KR20140088610A - 암을 치료하기 위한 met 및 vegf의 이중 저해제 - Google Patents
암을 치료하기 위한 met 및 vegf의 이중 저해제 Download PDFInfo
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- KR20140088610A KR20140088610A KR1020147015127A KR20147015127A KR20140088610A KR 20140088610 A KR20140088610 A KR 20140088610A KR 1020147015127 A KR1020147015127 A KR 1020147015127A KR 20147015127 A KR20147015127 A KR 20147015127A KR 20140088610 A KR20140088610 A KR 20140088610A
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- 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
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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| US201161557358P | 2011-11-08 | 2011-11-08 | |
| US61/557,358 | 2011-11-08 | ||
| PCT/US2012/064116 WO2013070890A1 (en) | 2011-11-08 | 2012-11-08 | Dual inhibitor of met and vegf for treating cancer |
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| KR20140088610A true KR20140088610A (ko) | 2014-07-10 |
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Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
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| UA108618C2 (uk) | 2009-08-07 | 2015-05-25 | Застосування c-met-модуляторів в комбінації з темозоломідом та/або променевою терапією для лікування раку | |
| PL2621481T5 (pl) | 2010-09-27 | 2023-03-13 | Exelixis, Inc. | Podwójne inhibitory MET i VEGF do leczenia opornego na kastrację raka prostaty i osteoblastycznych przerzutów do kości |
| CA2826751C (en) | 2011-02-10 | 2021-05-18 | Exelixis, Inc. | Processes for preparing quinoline compounds and pharmaceutical compositions containing such compounds |
| US20120252840A1 (en) | 2011-04-04 | 2012-10-04 | Exelixis, Inc. | Method of Treating Cancer |
| JP2014513129A (ja) | 2011-05-02 | 2014-05-29 | エクセリクシス， インク． | 癌および骨癌疼痛の治療方法 |
| EP2758057B1 (en) | 2011-09-22 | 2017-05-31 | Exelixis, Inc. | Method for treating osteoporosis |
| CN104395284A (zh) | 2011-10-20 | 2015-03-04 | 埃克塞里艾克西斯公司 | 制备喹啉衍生物的方法 |
| HK1207587A1 (en) * | 2012-05-02 | 2016-02-05 | Exelixis, Inc. | A dual met - vegf modulator for treating osteolytic bone metastases |
| GEP20196995B (en) | 2013-03-15 | 2019-07-25 | Inc Exelixis | Metabolites of n-(4-{[6,7-bis (methyloxy)quinolin-4-yl] oxy}phenyl)-n'-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide |
| ES2927651T3 (es) | 2013-04-04 | 2022-11-10 | Exelixis Inc | Forma de dosificación de cabozantinib y uso en el tratamiento del cáncer |
| US9149471B2 (en) * | 2013-09-30 | 2015-10-06 | National University Corporation Tokyo University Of Agriculture And Technology | Therapeutic agent for osteoporosis |
| EP3738952A1 (en) | 2014-02-14 | 2020-11-18 | Exelixis, Inc. | Crystalline solid forms of n-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-n'-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, processes for making, and methods of use |
| WO2015142928A1 (en) | 2014-03-17 | 2015-09-24 | Exelixis, Inc. | Dosing of cabozantinib formulations |
| CN104788372B (zh) * | 2014-07-25 | 2018-01-30 | 上海圣考医药科技有限公司 | 一种氘代卡博替尼衍生物、其制备方法、应用及其中间体 |
| MA40386A (fr) | 2014-07-31 | 2016-02-04 | Exelixis Inc | Procédé de préparation de cabozantinib marqué au fluor-18 et d'analogues de celui-ci |
| EA034992B1 (ru) | 2014-08-05 | 2020-04-15 | Экселиксис, Инк. | Комбинации лекарственных средств для лечения множественной миеломы |
