CN102656159B - Cgrp受体拮抗剂 - Google Patents
Cgrp受体拮抗剂 Download PDFInfo
- Publication number
- CN102656159B CN102656159B CN201080056672.4A CN201080056672A CN102656159B CN 102656159 B CN102656159 B CN 102656159B CN 201080056672 A CN201080056672 A CN 201080056672A CN 102656159 B CN102656159 B CN 102656159B
- Authority
- CN
- China
- Prior art keywords
- hydrogen
- pyridin
- difluorophenyl
- tetrahydro
- cyclohepta
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 0 C*C(*)(C(*C(*)=O)c1ncccc1*1C)C(*)(*)C1=* Chemical compound C*C(*)(C(*C(*)=O)c1ncccc1*1C)C(*)(*)C1=* 0.000 description 3
- ZCXXDEJQLTXXJL-UHFFFAOYSA-N C(CCC1)CCc2c1nccc2 Chemical compound C(CCC1)CCc2c1nccc2 ZCXXDEJQLTXXJL-UHFFFAOYSA-N 0.000 description 1
- HBGPBDDEMSQOLC-QCSRNSKWSA-N CC1(C)[O]=C(NC(C2)C22c3cccnc3C3(CC3)CC[C@H]2c(cccc2F)c2F)O1 Chemical compound CC1(C)[O]=C(NC(C2)C22c3cccnc3C3(CC3)CC[C@H]2c(cccc2F)c2F)O1 HBGPBDDEMSQOLC-QCSRNSKWSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- 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]
-
- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/20—Spiro-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Rheumatology (AREA)
- Heart & Thoracic Surgery (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US25147709P | 2009-10-14 | 2009-10-14 | |
| US61/251,477 | 2009-10-14 | ||
| PCT/US2010/052433 WO2011046997A1 (en) | 2009-10-14 | 2010-10-13 | Cgrp receptor antagonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102656159A CN102656159A (zh) | 2012-09-05 |
| CN102656159B true CN102656159B (zh) | 2015-07-01 |
Family
ID=43242489
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201080056672.4A Active CN102656159B (zh) | 2009-10-14 | 2010-10-13 | Cgrp受体拮抗剂 |
Country Status (35)
Families Citing this family (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8314117B2 (en) * | 2009-10-14 | 2012-11-20 | Bristol-Myers Squibb Company | CGRP receptor antagonists |
| US8669368B2 (en) * | 2010-10-12 | 2014-03-11 | Bristol-Myers Squibb Company | Process for the preparation of cycloheptapyridine CGRP receptor antagonists |
| US8748429B2 (en) * | 2011-04-12 | 2014-06-10 | Bristol-Myers Squibb Company | CGRP receptor antagonists |
| ES2746031T3 (es) | 2012-02-27 | 2020-03-04 | Bristol Myers Squibb Co | Sal de N-(5S,6S,9R)-5-amino-6-(2,3-difluorofenil)-6,7,8,9-tetrahidro-5H-ciclohepta[B]piridin-9-IL-4-(2-oxo-2,3-dihidro-1H-imidazo[4,5-B]piridin-1-il)piperidina-1-carboxilato |
| US9227973B2 (en) * | 2012-05-09 | 2016-01-05 | Merck Sharp & Dohme Corp. | Pyridine CGRP receptor antagonists |
| EP2815749A1 (en) | 2013-06-20 | 2014-12-24 | IP Gesellschaft für Management mbH | Solid form of 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione having specified X-ray diffraction pattern |
| TW201718574A (zh) * | 2015-08-12 | 2017-06-01 | 美國禮來大藥廠 | Ｃｇｒｐ受體拮抗劑 |
| GB201519195D0 (en) | 2015-10-30 | 2015-12-16 | Heptares Therapeutics Ltd | CGRP Receptor Antagonists |
| 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 |
| GB201707938D0 (en) | 2017-05-17 | 2017-06-28 | Univ Sheffield | Compounds |
| SI4088720T1 (sl) | 2018-03-25 | 2026-01-30 | Pfizer Ireland Pharmaceuticals Unlimited Company | Rimegepant za motnje, povezane s cgrp |
