CN114269738A - 一种mor受体激动剂化合物、制备方法及其用途 - Google Patents
一种mor受体激动剂化合物、制备方法及其用途 Download PDFInfo
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- CN114269738A CN114269738A CN202180005003.2A CN202180005003A CN114269738A CN 114269738 A CN114269738 A CN 114269738A CN 202180005003 A CN202180005003 A CN 202180005003A CN 114269738 A CN114269738 A CN 114269738A
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Classifications
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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
- C07D405/14—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- C07D405/12—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 chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Rheumatology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及药物化学领域，具体涉及一类6‑氧杂螺[4.5]癸烷类衍生物作为MOR受体激动剂的用途，用于治疗如疼痛和疼痛相关的紊乱。
Description
PCT国内申请，说明书已公开。
Claims (11)
- PCT国内申请，权利要求书已公开。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2020107944917 | 2020-08-10 | ||
| CN202010794491 | 2020-08-10 | ||
| PCT/CN2021/110702 WO2022033380A1 (zh) | 2020-08-10 | 2021-08-05 | 一种mor受体激动剂化合物、制备方法及其用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114269738A true CN114269738A (zh) | 2022-04-01 |
| CN114269738B CN114269738B (zh) | 2023-09-29 |
Family
ID=80247702
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202180005003.2A Active CN114269738B (zh) | 2020-08-10 | 2021-08-05 | 一种mor受体激动剂化合物、制备方法及其用途 |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US20230096978A1 (zh) |
| EP (1) | EP4089088A4 (zh) |
| CN (1) | CN114269738B (zh) |
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| CN115819171A (zh) * | 2022-07-25 | 2023-03-21 | 成都苑东生物制药股份有限公司 | 一种mor受体激动剂合成路线中关键中间体的手性拆分方法 |
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| CN116075505A (zh) * | 2021-08-31 | 2023-05-05 | 天地恒一制药股份有限公司 | 阿片受体激动剂及其制备方法和用途 |
| CN116589451A (zh) * | 2022-02-11 | 2023-08-15 | 成都苑东生物制药股份有限公司 | 一种6-氧杂螺[4,5]癸烷类化合物的新晶型、用途及其制备方法 |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103702561A (zh) * | 2011-03-23 | 2014-04-02 | 特维娜有限公司 | 阿片样物质受体配体以及使用和制备其的方法 |
| CN106588899A (zh) * | 2015-10-15 | 2017-04-26 | 江苏恒瑞医药股份有限公司 | 吡啶基取代的6‑氧杂螺[4.5]癸烷类衍生物、其制备方法及其在医药上的应用 |
| CN108366997A (zh) * | 2015-12-14 | 2018-08-03 | 特维娜有限公司 | 治疗痛觉过敏的方法 |
| CN108601775A (zh) * | 2015-12-17 | 2018-09-28 | 特维娜有限公司 | 阿片受体配体和细胞色素p450抑制剂的组合 |
| CN109206417A (zh) * | 2017-07-04 | 2019-01-15 | 四川海思科制药有限公司 | 阿片受体激动剂及其应用 |
| CN109516982A (zh) * | 2017-09-18 | 2019-03-26 | 上海华汇拓医药科技有限公司 | μ-阿片受体激动剂及其制备方法和在医药领域的应用 |
| CN111065390A (zh) * | 2017-12-06 | 2020-04-24 | 江苏恒瑞医药股份有限公司 | Kor激动剂与mor激动剂联合在制备治疗疼痛的药物中的用途 |
| CN115677675A (zh) * | 2021-07-21 | 2023-02-03 | 成都苑东生物制药股份有限公司 | 一种6-氧杂螺[4,5]癸烷类化合物的盐、制备方法及用途 |
-
2021
- 2021-08-05 US US17/792,461 patent/US20230096978A1/en active Pending
- 2021-08-05 WO PCT/CN2021/110702 patent/WO2022033380A1/zh unknown
- 2021-08-05 EP EP21855433.5A patent/EP4089088A4/en active Pending
- 2021-08-05 CN CN202180005003.2A patent/CN114269738B/zh active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103702561A (zh) * | 2011-03-23 | 2014-04-02 | 特维娜有限公司 | 阿片样物质受体配体以及使用和制备其的方法 |
| CN106588899A (zh) * | 2015-10-15 | 2017-04-26 | 江苏恒瑞医药股份有限公司 | 吡啶基取代的6‑氧杂螺[4.5]癸烷类衍生物、其制备方法及其在医药上的应用 |
| CN108366997A (zh) * | 2015-12-14 | 2018-08-03 | 特维娜有限公司 | 治疗痛觉过敏的方法 |
| CN108601775A (zh) * | 2015-12-17 | 2018-09-28 | 特维娜有限公司 | 阿片受体配体和细胞色素p450抑制剂的组合 |
| CN109206417A (zh) * | 2017-07-04 | 2019-01-15 | 四川海思科制药有限公司 | 阿片受体激动剂及其应用 |
| CN109516982A (zh) * | 2017-09-18 | 2019-03-26 | 上海华汇拓医药科技有限公司 | μ-阿片受体激动剂及其制备方法和在医药领域的应用 |
| CN111065390A (zh) * | 2017-12-06 | 2020-04-24 | 江苏恒瑞医药股份有限公司 | Kor激动剂与mor激动剂联合在制备治疗疼痛的药物中的用途 |
| CN115677675A (zh) * | 2021-07-21 | 2023-02-03 | 成都苑东生物制药股份有限公司 | 一种6-氧杂螺[4,5]癸烷类化合物的盐、制备方法及用途 |
Non-Patent Citations (2)
| Title |
|---|
| VASUDEVAN, LAKSHMI，等: "Assessment of structure-activity relationships and biased agonism at the Mu opioid receptor of novel synthetic opioids using a novel, stable bio-assay platform", 《BIOCHEMICAL PHARMACOLOGY (AMSTERDAM, NETHERLANDS)》, pages 1 - 11 * |
| ZHAO, ZHENNAN，等: "Molecular dynamics simulations to investigate how PZM21 affects the conformational state of the μ-opioid receptor upon activation", 《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》, vol. 21, no. 13, pages 1 - 16 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115819171A (zh) * | 2022-07-25 | 2023-03-21 | 成都苑东生物制药股份有限公司 | 一种mor受体激动剂合成路线中关键中间体的手性拆分方法 |
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| Publication number | Publication date |
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| WO2022033380A1 (zh) | 2022-02-17 |
| CN114269738B (zh) | 2023-09-29 |
| EP4089088A4 (en) | 2023-09-13 |
| EP4089088A1 (en) | 2022-11-16 |
| US20230096978A1 (en) | 2023-03-30 |
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