JP4751063B2 - キナーゼ阻害剤として活性のアミノインダゾール誘導体、それらの調製方法、及びそれらを含む薬学的組成物 - Google Patents
キナーゼ阻害剤として活性のアミノインダゾール誘導体、それらの調製方法、及びそれらを含む薬学的組成物 Download PDFInfo
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- JP4751063B2 JP4751063B2 JP2004505343A JP2004505343A JP4751063B2 JP 4751063 B2 JP4751063 B2 JP 4751063B2 JP 2004505343 A JP2004505343 A JP 2004505343A JP 2004505343 A JP2004505343 A JP 2004505343A JP 4751063 B2 JP4751063 B2 JP 4751063B2
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Classifications
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- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
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- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
- C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
Landscapes
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- Vascular Medicine (AREA)
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- Psychiatry (AREA)
- Hematology (AREA)
- Pulmonology (AREA)
- Structural Engineering (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US38109202P | 2002-05-17 | 2002-05-17 | |
| US60/381,092 | 2002-05-17 | ||
| PCT/EP2003/004862 WO2003097610A1 (en) | 2002-05-17 | 2003-05-08 | Aminoindazole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2005534635A JP2005534635A (ja) | 2005-11-17 |
| JP2005534635A5 JP2005534635A5 (enExample) | 2010-10-07 |
| JP4751063B2 true JP4751063B2 (ja) | 2011-08-17 |
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| Application Number | Title | Priority Date | Filing Date |
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| JP2004505343A Expired - Lifetime JP4751063B2 (ja) | 2002-05-17 | 2003-05-08 | キナーゼ阻害剤として活性のアミノインダゾール誘導体、それらの調製方法、及びそれらを含む薬学的組成物 |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP1506176B1 (enExample) |
| JP (1) | JP4751063B2 (enExample) |
| AU (1) | AU2003227741A1 (enExample) |
| BR (1) | BR0311291A (enExample) |
| CA (1) | CA2486101C (enExample) |
| ES (1) | ES2411655T3 (enExample) |
| MX (1) | MXPA04011417A (enExample) |
| WO (1) | WO2003097610A1 (enExample) |
Families Citing this family (95)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0217757D0 (en) * | 2002-07-31 | 2002-09-11 | Glaxo Group Ltd | Novel compounds |
| US7297709B2 (en) | 2003-05-22 | 2007-11-20 | Abbott Laboratories | Indazole, benzisoxazole, and benzisothiazole kinase inhibitors |
| JP4810427B2 (ja) * | 2003-05-22 | 2011-11-09 | アボット・ラボラトリーズ | インダゾール、ベンズイソオキサゾールおよびベンズイソチアゾールキナーゼ阻害剤 |
| JP2007514759A (ja) | 2003-12-19 | 2007-06-07 | タケダ サン ディエゴ インコーポレイテッド | キナーゼ阻害剤 |
| GB0402140D0 (en) * | 2004-01-30 | 2004-03-03 | Smithkline Beecham Corp | Novel compounds |
| GB0402138D0 (en) * | 2004-01-30 | 2004-03-03 | Smithkline Beecham Corp | Novel compounds |
| DE102004005172A1 (de) * | 2004-02-02 | 2005-08-18 | Aventis Pharma Deutschland Gmbh | Indazolderivate als Inhibitoren der Hormon Sensitiven Lipase |
| TW200526204A (en) | 2004-02-03 | 2005-08-16 | Pharmacia Italia Spa | 1h-thieno[2,3-c]pyrazole derivatives useful as kinase inhibitors |
| EP1714961B1 (en) * | 2004-02-12 | 2015-12-09 | Mitsubishi Tanabe Pharma Corporation | Indazole compound and pharmaceutical use thereof |
| US20070185152A1 (en) * | 2004-03-02 | 2007-08-09 | Smithkline Beecham Corporation | Inhibitors of akt activity |
| FR2871158A1 (fr) * | 2004-06-04 | 2005-12-09 | Aventis Pharma Sa | Indazoles substitues, compositions les contenant, procede de fabrication et utilisation |