| CN114805206B (zh) * | 2021-01-27 | 2025-01-14 | 奥锐特药业(天津)有限公司 | 高光学纯度瑞美吉泮中间体的工业化制备方法 |
| CA3212151A1 (en) | 2021-03-02 | 2022-09-09 | Cgrp Diagnostics Gmbh | Treatment and/or reduction of occurrence of migraine |
| US20250109188A1 (en) | 2021-08-24 | 2025-04-03 | Cgrp Diagnostics Gmbh | Preventative treatment of migraine |
| CN115850266A (zh) * | 2021-09-26 | 2023-03-28 | 奥锐特药业(天津)有限公司 | 瑞美吉泮新晶型及其制备方法 |
| CN116554164B (zh) * | 2022-01-27 | 2025-10-03 | 奥锐特药业(天津)有限公司 | 一种瑞美吉泮的制备方法 |
| WO2023175632A1 (en) * | 2022-03-17 | 2023-09-21 | Msn Laboratories Private Limited, R&D Center | Solid state forms of (5s,6s,9r)-5-amino-6-(2,3difluorophenyl)-6,7,8,9-tetrahydro-5h-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1h-imidazo[4,5-b]pyridin-1-yl)-1-piperidinecarboxylate hemisulfate and processes for preparation thereof |
| CN116478211B (zh) * | 2022-04-19 | 2023-10-24 | 石家庄迪斯凯威医药科技有限公司 | 一种新型cgrp受体拮抗剂及其用途 |
| CN115060824B (zh) * | 2022-06-14 | 2024-03-12 | 浙江宏元药业股份有限公司 | 一种瑞米吉泮中间体对映异构体杂质的液相色谱检测方法 |
| CN117466893A (zh) * | 2022-07-29 | 2024-01-30 | 熙源安健医药（上海）有限公司 | 吡啶并环庚烷类衍生物及其制备方法和用途 |
| CN115677694A (zh) * | 2022-11-30 | 2023-02-03 | 南通常佑药业科技有限公司 | 一种瑞美吉泮的合成方法 |
| WO2024180562A1 (en) * | 2023-03-02 | 2024-09-06 | Natco Pharma Limited | A process for the preparation of pure crystalline rimegepant and its salts thereof |
| CN116768938B (zh) * | 2023-05-17 | 2025-11-11 | 南京艾德凯腾生物医药有限责任公司 | 一种铁催化剂及瑞美吉泮中间体的制备方法 |
| WO2025061177A1 (zh) * | 2023-09-21 | 2025-03-27 | 成都康弘药业集团股份有限公司 | 一种治疗cgrp相关障碍的小分子药物 |
| CN117486798B (zh) * | 2023-12-21 | 2025-02-07 | 南京威凯尔生物医药科技有限公司 | 一种瑞美吉泮中间体盐酸盐的晶型及其制备方法 |
| WO2025193980A2 (en) * | 2024-03-13 | 2025-09-18 | CNS Biosciences, Inc. | Method of treating neuropathic pain using an anti-cgrp inhibitor |
| CN119707808B (zh) * | 2024-12-23 | 2025-12-05 | 上海彩迩文生化科技有限公司 | 一种制备cgrp受体拮抗剂中间体的方法 |
| CN119977885A (zh) * | 2025-04-15 | 2025-05-13 | 常州制药厂有限公司 | (5S,6S,9R)-5-氨基-6-(2,3-二氟苯基)-6,7,8,9-四氢-5H-环庚[b]吡啶-9-醇L-酒石酸盐及其制备方法 |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JO2355B1 (en) | 2003-04-15 | 2006-12-12 | ميرك شارب اند دوم كوربوريشن | Hereditary calcitonin polypeptide receptor antagonists |
| JPWO2005085228A1 (ja) | 2004-03-05 | 2008-01-17 | 萬有製薬株式会社 | シクロアルカノピリジン誘導体 |
| BRPI0517418A (pt) | 2004-10-13 | 2008-10-07 | Merck & Co Inc | composto, composição farmacêutica, e, métodos para antagonismo de atividade do receptor de cgrp em um mamìfero, para tratar, controlar, melhorar ou reduzir o risco de dor de cabeça, enxaqueca ou cefalgia, e de tratamento ou prevenção de dores de cabeça de enxaqueca, cefalgias, e dores de cabeça |
| US20060084708A1 (en) | 2004-10-14 | 2006-04-20 | Bayer Materialscience Llc | Rigid foams with good insulation properties and a process for the production of such foams |
| AU2005299852B2 (en) | 2004-10-22 | 2011-08-04 | Merck Sharp & Dohme Corp. | CGRP receptor antagonists |
| AU2007238894A1 (en) | 2006-04-10 | 2007-10-25 | Merck Sharp & Dohme Corp. | Process for the preparation of pyridine heterocycle CGRP antagonist intermediate |
| US8143403B2 (en) | 2008-04-11 | 2012-03-27 | Bristol-Myers Squibb Company | CGRP receptor antagonists |
| US8044043B2 (en) * | 2008-04-11 | 2011-10-25 | Bristol-Myers Squibb Company | CGRP receptor antagonists |
