CN111100078A - 3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-脲及其盐的晶型 - Google Patents
3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-脲及其盐的晶型 Download PDFInfo
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- CN111100078A CN111100078A CN201911273119.5A CN201911273119A CN111100078A CN 111100078 A CN111100078 A CN 111100078A CN 201911273119 A CN201911273119 A CN 201911273119A CN 111100078 A CN111100078 A CN 111100078A
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| Application Number | Priority Date | Filing Date | Title |
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| US26715509P | 2009-12-07 | 2009-12-07 | |
| US61/267,155 | 2009-12-07 | ||
| CN2010800550783A CN102639510A (zh) | 2009-12-07 | 2010-12-06 | 3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-脲及其盐的晶型 |
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| CN2010800550783A Division CN102639510A (zh) | 2009-12-07 | 2010-12-06 | 3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-脲及其盐的晶型 |
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| CN201911278014.9A Pending CN111269186A (zh) | 2009-12-07 | 2010-12-06 | 激酶抑制剂及其盐的晶型 |
| CN201911273119.5A Pending CN111100078A (zh) | 2009-12-07 | 2010-12-06 | 3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-脲及其盐的晶型 |
| CN2010800550783A Pending CN102639510A (zh) | 2009-12-07 | 2010-12-06 | 3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-脲及其盐的晶型 |
| CN201911272657.2A Pending CN111100077A (zh) | 2009-12-07 | 2010-12-06 | 3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-脲及其盐的晶型 |
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| CN201911278014.9A Pending CN111269186A (zh) | 2009-12-07 | 2010-12-06 | 激酶抑制剂及其盐的晶型 |
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| CN2010800550783A Pending CN102639510A (zh) | 2009-12-07 | 2010-12-06 | 3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-脲及其盐的晶型 |
| CN201911272657.2A Pending CN111100077A (zh) | 2009-12-07 | 2010-12-06 | 3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-脲及其盐的晶型 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111100077A (zh) * | 2009-12-07 | 2020-05-05 | 诺华股份有限公司 | 3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-脲及其盐的晶型 |
Families Citing this family (54)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0512324D0 (en) * | 2005-06-16 | 2005-07-27 | Novartis Ag | Organic compounds |
| WO2012088266A2 (en) | 2010-12-22 | 2012-06-28 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of fgfr3 |
| WO2013144339A1 (en) * | 2012-03-30 | 2013-10-03 | Novartis Ag | Fgfr inhibitor for use in the treatment of hypophosphatemic disorders |
| SI2861595T1 (sl) | 2012-06-13 | 2017-04-26 | Incyte Holdings Corporation | Substituirane triciklične spojine kot inhibitorji fgfr |
| US9388185B2 (en) | 2012-08-10 | 2016-07-12 | Incyte Holdings Corporation | Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors |
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| UA120248C2 (uk) | 2013-03-15 | 2019-11-11 | Селджен Кар Ллс | Гетероарильні сполуки та їх застосування |
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| CA2917667A1 (en) * | 2013-07-09 | 2015-01-15 | Dana-Farber Cancer Institute, Inc. | Kinase inhibitors for the treatment of disease |
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| SG10202104627UA (en) | 2013-12-13 | 2021-06-29 | Novartis Ag | Pharmaceutical dosage forms |
| MX369646B (es) | 2014-08-18 | 2019-11-15 | Eisai R&D Man Co Ltd | Sal de derivado de piridina monociclico y su cristal. |
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| SG10201913036RA (en) | 2015-02-20 | 2020-02-27 | Incyte Corp | Bicyclic heterocycles as fgfr inhibitors |
| MA41551A (fr) | 2015-02-20 | 2017-12-26 | Incyte Corp | Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4 |
| WO2016134294A1 (en) | 2015-02-20 | 2016-08-25 | Incyte Corporation | Bicyclic heterocycles as fgfr4 inhibitors |
| CN107787226A (zh) * | 2015-03-25 | 2018-03-09 | 诺华股份有限公司 | 药物组合 |
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| WO2016189472A1 (en) | 2015-05-28 | 2016-12-01 | Novartis Ag | Fgfr inhibitor for use in the treatment of the phosphaturic mesenchymal tumor |