| GB0412741D0 (en) | 2004-06-08 | 2004-07-07 | Univ St Andrews | "A multicore chemical compound library" |
| DE102004028862A1 (de) * | 2004-06-15 | 2005-12-29 | Merck Patent Gmbh | 3-Aminoindazole |
| WO2006023931A2 (en) | 2004-08-18 | 2006-03-02 | Takeda San Diego, Inc. | Kinase inhibitors |
| ATE479687T1 (de) | 2004-10-15 | 2010-09-15 | Takeda Pharmaceutical | Kinaseinhibitoren |
| JP5303271B2 (ja) | 2005-07-19 | 2013-10-02 | ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ | キナーゼ阻害剤として有用な1H−チエノ[2,3−c]ピラゾール化合物 |
| US8119655B2 (en) | 2005-10-07 | 2012-02-21 | Takeda Pharmaceutical Company Limited | Kinase inhibitors |
| AU2007219509A1 (en) * | 2006-01-18 | 2007-09-07 | Siena Biotech S.P.A | Modulators of alpha7 nicotinic acetylcholine receptors and therapeutic uses thereof |
| DE102006005180A1 (de) * | 2006-02-06 | 2007-08-09 | Merck Patent Gmbh | Indazol-heteroaryl-derivate |
| DE102006005179A1 (de) * | 2006-02-06 | 2007-08-09 | Merck Patent Gmbh | Aminoindazolderivate |
| EP2036893A4 (en) * | 2006-06-30 | 2011-04-13 | Kyowa Hakko Kirin Co Ltd | ABL Kinase Inhibitor |
| US20090209537A1 (en) * | 2006-06-30 | 2009-08-20 | Kyowa Hakko Kirin Co., Ltd. | Aurora inhibitors |
| BRPI0719883A2 (pt) | 2006-10-09 | 2015-05-05 | Takeda Pharmaceutical | Inibidores de quinase |
| DE102007002717A1 (de) | 2007-01-18 | 2008-07-24 | Merck Patent Gmbh | Heterocyclische Indazolderivate |
| GB0706793D0 (en) * | 2007-04-05 | 2007-05-16 | Evotec Ag | Compounds |
| DE102007022565A1 (de) | 2007-05-14 | 2008-11-20 | Merck Patent Gmbh | Heterocyclische Indazolderivate |
| WO2009012312A1 (en) * | 2007-07-16 | 2009-01-22 | Abbott Laboratories | Indazoles, benzisoxazoles and benzisothiazoles as inhibitors of protein kinases |
| CN102105148B (zh) | 2008-07-24 | 2013-04-10 | 内尔维阿诺医学科学有限公司 | 包含aurora激酶抑制剂和抗肿瘤药的治疗组合 |
| DE102008038221A1 (de) | 2008-08-18 | 2010-02-25 | Merck Patent Gmbh | 7-Azaindolderivate |
| DE102008038220A1 (de) | 2008-08-18 | 2010-02-25 | Merck Patent Gmbh | Oxadiazolderivate |
| DE102008038222A1 (de) | 2008-08-18 | 2010-02-25 | Merck Patent Gmbh | Indazol-5-carbonsäurehydrazid-derivate |
| JP5743897B2 (ja) | 2008-11-20 | 2015-07-01 | グラクソスミスクライン・リミテッド・ライアビリティ・カンパニーGlaxoSmithKline LLC | 化合物 |
| WO2010102958A1 (en) * | 2009-03-09 | 2010-09-16 | Glaxo Group Limited | 4-oxadiazol-2 -yl- indazoles as inhibitors of p13 kinases |
| ES2835553T3 (es) | 2009-08-10 | 2021-06-22 | Biosplice Therapeutics Inc | Inhibidores de indazol de la vía de señalización de Wnt y sus usos terapéuticos |
| WO2011067366A1 (en) * | 2009-12-03 | 2011-06-09 | Glaxo Group Limited | Indazole derivatives as pi 3 - kinase inhibitors |
| CN102821607B (zh) | 2009-12-21 | 2014-12-17 | 萨穆梅德有限公司 | 1H-吡唑并[3,4-b]吡啶及其治疗应用 |
| AU2010343102B2 (en) | 2009-12-29 | 2016-03-24 | Dana-Farber Cancer Institute, Inc. | Type II Raf kinase inhibitors |
| MX2012010617A (es) * | 2010-03-16 | 2012-10-05 | Dana Farber Cancer Inst Inc | Compuestos de imidazol y sus usos. |
| US8592426B2 (en) * | 2011-01-24 | 2013-11-26 | Hoffmann—La Roche Inc. | Aryl-benzocycloalkyl amide derivatives |
| HRP20190281T1 (hr) | 2011-09-14 | 2019-05-31 | Samumed, Llc | Indazol-3-karboksamidi i njihova uporaba kao inhibitora signalizacijskog puta wnt/b-katenin |
| JP6106685B2 (ja) | 2011-11-17 | 2017-04-05 | ダナ−ファーバー キャンサー インスティテュート, インコーポレイテッド | C−jun−n−末端キナーゼ(jnk)の阻害剤 |