| US8314117B2 (en) * | 2009-10-14 | 2012-11-20 | Bristol-Myers Squibb Company | CGRP receptor antagonists |
-
2010
- 2010-10-12 US US12/902,714 patent/US8314117B2/en active Active
- 2010-10-13 RS RS20140035A patent/RS53149B/sr unknown
- 2010-10-13 CA CA2968176A patent/CA2968176C/en active Active
- 2010-10-13 JP JP2012534309A patent/JP5836279B2/ja active Active
- 2010-10-13 EP EP10768347.6A patent/EP2488512B1/en active Active
- 2010-10-13 DK DK10768347.6T patent/DK2488512T3/en active
- 2010-10-13 HR HRP20140111AT patent/HRP20140111T1/hr unknown
- 2010-10-13 AU AU2010306954A patent/AU2010306954B2/en active Active
- 2010-10-13 CA CA2777518A patent/CA2777518C/en active Active
- 2010-10-13 KR KR1020177018206A patent/KR101875353B1/ko active Active
- 2010-10-13 ES ES10768347.6T patent/ES2441192T3/es active Active
- 2010-10-13 WO PCT/US2010/052433 patent/WO2011046997A1/en not_active Ceased
- 2010-10-13 EA EA201270561A patent/EA020409B1/ru not_active IP Right Cessation
- 2010-10-13 PE PE2012000490A patent/PE20121137A1/es active IP Right Grant
- 2010-10-13 PL PL10768347T patent/PL2488512T3/pl unknown
- 2010-10-13 NZ NZ599281A patent/NZ599281A/xx unknown
- 2010-10-13 BR BR112012008828-9A patent/BR112012008828B1/pt active IP Right Grant
- 2010-10-13 PT PT107683476T patent/PT2488512E/pt unknown
- 2010-10-13 MX MX2012004182A patent/MX2012004182A/es active IP Right Grant
- 2010-10-13 KR KR1020187018446A patent/KR101990755B1/ko active Active
- 2010-10-13 CN CN201080056672.4A patent/CN102656159B/zh active Active
- 2010-10-13 KR KR1020127012197A patent/KR101755742B1/ko active Active
- 2010-10-13 SI SI201030486T patent/SI2488512T1/sl unknown
- 2010-10-14 TW TW099135091A patent/TWI465448B/zh active
- 2010-10-14 AR ARP100103755A patent/AR078638A1/es not_active Application Discontinuation
-
2012
- 2012-03-28 TN TNP2012000139A patent/TN2012000139A1/en unknown
- 2012-04-05 IL IL219120A patent/IL219120A/en active IP Right Grant
- 2012-04-12 CL CL2012000925A patent/CL2012000925A1/es unknown
- 2012-04-26 CO CO12068979A patent/CO6460732A2/es unknown
- 2012-05-11 ZA ZA2012/03452A patent/ZA201203452B/en unknown
- 2012-10-16 US US13/652,690 patent/US20130053570A1/en not_active Abandoned
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2014
- 2014-02-17 SM SM201400019T patent/SMT201400019B/xx unknown
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2015
- 2015-04-30 JP JP2015092727A patent/JP6109874B2/ja active Active
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2017
- 2017-03-08 JP JP2017043761A patent/JP6258537B2/ja active Active
- 2017-11-13 AR ARP170103159A patent/AR110069A2/es not_active Application Discontinuation
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2022
- 2022-07-12 CY CY2022023C patent/CY2022023I1/el unknown
- 2022-07-14 NL NL301187C patent/NL301187I2/nl unknown
- 2022-07-18 HU HUS2200033C patent/HUS2200033I1/hu unknown
- 2022-07-19 LU LU00272C patent/LUC00272I2/fr unknown
- 2022-07-22 NO NO2022033C patent/NO2022033I1/no unknown
- 2022-08-02 LT LTPA2022516C patent/LTC2488512I2/lt unknown
- 2022-08-11 FR FR22C1044C patent/FR22C1044I2/fr active Active
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