RU2316554C2 - Производные индолина, используемые как ингибиторы протеинкиназы - Google Patents
Производные индолина, используемые как ингибиторы протеинкиназы Download PDFInfo
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- RU2316554C2 RU2316554C2 RU2004122918/04A RU2004122918A RU2316554C2 RU 2316554 C2 RU2316554 C2 RU 2316554C2 RU 2004122918/04 A RU2004122918/04 A RU 2004122918/04A RU 2004122918 A RU2004122918 A RU 2004122918A RU 2316554 C2 RU2316554 C2 RU 2316554C2
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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
- C07D403/06—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 linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- 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
- C07D403/14—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 three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
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- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Cardiology (AREA)
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- Hematology (AREA)
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- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
- Peptides Or Proteins (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US34374601P | 2001-12-27 | 2001-12-27 | |
| US34381301P | 2001-12-27 | 2001-12-27 | |
| US60/343,813 | 2001-12-27 | ||
| US60/343,746 | 2001-12-27 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| RU2004122918A RU2004122918A (ru) | 2005-03-27 |
| RU2316554C2 true RU2316554C2 (ru) | 2008-02-10 |
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| RU2004122918/04A RU2316554C2 (ru) | 2001-12-27 | 2002-12-20 | Производные индолина, используемые как ингибиторы протеинкиназы |
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| JP (1) | JP4363985B2 (enExample) |
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| CN (1) | CN1290844C (enExample) |
| AT (1) | ATE302771T1 (enExample) |
| AU (1) | AU2002360753B2 (enExample) |
| BR (1) | BR0215360A (enExample) |
| CA (1) | CA2470480C (enExample) |
| CO (1) | CO5611126A2 (enExample) |
| DE (1) | DE60205776T2 (enExample) |
| DK (1) | DK1458713T3 (enExample) |
| ES (1) | ES2247411T3 (enExample) |
| HU (1) | HUP0500111A3 (enExample) |
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| MX (1) | MXPA04006271A (enExample) |
| NO (1) | NO327550B1 (enExample) |
| NZ (1) | NZ533219A (enExample) |
| PL (1) | PL208283B1 (enExample) |
| RU (1) | RU2316554C2 (enExample) |
| WO (1) | WO2003057690A1 (enExample) |
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| EA019481B1 (ru) * | 2009-08-04 | 2014-04-30 | Ле Лаборатуар Сервье | Новые дигидроиндолоновые соединения, способ их получения и фармацевтические композиции, содержащие их |
| RU2680826C2 (ru) * | 2013-07-12 | 2019-02-28 | Ле Лаборатуар Сервье | Новая соль 3-[(3-{ [4-(4-морфолинилметил)-1н-пиррол-2-ил]метилен} -2-оксо-2,3-дигидро-1н-индол-5-ил)метил]-1,3-тиазолидин-2,4-диона, ее получение и содержащие ее композиции |
Families Citing this family (30)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7195876B2 (en) * | 2002-08-09 | 2007-03-27 | Theravance, Inc. | Oncokinase fusion polypeptides associated with hyperproliferative and related disorders, nucleic acids encoding the same and methods for detecting and identifying the same |
| MXPA06004438A (es) * | 2003-10-24 | 2006-06-20 | Schering Ag | Derivados de indolinona y su uso en el tratamiento de enfermedades como el cancer. |
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| SE0401790D0 (sv) * | 2004-07-07 | 2004-07-07 | Forskarpatent I Syd Ab | Tamoxifen response in pre- and postmenopausal breast cancer patients |
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| AU2007296740B2 (en) * | 2006-09-11 | 2012-09-27 | Curis, Inc. | Substituted 2-indolinone as PTK inhibitors containing a zinc binding moiety |
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| JP6407504B2 (ja) | 2012-09-21 | 2018-10-17 | アログ・ファーマシューティカルズ・インコーポレイテッドＡｒｏｇ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． | 恒常的に活性であるリン酸化型ｆｌｔ３キナーゼの阻害方法 |
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| US10463658B2 (en) | 2013-10-25 | 2019-11-05 | Videra Pharmaceuticals, Llc | Method of inhibiting FLT3 kinase |
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| EP3254698A1 (en) | 2016-06-08 | 2017-12-13 | Universite De Montpellier | Flt3 receptor inhibitor at low dosage for the treatment of neuropathic pain |
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| WO2022019998A1 (en) | 2020-07-20 | 2022-01-27 | Arog Pharmaceuticals, Inc. | Crystal forms of crenolanib and methods of use thereof |