| PH12017500997A1 (en) | 2012-04-04 | 2018-02-19 | Samumed Llc | Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof |
| PL2770994T3 (pl) | 2012-05-04 | 2020-03-31 | Samumed, Llc | 1H-Pirazolo[3,4-b]pirydyny i ich zastosowania terapeutyczne |
| US10112927B2 (en) | 2012-10-18 | 2018-10-30 | Dana-Farber Cancer Institute, Inc. | Inhibitors of cyclin-dependent kinase 7 (CDK7) |
| WO2014063054A1 (en) | 2012-10-19 | 2014-04-24 | Dana-Farber Cancer Institute, Inc. | Bone marrow on x chromosome kinase (bmx) inhibitors and uses thereof |
| WO2014063061A1 (en) | 2012-10-19 | 2014-04-24 | Dana-Farber Cancer Institute, Inc. | Hydrophobically tagged small molecules as inducers of protein degradation |
| EP2943198B1 (en) | 2013-01-08 | 2019-07-17 | Samumed, LLC | 3-(benzoimidazol-2-yl)-indazole inhibitors of the wnt signaling pathway and therapeutic uses thereof |
| EP3057956B1 (en) | 2013-10-18 | 2021-05-05 | Dana-Farber Cancer Institute, Inc. | Polycyclic inhibitors of cyclin-dependent kinase 7 (cdk7) |
| EP3057955B1 (en) | 2013-10-18 | 2018-04-11 | Syros Pharmaceuticals, Inc. | Heteroaromatic compounds useful for the treatment of prolferative diseases |
| WO2015112445A1 (en) * | 2014-01-24 | 2015-07-30 | Abbvie Inc. | 6-phenyl- or 6-(pyridin-3-yl)indazole derivatives and methods of use |
| US9862688B2 (en) | 2014-04-23 | 2018-01-09 | Dana-Farber Cancer Institute, Inc. | Hydrophobically tagged janus kinase inhibitors and uses thereof |
| WO2015164614A1 (en) | 2014-04-23 | 2015-10-29 | Dana-Farber Cancer Institute, Inc. | Janus kinase inhibitors and uses thereof |
| WO2016040193A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 3-(1h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridine and therapeutic uses thereof |
| WO2016040182A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 2-(1h-indazol-3-yl)-1h-imidazo[4,5-c]pyridine and therapeutic uses thereof |
| WO2016040180A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 3-(1h-benzo[d]imidazol-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof |
| WO2016040190A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 3-(3h-imidazo[4,5-b]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridine and therapeutic uses thereof |
| WO2016040185A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 2-(1h-indazol-3-yl)-3h-imidazo[4,5-b]pyridine and therapeutic uses thereof |
| WO2016040184A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 3-(3h-imidazo[4,5-b]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof |
| WO2016040188A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 3-(3h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof |
| WO2016040181A1 (en) | 2014-09-08 | 2016-03-17 | Samumed, Llc | 3-(1h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof |
| EP3233840B1 (en) | 2014-12-16 | 2018-11-21 | Eudendron S.r.l. | Heterocyclic derivatives modulating activity of certain protein kinases |
| CA2972239A1 (en) | 2014-12-23 | 2016-06-30 | Dana-Farber Cancer Institute, Inc. | Inhibitors of cyclin-dependent kinase 7 (cdk7) |
| CN106032359B (zh) * | 2015-03-09 | 2018-07-20 | 复旦大学 | 吲唑类化合物及其制备方法和用途 |
| CN107427521B (zh) | 2015-03-27 | 2021-08-03 | 达纳-法伯癌症研究所股份有限公司 | 细胞周期蛋白依赖性激酶的抑制剂 |
| CN106279119B (zh) * | 2015-05-27 | 2020-06-16 | 上海海和药物研究开发有限公司 | 一种新型激酶抑制剂的制备及其应用 |
