CN112384513A - Gabaa正变构调节剂化合物、其制备方法和用途 - Google Patents
Gabaa正变构调节剂化合物、其制备方法和用途 Download PDFInfo
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113840610A (zh) * | 2019-03-18 | 2021-12-24 | 纽罗塞克医疗公司 | Gabaa受体调节剂用于治疗疼痛的用途 |
| CN114981266A (zh) * | 2019-10-22 | 2022-08-30 | 纽罗塞克医疗公司 | Gabaa正向变构调节剂化合物、其制备方法和用途 |
| CN115003301A (zh) * | 2019-10-23 | 2022-09-02 | 纽罗塞克医疗公司 | 用gabaa受体调节剂的癫痫状况的治疗 |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP7449272B2 (ja) * | 2018-04-18 | 2024-03-13 | ニューロサイクル・セラピューティクス・インコーポレイテッド | Gabaa陽性アロステリックモジュレーター化合物、その作製の方法および使用 |
| US12233070B2 (en) * | 2020-06-30 | 2025-02-25 | University Of Mississippi Medical Center | Methods for treating benzodiazepine misuse/use disorder |
| AU2023356939A1 (en) * | 2022-10-04 | 2025-04-10 | Engrail Therapeutics, Inc. | Gaba a receptor modulators and uses thereof |
| WO2025175214A1 (en) * | 2024-02-16 | 2025-08-21 | Engrail Therapeutics, Inc. | Methods of treating generalized anxiety disorder |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002038568A1 (en) * | 2000-11-10 | 2002-05-16 | Merck Sharp & Dohme Limited | Imidazo-triazine derivatives as ligands for gaba receptors |
| WO2003008418A1 (en) * | 2001-07-16 | 2003-01-30 | Merck Sharp & Dohme Limited | Imidazo-triazine derivatives as ligands for gaba receptors |
| WO2011011712A1 (en) * | 2009-07-24 | 2011-01-27 | Concert Pharmaceuticals, Inc. | Substituted imidazotriazines |
| WO2017129801A1 (en) * | 2016-01-27 | 2017-08-03 | Universität Zürich | Use of gabaa receptor modulators for treatment of itch |
| US20170258800A1 (en) * | 2008-05-21 | 2017-09-14 | Incyte Corporation | Salts of 2-fluoro-n-methyl-4-[7-(quinolin-6-yl-methyl)- imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2802343C2 (de) | 1978-01-20 | 1982-04-22 | Peter Prof. Dr.-Ing. Friderichs | Latentwärmespeicher-Behälter |
| GB9813576D0 (en) * | 1998-06-24 | 1998-08-19 | Merck Sharp & Dohme | Therapeutic agents |
| TWI248936B (en) | 2001-03-21 | 2006-02-11 | Merck Sharp & Dohme | Imidazo-pyrimidine derivatives as ligands for GABA receptors |
| JP2004170323A (ja) | 2002-11-22 | 2004-06-17 | Sumitomo Pharmaceut Co Ltd | 皮膚疾患治療剤のスクリーニング方法 |
| WO2009021957A2 (en) | 2007-08-14 | 2009-02-19 | Novartis Ag | Tricyclic heterocyclic compounds as gaba a modulators |
| MX362181B (es) | 2013-02-19 | 2019-01-08 | Ono Pharmaceutical Co | Compuesto inhibidor de cinasa del receptor de tropomiosina (trk). |
| WO2015072853A1 (en) | 2013-11-13 | 2015-05-21 | Rjg Developments B.V. | Treatment of herpes virus infection outbreaks |
| JP7449272B2 (ja) * | 2018-04-18 | 2024-03-13 | ニューロサイクル・セラピューティクス・インコーポレイテッド | Gabaa陽性アロステリックモジュレーター化合物、その作製の方法および使用 |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002038568A1 (en) * | 2000-11-10 | 2002-05-16 | Merck Sharp & Dohme Limited | Imidazo-triazine derivatives as ligands for gaba receptors |
| WO2003008418A1 (en) * | 2001-07-16 | 2003-01-30 | Merck Sharp & Dohme Limited | Imidazo-triazine derivatives as ligands for gaba receptors |
| US20170258800A1 (en) * | 2008-05-21 | 2017-09-14 | Incyte Corporation | Salts of 2-fluoro-n-methyl-4-[7-(quinolin-6-yl-methyl)- imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same |
| WO2011011712A1 (en) * | 2009-07-24 | 2011-01-27 | Concert Pharmaceuticals, Inc. | Substituted imidazotriazines |
| WO2017129801A1 (en) * | 2016-01-27 | 2017-08-03 | Universität Zürich | Use of gabaa receptor modulators for treatment of itch |
Non-Patent Citations (2)
| Title |
|---|
| DONALD R. GAUTHIER ET AL.: "Palladium-Catalyzed Regioselective Arylation of Imidazo[1,2-b][1,2,4]triazine: Synthesis of an r2/3-Selective GABA Agonist", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| MICHAEL G. N. RUSSELL ET AL.: "Discovery of Imidazo[1,2-b][1,2,4]triazines as GABAA r2/3 Subtype Selective Agonists for the Treatment of Anxiety", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113840610A (zh) * | 2019-03-18 | 2021-12-24 | 纽罗塞克医疗公司 | Gabaa受体调节剂用于治疗疼痛的用途 |
| CN114981266A (zh) * | 2019-10-22 | 2022-08-30 | 纽罗塞克医疗公司 | Gabaa正向变构调节剂化合物、其制备方法和用途 |
| CN115003301A (zh) * | 2019-10-23 | 2022-09-02 | 纽罗塞克医疗公司 | 用gabaa受体调节剂的癫痫状况的治疗 |
| CN115003301B (zh) * | 2019-10-23 | 2025-05-06 | 纽罗塞克医疗公司 | 用gabaa受体调节剂的癫痫状况的治疗 |
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| JP7449272B2 (ja) | 2024-03-13 |
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| BR112020021104A2 (pt) | 2021-02-23 |
| JP2021522330A (ja) | 2021-08-30 |
| MX2020010878A (es) | 2021-01-29 |
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| CA3096890A1 (en) | 2019-10-24 |
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| TW202012402A (zh) | 2020-04-01 |
| CL2020002663A1 (es) | 2021-06-11 |
| EP3781566A1 (en) | 2021-02-24 |
| US11542263B2 (en) | 2023-01-03 |
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