MX2011004683A - Antagonistas de la via hedgehog de ftalazina disustituida. - Google Patents
Antagonistas de la via hedgehog de ftalazina disustituida.Info
- Publication number
- MX2011004683A MX2011004683A MX2011004683A MX2011004683A MX2011004683A MX 2011004683 A MX2011004683 A MX 2011004683A MX 2011004683 A MX2011004683 A MX 2011004683A MX 2011004683 A MX2011004683 A MX 2011004683A MX 2011004683 A MX2011004683 A MX 2011004683A
- Authority
- MX
- Mexico
- Prior art keywords
- cancer
- fluoro
- pharmaceutically acceptable
- hydrogen
- acceptable salt
- Prior art date
Links
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A61K31/495—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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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| US11070308P | 2008-11-03 | 2008-11-03 | |
| PCT/US2009/061573 WO2010062507A1 (en) | 2008-11-03 | 2009-10-22 | Disubstituted phthalazine hedgehog pathway antagonists |
Publications (1)
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| MX2011004683A true MX2011004683A (es) | 2011-06-20 |
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| MX2011004683A MX2011004683A (es) | 2008-11-03 | 2009-10-22 | Antagonistas de la via hedgehog de ftalazina disustituida. |
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| EP (1) | EP2364185B1 (OSRAM) |
| JP (1) | JP2012507535A (OSRAM) |
| KR (1) | KR101335746B1 (OSRAM) |
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| BR (1) | BRPI0921437A2 (OSRAM) |
| CA (1) | CA2742539C (OSRAM) |
| CL (1) | CL2011000979A1 (OSRAM) |
| CO (1) | CO6382123A2 (OSRAM) |
| CR (1) | CR20110202A (OSRAM) |
| CY (1) | CY1114023T1 (OSRAM) |
| DK (1) | DK2364185T3 (OSRAM) |
| EA (1) | EA018931B1 (OSRAM) |
| EC (1) | ECSP11011021A (OSRAM) |
| ES (1) | ES2418479T3 (OSRAM) |
| HR (1) | HRP20130527T1 (OSRAM) |
| IL (1) | IL211841A0 (OSRAM) |
| MA (1) | MA32726B1 (OSRAM) |
| MX (1) | MX2011004683A (OSRAM) |
| NZ (1) | NZ591945A (OSRAM) |
| PE (1) | PE20110433A1 (OSRAM) |
| PL (1) | PL2364185T3 (OSRAM) |
| PT (1) | PT2364185E (OSRAM) |
| SI (1) | SI2364185T1 (OSRAM) |
| TN (1) | TN2011000166A1 (OSRAM) |
| UA (1) | UA102115C2 (OSRAM) |
| WO (1) | WO2010062507A1 (OSRAM) |
| ZA (1) | ZA201102448B (OSRAM) |
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| PE20090188A1 (es) * | 2007-03-15 | 2009-03-20 | Novartis Ag | Compuestos heterociclicos como moduladores de la senda de hedgehog |
| UA102250C2 (ru) | 2008-04-29 | 2013-06-25 | Эли Лилли Энд Компани | Двухзамещенные фталазины - антагонисты проводящего пути hedgehog |
| US20100041663A1 (en) | 2008-07-18 | 2010-02-18 | Novartis Ag | Organic Compounds as Smo Inhibitors |
| KR101335770B1 (ko) | 2008-11-17 | 2013-12-12 | 일라이 릴리 앤드 캄파니 | 사치환된 피리다진 헷지호그 경로 길항제 |
| EP2358698B1 (en) | 2008-11-17 | 2012-09-05 | Eli Lilly and Company | Tetrasubstituted pyridazine as hedgehog pathway antagonists |
| AR077014A1 (es) | 2009-06-19 | 2011-07-27 | Lilly Co Eli | Compuesto derivado de ftalazina 1,4-disustituida, composicion farmaceutica que lo comprende y uso para preparar un medicamento util para el tratamiento de cancer |
| US9814703B2 (en) | 2013-11-14 | 2017-11-14 | The Board Of Trustees Of The Leland Stanford Junior University | Methods for treating cancer by activation of BMP signaling |
| CN105985320B (zh) * | 2015-02-11 | 2018-10-26 | 复旦大学 | 苄基酞嗪化合物及其制备方法和用途 |