| WO2016201370A1 (en) | 2015-06-12 | 2016-12-15 | Dana-Farber Cancer Institute, Inc. | Combination therapy of transcription inhibitors and kinase inhibitors |
| US10285982B2 (en) | 2015-08-03 | 2019-05-14 | Samumed, Llc | 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
| WO2017023972A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(1h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
| WO2017024010A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(1h-pyrrolo[3,2-c]pyridin-2-yl)-1h-indazoles and therapeutic uses thereof |
| US10285983B2 (en) | 2015-08-03 | 2019-05-14 | Samumed, Llc | 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[3,4-B] pyridines and therapeutic uses thereof |
| US10188634B2 (en) | 2015-08-03 | 2019-01-29 | Samumed, Llc | 3-(3H-imidazo[4,5-C]pyridin-2-yl)-1 H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
| WO2017023987A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(1h-pyrrolo[3,2-c]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridines and therapeutic uses thereof |
| WO2017023993A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(1h-indol-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
| US10166218B2 (en) | 2015-08-03 | 2019-01-01 | Samumed, Llc | 3-(1H-indol-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
| US10231956B2 (en) | 2015-08-03 | 2019-03-19 | Samumed, Llc | 3-(1H-pyrrolo[3,2-C]pyridin-2-YL)-1 H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
| WO2017023984A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(1h-pyrrolo[3,2-c]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridines and therapeutic uses thereof |
| US10206909B2 (en) | 2015-08-03 | 2019-02-19 | Samumed, Llc | 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
| WO2017024015A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(3h-imidazo[4,5-b]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
| US10350199B2 (en) | 2015-08-03 | 2019-07-16 | Samumed, Llc | 3-(1h-pyrrolo[2,3-b]pyridin-2-yl)-1h-indazoles and therapeutic uses thereof |
| US10519169B2 (en) | 2015-08-03 | 2019-12-31 | Samumed, Llc | 3-(1H-pyrrolo[2,3-C]pyridin-2-yl)-1 H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
| WO2017023975A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc. | 3-(1h-pyrrolo[2,3-c]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridines and therapeutic uses thereof |
| US10392383B2 (en) | 2015-08-03 | 2019-08-27 | Samumed, Llc | 3-(1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
| WO2017023986A1 (en) | 2015-08-03 | 2017-02-09 | Samumed, Llc | 3-(1h-indol-2-yl)-1h-indazoles and therapeutic uses thereof |
| EP4019515A1 (en) | 2015-09-09 | 2022-06-29 | Dana-Farber Cancer Institute, Inc. | Inhibitors of cyclin-dependent kinases |
| KR20180080262A (ko) | 2015-11-06 | 2018-07-11 | 사뮤메드, 엘엘씨 | 골관절염의 치료 |
| AR108325A1 (es) | 2016-04-27 | 2018-08-08 | Samumed Llc | Isoquinolin-3-il carboxamidas y preparación y uso de las mismas |
| ES2933109T3 (es) | 2016-06-01 | 2023-02-02 | Biosplice Therapeutics Inc | Proceso para preparar N-(5-(3-(7-(3-fluorofenil)-3h-imidazo[4,5-c]piridin-2-il)-1h-indazol-5-il)piridin-3-il)-3-metilbutanamida |
| CN110709082A (zh) | 2016-10-21 | 2020-01-17 | 萨穆梅德有限公司 | 吲唑-3-甲酰胺的使用方法及其作为Wnt/β-连环蛋白信号传导途径抑制剂的用途 |
| KR102558716B1 (ko) | 2016-11-07 | 2023-07-21 | 사뮤메드, 엘엘씨 | 단일-투여량, 즉시-사용가능한 주사용 제제 |
| WO2018113785A1 (zh) * | 2016-12-22 | 2018-06-28 | 广州华睿光电材料有限公司 | 含呋喃交联基团的聚合物及其应用 |