| CN105503717A (zh) * | 2014-09-24 | 2016-04-20 | 江苏奥赛康药业股份有限公司 | 一种苹果酸卡博替尼化合物及其药物组合物 |
| EP3442531A1 (en) | 2016-04-15 | 2019-02-20 | Exelixis, Inc. | Method of treating renal cell carcinoma using n-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-n'-(4-fluoropheny)cyclopropane-1,1-dicarboxamide, (2s)-hydroxybutanedioate |
| CN109496212B (zh) * | 2016-10-18 | 2020-08-14 | 北京康辰药业股份有限公司 | 一种喹啉基取代的羧酸化合物或其药学上可接受的盐、其药物组合物及应用 |
| CA3060370A1 (en) | 2017-05-26 | 2018-11-29 | Exelixis, Inc. | Crystalline solid forms of salts of n-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-n'-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, processes for making, and methods of use |
| MY210421A (en) | 2018-01-26 | 2025-09-22 | Exelixis Inc | Compounds for the treatment of kinase-dependent disorders |
| AU2019285066B2 (en) | 2018-06-15 | 2024-06-13 | Handa Pharmaceuticals, Inc. | Kinase inhibitor salts and compositions thereof |
| EP4658271A1 (en) | 2023-01-31 | 2025-12-10 | Handa Oncology, LLC | Improved cabozantinib compositions and methods of use |
Family Cites Families (7)
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|---|---|---|---|---|
| US4107288A (en) | 1974-09-18 | 1978-08-15 | Pharmaceutical Society Of Victoria | Injectable compositions, nanoparticles useful therein, and process of manufacturing same |
| US5145684A (en) | 1991-01-25 | 1992-09-08 | Sterling Drug Inc. | Surface modified drug nanoparticles |
| EP2392565B1 (en) | 2003-09-26 | 2014-03-19 | Exelixis, Inc. | c-Met modulators and methods of use |
| US20080200515A1 (en) | 2006-12-29 | 2008-08-21 | Tap Pharmaceutical Products Inc. | Solid state forms of enantiopure ilaprazole |
| UA108618C2 (uk) * | 2009-08-07 | 2015-05-25 | Застосування c-met-модуляторів в комбінації з темозоломідом та/або променевою терапією для лікування раку | |
| PL2621481T5 (pl) * | 2010-09-27 | 2023-03-13 | Exelixis, Inc. | Podwójne inhibitory MET i VEGF do leczenia opornego na kastrację raka prostaty i osteoblastycznych przerzutów do kości |
| JP2013537918A (ja) * | 2010-09-27 | 2013-10-07 | エクセリクシス， インク． | 去勢抵抗性前立腺癌および骨芽細胞骨転移の治療のためのｍｅｔおよびｖｅｇｆの二元阻害薬 |
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- 2012-11-08 BR BR112014011009A patent/BR112014011009A2/pt not_active IP Right Cessation
- 2012-11-08 EA EA201490944A patent/EA201490944A1/ru unknown
- 2012-11-08 TW TW106131943A patent/TW201818937A/zh unknown
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2014
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2017
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- 2017-10-04 JP JP2017193945A patent/JP2018048154A/ja active Pending
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| IN2014CN04067A (enExample) | 2015-10-23 |
| JP2018048154A (ja) | 2018-03-29 |
| AU2017225103A1 (en) | 2017-09-28 |
| IL232421A0 (en) | 2014-06-30 |
| TWI662962B (zh) | 2019-06-21 |
| US20140323522A1 (en) | 2014-10-30 |
| TW201818937A (zh) | 2018-06-01 |
| BR112014011009A2 (pt) | 2017-06-06 |
| MX2014005458A (es) | 2015-04-16 |
| CA2854336A1 (en) | 2013-05-16 |
| AU2012335737A1 (en) | 2014-06-05 |
| TW201322981A (zh) | 2013-06-16 |
| JP2014532766A (ja) | 2014-12-08 |
| WO2013070890A1 (en) | 2013-05-16 |
| CN104159585A (zh) | 2014-11-19 |
| HK1202062A1 (en) | 2015-09-18 |
| EP2776033A1 (en) | 2014-09-17 |
| EA201490944A1 (ru) | 2014-10-30 |
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