| CN105985321B (zh) * | 2015-02-11 | 2018-10-26 | 复旦大学 | 吡唑酞嗪化合物及其制备方法和用途 |
| CN105985319B (zh) * | 2015-02-11 | 2019-02-26 | 复旦大学 | 芳基酞嗪化合物及其制备方法和用途 |
| CN116349204A (zh) | 2020-10-13 | 2023-06-27 | 奋进生物医药公司 | 治疗纤维化的方法 |
| WO2024064245A1 (en) * | 2022-09-23 | 2024-03-28 | Merck Sharp & Dohme Llc | Phthalazine derivatives useful as inhibitors of nod-like receptor protein 3 |
| US12447148B2 (en) | 2024-03-05 | 2025-10-21 | Endeavor Biomedicines, Inc. | Methods of improving lung function |
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| GB1293565A (en) | 1969-05-03 | 1972-10-18 | Aspro Nicholas Ltd | Aminophthalazines and pharmaceutical compositions thereof |
| WO1998014431A1 (en) * | 1996-10-01 | 1998-04-09 | Kyowa Hakko Kogyo Co., Ltd. | Nitrogenous heterocyclic compounds |
| ES2162235T3 (es) | 1996-01-15 | 2001-12-16 | Janssen Pharmaceutica Nv | Piridazinaminas inhibidoras de la angiogenesis. |
| US6432970B2 (en) | 1998-04-09 | 2002-08-13 | Johns Hopkins University School Of Medicine | Inhibitors of hedgehog signaling pathways, compositions and uses related thereto |
| WO1999052534A1 (en) | 1998-04-09 | 1999-10-21 | Johns Hopkins University School Of Medicine | Use of steroidal alkaloid derivatives as inhibitors of hedgehog signaling pathways |
| AU780358B2 (en) | 1999-06-08 | 2005-03-17 | Lorantis Limited | Therapeutic use of an inhibitor of a hedgehog or a hedgehog-related signalling pathway |
| ATE404200T1 (de) | 2002-04-22 | 2008-08-15 | Univ Johns Hopkins Med | Modulatoren von hedgehog signalpfaden, zusammensetzungen und verwandte verwendungen |
| AU2003265853A1 (en) | 2002-08-29 | 2004-03-19 | Curis, Inc. | Hedgehog antagonists, methods and uses related thereto |
| WO2005033288A2 (en) * | 2003-09-29 | 2005-04-14 | The Johns Hopkins University | Hedgehog pathway antagonists |
| TW200533356A (en) | 2004-02-24 | 2005-10-16 | Mitsubishi Pharma Corp | Fused pyridazine derivatives |
| CA2564996A1 (en) | 2004-05-08 | 2006-01-12 | Taeyoung Yoon | 3-aryl-5,6-disubstituted pyridazines |
| KR20160058972A (ko) * | 2004-09-02 | 2016-05-25 | 제넨테크, 인크. | 헤지호그 신호전달에 대한 피리딜 억제제 |
| EP1900731A1 (de) | 2006-09-07 | 2008-03-19 | Bayer Schering Pharma Aktiengesellschaft | N-(1-Phthalazin-1-yl-piperidin-4-yl)-amide als EP2-Rezeptor Modulatoren |
| PE20090188A1 (es) | 2007-03-15 | 2009-03-20 | Novartis Ag | Compuestos heterociclicos como moduladores de la senda de hedgehog |
| ES2505091T3 (es) | 2007-06-25 | 2014-10-09 | Amgen Inc. | Compuestos, composiciones y métodos de uso de ftalazina |
| WO2009035568A1 (en) | 2007-09-07 | 2009-03-19 | Amgen Inc. | Annelated pyridazines for the treatment of tumors driven by inappropriate hedgehog signalling |
| UA102250C2 (ru) | 2008-04-29 | 2013-06-25 | Эли Лилли Энд Компани | Двухзамещенные фталазины - антагонисты проводящего пути hedgehog |
| US20100041663A1 (en) | 2008-07-18 | 2010-02-18 | Novartis Ag | Organic Compounds as Smo Inhibitors |
| EP2358698B1 (en) | 2008-11-17 | 2012-09-05 | Eli Lilly and Company | Tetrasubstituted pyridazine as hedgehog pathway antagonists |
| KR101335770B1 (ko) | 2008-11-17 | 2013-12-12 | 일라이 릴리 앤드 캄파니 | 사치환된 피리다진 헷지호그 경로 길항제 |
| AR077014A1 (es) | 2009-06-19 | 2011-07-27 | Lilly Co Eli | Compuesto derivado de ftalazina 1,4-disustituida, composicion farmaceutica que lo comprende y uso para preparar un medicamento util para el tratamiento de cancer |
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