| JP7590185B2 (ja) | 2018-06-25 | 2024-11-26 | ダナ-ファーバー キャンサー インスティテュート, インコーポレイテッド | Taireファミリーキナーゼインヒビターおよびそれらの使用 |
| JP7566731B2 (ja) | 2018-07-03 | 2024-10-15 | アイエフエム デュー インコーポレイテッド | Sting活性に関連する状態を治療するための化合物および組成物 |
| EP3902542A4 (en) | 2018-12-28 | 2022-09-07 | Dana-Farber Cancer Institute, Inc. | Inhibitors of cyclin-dependent kinase 7 and uses thereof |
| WO2021067801A1 (en) * | 2019-10-03 | 2021-04-08 | Ifm Due, Inc. | Compounds and compositions for treating conditions associated with sting activity |
| US12152018B2 (en) | 2021-01-08 | 2024-11-26 | Ifm Due, Inc. | Compounds and compositions for treating conditions associated with STING activity |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0822109A (ja) * | 1994-07-05 | 1996-01-23 | Konica Corp | 写真用シアンカプラー |
| JP2005516927A (ja) * | 2001-12-13 | 2005-06-09 | アボット・ラボラトリーズ | 癌治療用のキナーゼ阻害剤としての3−(フェニル−アルコキシ)−5−(フェニル)−ピリジン誘導体および関連化合物 |
| JP2005530711A (ja) * | 2002-03-11 | 2005-10-13 | アベンティス・ファーマ・ソシエテ・アノニム | アミノインダゾール誘導体、その製造方法、医薬としての該方法の中間体の使用および該誘導体を含む医薬組成物 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE626284A (enExample) | 1962-04-28 | |||
| DE2458965C3 (de) | 1974-12-13 | 1979-10-11 | Bayer Ag, 5090 Leverkusen | 3-Amino-indazol-N-carbonsäure-Derivate, Verfahren zu ihrer Herstellung sowie sie enthaltende Arzneimittel |
| US4864032A (en) | 1987-07-02 | 1989-09-05 | Ortho Pharmaceutical Corporation | Process for the preparation of indazoles |
| AU739642B2 (en) * | 1997-12-22 | 2001-10-18 | Bayer Healthcare Llc | Inhibition of p38 kinase activity using substituted heterocyclic ureas |
| US6387900B1 (en) * | 1999-08-12 | 2002-05-14 | Pharmacia & Upjohn S.P.A. | 3(5)-ureido-pyrazole derivatives process for their preparation and their use as antitumor agents |
| EE05405B1 (et) * | 2000-08-10 | 2011-04-15 | Pharmacia Italia S.P.A. | Kinaasi inhibiitoritena toimivad bitskloprasoolid, nende valmistamismeetod, kasutamine ja neid sisaldavad farmatseutilised kompositsioonid |
| WO2003051847A1 (en) * | 2001-12-19 | 2003-06-26 | Smithkline Beecham P.L.C. | (1-h-indazol-3-yl) -amide derivatives as gsk-3 inhibitors |
-
2003
- 2003-05-08 ES ES03725180T patent/ES2411655T3/es not_active Expired - Lifetime
- 2003-05-08 WO PCT/EP2003/004862 patent/WO2003097610A1/en not_active Ceased
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- 2003-05-08 AU AU2003227741A patent/AU2003227741A1/en not_active Abandoned
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- 2003-05-08 EP EP03725180.8A patent/EP1506176B1/en not_active Expired - Lifetime
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0822109A (ja) * | 1994-07-05 | 1996-01-23 | Konica Corp | 写真用シアンカプラー |
| JP2005516927A (ja) * | 2001-12-13 | 2005-06-09 | アボット・ラボラトリーズ | 癌治療用のキナーゼ阻害剤としての3−(フェニル−アルコキシ)−5−(フェニル)−ピリジン誘導体および関連化合物 |
| JP2005530711A (ja) * | 2002-03-11 | 2005-10-13 | アベンティス・ファーマ・ソシエテ・アノニム | アミノインダゾール誘導体、その製造方法、医薬としての該方法の中間体の使用および該誘導体を含む医薬組成物 |
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| ES2411655T3 (es) | 2013-07-08 |
| MXPA04011417A (es) | 2005-02-14 |
| WO2003097610A1 (en) | 2003-11-27 |
| EP1506176B1 (en) | 2013-04-24 |
| JP2005534635A (ja) | 2005-11-17 |
| CA2486101A1 (en) | 2003-11-27 |
| EP1506176A1 (en) | 2005-02-16 |
| BR0311291A (pt) | 2005-03-29 |
| AU2003227741A1 (en) | 2003-12-02 |
| CA2486101C (en) | 2009-07-07 |
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