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| AR111960A1 (es) | 2017-05-26 | 2019-09-04 | Incyte Corp | Formas cristalinas de un inhibidor de fgfr y procesos para su preparación |
| CN107176954B (zh) | 2017-06-02 | 2019-01-11 | 无锡双良生物科技有限公司 | 一种egfr抑制剂的药用盐及其晶型、制备方法和应用 |
| AU2018361264B2 (en) * | 2017-11-01 | 2021-04-01 | Guangdong Xianqiang Pharmaceutical Co., Ltd | Salt form and crystal form of compound as FGFR4 inhibitor and preparation method thereof |
| WO2019189241A1 (ja) | 2018-03-28 | 2019-10-03 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 肝細胞癌治療剤 |
| PL3788047T3 (pl) | 2018-05-04 | 2025-04-14 | Incyte Corporation | Stałe postacie inhibitora fgfr i sposoby ich otrzymywania |
| KR20210018264A (ko) | 2018-05-04 | 2021-02-17 | 인사이트 코포레이션 | Fgfr 억제제의 염 |
| WO2020185532A1 (en) | 2019-03-08 | 2020-09-17 | Incyte Corporation | Methods of treating cancer with an fgfr inhibitor |
| US11591329B2 (en) | 2019-07-09 | 2023-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
| WO2021067374A1 (en) | 2019-10-01 | 2021-04-08 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
| CR20220169A (es) | 2019-10-14 | 2022-10-27 | Incyte Corp | Heterociclos bicíclicos como inhibidores de fgfr |
| CN119462616A (zh) * | 2019-10-14 | 2025-02-18 | 和记黄埔医药(上海)有限公司 | 化合物的盐及其晶型 |
| US11566028B2 (en) | 2019-10-16 | 2023-01-31 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
| AU2020395185A1 (en) | 2019-12-04 | 2022-06-02 | Incyte Corporation | Derivatives of an FGFR inhibitor |
| JP7720840B2 (ja) | 2019-12-04 | 2025-08-08 | インサイト・コーポレイション | Fgfr阻害剤としての三環式複素環 |
| WO2021146424A1 (en) | 2020-01-15 | 2021-07-22 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
| TW202304459A (zh) | 2021-04-12 | 2023-02-01 | 美商英塞特公司 | 包含fgfr抑制劑及nectin-4靶向劑之組合療法 |
| EP4352060A1 (en) | 2021-06-09 | 2024-04-17 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
| US11939331B2 (en) | 2021-06-09 | 2024-03-26 | Incyte Corporation | Tricyclic heterocycles as FGFR inhibitors |
| WO2022271933A1 (en) | 2021-06-23 | 2022-12-29 | Kimtron, Inc. | System and method for ultra-close proximity irradiation of rotating biomass |
| AU2023236231A1 (en) * | 2022-03-18 | 2024-09-05 | Shanghai Institute Of Materia Medica , Chinese Academy Of Sciences | Salt of substituted amino six-membered nitric heterocyclic compound, crystal form thereof, method for preparing same, and use thereof |
| CN115785001B (zh) * | 2022-11-23 | 2023-09-15 | 斯坦德药典标准物质研发(湖北)有限公司 | 一种英菲格拉替尼的制备方法 |
| WO2024186882A1 (en) | 2023-03-06 | 2024-09-12 | Qed Therapeutics, Inc. | Methods of treating skeletal dysplasias |
| WO2025061013A1 (zh) * | 2023-09-18 | 2025-03-27 | 上海润石医药科技有限公司 | 包含杂芳基氧基萘类化合物的药物组合物及其制备方法和应用 |
| WO2025090870A1 (en) | 2023-10-27 | 2025-05-01 | Qed Therapeutics, Inc. | Infigratinib and metabolites thereof for use in methods of treating skeletal disorders |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006000420A1 (en) * | 2004-06-24 | 2006-01-05 | Novartis Ag | Pyrimidine urea derivatives as kinase inhibitors |
| CN101336237A (zh) * | 2005-12-21 | 2008-12-31 | 诺瓦提斯公司 | 作为fgf抑制剂的嘧啶基芳基脲衍生物 |
| CN111100077A (zh) * | 2009-12-07 | 2020-05-05 | 诺华股份有限公司 | 3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-脲及其盐的晶型 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101242843A (zh) * | 2005-06-10 | 2008-08-13 | 詹森药业有限公司 | 作为激酶调节剂的氨基嘧啶类化合物 |
| AU2006311433B2 (en) * | 2005-11-08 | 2012-06-28 | Choongwae Pharma Corporation | Alpha-helix mimetics and method relating to the treatment of cancer stem cells |
| MX342553B (es) * | 2008-04-29 | 2016-10-04 | Novartis Ag | Metodos para monitorear la modulacion de la actividad de cinasa del receptor del factor de crecimiento de fibroblastos y uso de dichos metodos. |
-
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006000420A1 (en) * | 2004-06-24 | 2006-01-05 | Novartis Ag | Pyrimidine urea derivatives as kinase inhibitors |
| CN101336237A (zh) * | 2005-12-21 | 2008-12-31 | 诺瓦提斯公司 | 作为fgf抑制剂的嘧啶基芳基脲衍生物 |
| CN111100077A (zh) * | 2009-12-07 | 2020-05-05 | 诺华股份有限公司 | 3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-脲及其盐的晶型 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111100077A (zh) * | 2009-12-07 | 2020-05-05 | 诺华股份有限公司 | 3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-脲及其盐的晶型 |
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