2-amino-3-(7-methyl-1h-indazol-5-yl) methyl propanoate, and use thereof as intermediate for the synthesis of zavegepant |
| CN119306698B (zh) * | 2024-10-09 | 2025-10-21 | 浙江工业大学 | 一种制备扎维吉泮中间体的新方法 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003104236A1 (en) | 2002-06-01 | 2003-12-18 | Bristol-Myers Squibb Company | Calcitonin gene related peptide receptor antagonists |
| WO2005084672A1 (de) | 2004-03-03 | 2005-09-15 | Boehringer Ingelheim International Gmbh | Ausgewählte cgrp-antagonisten, verfahren zu deren herstellung sowie deren verwendung als arzneimittel |
| US20070049577A1 (en) | 2005-08-25 | 2007-03-01 | Bristol-Myers Squibb Company | CGRP antagonists |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7220862B2 (en) | 2002-06-05 | 2007-05-22 | Bristol-Myers Squibb Company | Calcitonin gene related peptide receptor antagonists |
| CN101495480B (zh) * | 2006-05-03 | 2013-07-10 | 百时美施贵宝公司 | 作为降钙素基因相关肽受体拮抗剂的受限化合物 |
| WO2010006168A2 (en) | 2008-07-09 | 2010-01-14 | University Of Rochester | Methods of treating cancer using and agent that modulates activity of the calcitonin-gene related peptide ("cgrp") receptor |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003104236A1 (en) | 2002-06-01 | 2003-12-18 | Bristol-Myers Squibb Company | Calcitonin gene related peptide receptor antagonists |
| WO2005084672A1 (de) | 2004-03-03 | 2005-09-15 | Boehringer Ingelheim International Gmbh | Ausgewählte cgrp-antagonisten, verfahren zu deren herstellung sowie deren verwendung als arzneimittel |
| US20070049577A1 (en) | 2005-08-25 | 2007-03-01 | Bristol-Myers Squibb Company | CGRP antagonists |
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