| WO2022090547A1 (en) | 2020-10-30 | 2022-05-05 | Dsm Ip Assets B.V. | Production of carotenoids by fermentation |
| US11969420B2 (en) | 2020-10-30 | 2024-04-30 | Arog Pharmaceuticals, Inc. | Combination therapy of crenolanib and apoptosis pathway agents for the treatment of proliferative disorders |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999061422A1 (en) * | 1998-05-29 | 1999-12-02 | Sugen, Inc. | Pyrrole substituted 2-indolinone protein kinase inhibitors |
| RU2142460C1 (ru) * | 1989-02-23 | 1999-12-10 | Ф. Хоффманн-Ля Рош Аг | Замещенные пирролы и их фармацевтически приемлемые соли |
| WO2001060814A2 (en) * | 2000-02-15 | 2001-08-23 | Sugen, Inc. | Pyrrole substituted 2-indolinone protein kinase inhibitors |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5880141A (en) | 1995-06-07 | 1999-03-09 | Sugen, Inc. | Benzylidene-Z-indoline compounds for the treatment of disease |
| CO4950519A1 (es) | 1997-02-13 | 2000-09-01 | Novartis Ag | Ftalazinas, preparaciones farmaceuticas que las comprenden y proceso para su preparacion |
| DE69906152T2 (de) * | 1998-12-17 | 2004-02-12 | F. Hoffmann-La Roche Ag | 4-alkenyl (und alkinyl)oxoindole als inhibitoren cyclinabhängiger kinasen, insbesondere cdk2 |
| IL143920A0 (en) | 1998-12-31 | 2002-04-21 | Sugen Inc | 3-heteroarylidenyl-2-indolinone derivatives and pharmaceutical compositions containing the same |
| DE19924401A1 (de) | 1999-05-27 | 2000-11-30 | Boehringer Ingelheim Pharma | Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel |
| WO2001016130A1 (de) | 1999-08-27 | 2001-03-08 | Boehringer Ingelheim Pharma Kg | Substituierte indolinone als tyrosinkinase inhibitoren |
| DE60014130T2 (de) | 1999-10-06 | 2006-03-09 | Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield | Heterocyclische verbindungen verwendbar als tyrosinkinase inhibitoren |
| UA75054C2 (uk) | 1999-10-13 | 2006-03-15 | Бьорінгер Інгельхайм Фарма Гмбх & Ко. Кг | Заміщені в положенні 6 індолінони, їх одержання та їх застосування як лікарського засобу |
| DE19949209A1 (de) | 1999-10-13 | 2001-04-19 | Boehringer Ingelheim Pharma | In 5-Stellung substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel |
| AU2576501A (en) | 1999-12-08 | 2001-06-18 | Advanced Medicine, Inc. | Protein kinase inhibitors |
| WO2002002551A1 (en) | 2000-06-30 | 2002-01-10 | Sugen, Inc. | 4-heteroaryl-3-heteroarylidenyl-2-indolinones and their use as protein kinase inhibitors |
| HU228668B1 (hu) | 2000-08-18 | 2013-05-28 | Millennium Pharmaceuticals | Kináz inhibitor kinazolin-származékok és az ezeket tartalmazó gyógyszerkészítmények |
| PE20020776A1 (es) | 2000-12-20 | 2002-08-22 | Sugen Inc | Indolinonas 4-aril sustituidas |
| US7195876B2 (en) | 2002-08-09 | 2007-03-27 | Theravance, Inc. | Oncokinase fusion polypeptides associated with hyperproliferative and related disorders, nucleic acids encoding the same and methods for detecting and identifying the same |
| US20050171182A1 (en) * | 2003-12-11 | 2005-08-04 | Roger Briesewitz | Methods and compositions for use in the treatment of mutant receptor tyrosine kinase driven cellular proliferative diseases |
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- 2004-07-08 NO NO20042926A patent/NO327550B1/no not_active IP Right Cessation
- 2004-07-22 CO CO04070253A patent/CO5611126A2/es not_active Application Discontinuation
-
2006
- 2006-02-21 US US11/358,305 patent/US7223783B2/en not_active Expired - Lifetime
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2142460C1 (ru) * | 1989-02-23 | 1999-12-10 | Ф. Хоффманн-Ля Рош Аг | Замещенные пирролы и их фармацевтически приемлемые соли |
| WO1999061422A1 (en) * | 1998-05-29 | 1999-12-02 | Sugen, Inc. | Pyrrole substituted 2-indolinone protein kinase inhibitors |
| WO2001060814A2 (en) * | 2000-02-15 | 2001-08-23 | Sugen, Inc. | Pyrrole substituted 2-indolinone protein kinase inhibitors |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EA019481B1 (ru) * | 2009-08-04 | 2014-04-30 | Ле Лаборатуар Сервье | Новые дигидроиндолоновые соединения, способ их получения и фармацевтические композиции, содержащие их |
| RU2680826C2 (ru) * | 2013-07-12 | 2019-02-28 | Ле Лаборатуар Сервье | Новая соль 3-[(3-{ [4-(4-морфолинилметил)-1н-пиррол-2-ил]метилен} -2-оксо-2,3-дигидро-1н-индол-5-ил)метил]-1,3-тиазолидин-2,4-диона, ее получение и содержащие ее композиции |
| RU2680826C9 (ru) * | 2013-07-12 | 2019-03-01 | Ле Лаборатуар Сервье | Новая соль 3-[(3-{ [4-(4-морфолинилметил)-1н-пиррол-2-ил]метилен} -2-оксо-2,3-дигидро-1н-индол-5-ил)метил]-1,3-тиазолидин-2,4-диона, ее получение и содержащие ее композиции |
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