JP2008525453A - 緑内障と、ｒｈｏキナーゼを媒介とした他の疾患および症状を治療するためのアミノピラジン・アナログ - Google Patents
緑内障と、ｒｈｏキナーゼを媒介とした他の疾患および症状を治療するためのアミノピラジン・アナログ Download PDFInfo
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- JP2008525453A JP2008525453A JP2007548311A JP2007548311A JP2008525453A JP 2008525453 A JP2008525453 A JP 2008525453A JP 2007548311 A JP2007548311 A JP 2007548311A JP 2007548311 A JP2007548311 A JP 2007548311A JP 2008525453 A JP2008525453 A JP 2008525453A
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- heterocyclyl
- alkyl
- methylene chloride
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- HQUMFEJDMBJZDZ-UHFFFAOYSA-N tert-butyl 4-(6-bromo-3-pyrrolidin-1-ylpyrazin-2-yl)-1,4-diazepane-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCCN1C1=NC(Br)=CN=C1N1CCCC1 HQUMFEJDMBJZDZ-UHFFFAOYSA-N 0.000 description 1
- PWQLFIKTGRINFF-UHFFFAOYSA-N tert-butyl 4-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)CC1 PWQLFIKTGRINFF-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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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
-
- 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
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- Organic Chemistry (AREA)
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- Gynecology & Obstetrics (AREA)
- Urology & Nephrology (AREA)
- Transplantation (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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| PCT/US2005/045384 WO2006071548A2 (en) | 2004-12-27 | 2005-12-14 | Aminopyrazine analogs for treating glaucoma and other rho kinase-mediated diseases |
Publications (2)
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| JP2008525453A true JP2008525453A (ja) | 2008-07-17 |
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| JP2008545660A (ja) * | 2005-05-20 | 2008-12-18 | バーテックス ファーマシューティカルズ インコーポレイテッド | プロテインキナーゼ阻害剤として有用なピロロピリジン化合物 |
| JP2013509424A (ja) * | 2009-10-30 | 2013-03-14 | ヤンセン ファーマシューティカ エヌ．ベー． | デルタオピオイド受容体調節因子としてのピラジン |
| JP2013529200A (ja) * | 2010-05-12 | 2013-07-18 | バーテックス ファーマシューティカルズ インコーポレイテッド | Ａｔｒキナーゼ阻害剤として有用な化合物 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003045924A1 (en) * | 2001-11-21 | 2003-06-05 | Pharmacia & Upjohn Company | Substituted aryl 1,4-pyrazine derivatives |
| WO2003051870A1 (en) * | 2001-12-18 | 2003-06-26 | Astrazeneca Ab | Novel compounds |
| WO2004018473A2 (en) * | 2002-08-23 | 2004-03-04 | Institute Of Experimental Botany Ascr | Azapurine derivatives |
| WO2004084824A2 (en) * | 2003-03-24 | 2004-10-07 | Merck & Co., Inc. | Biaryl substituted 6-membered heterocyles as sodium channel blockers |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6271224B1 (en) * | 1995-12-21 | 2001-08-07 | Alcon Laboratories, Inc. | Use of certain isoquinolinesulfonyl compounds for the treatment of glaucoma and ocular ischemia |
| US6586425B2 (en) * | 1996-02-21 | 2003-07-01 | Wisconsin Alumni Research Foundation | Cytoskeletal active agents for glaucoma therapy |
| US5798380A (en) * | 1996-02-21 | 1998-08-25 | Wisconsin Alumni Research Foundation | Cytoskeletal active agents for glaucoma therapy |
| BR9711154A (pt) * | 1996-08-12 | 1999-08-17 | Yoshitomi Pharmaceutical | Agente farmac-utico contendo inibidor cinase rho |
| US6673812B1 (en) * | 1998-08-17 | 2004-01-06 | Senju Pharmaceutical Co., Ltd. | Preventives/remedies for glaucoma |
| DE60045890D1 (de) * | 1999-04-27 | 2011-06-09 | Mitsubishi Tanabe Pharma Corp | Arzneimittel zur präventiven oder therapeutische Behandlung von Lebererkrankungen |
| US6348494B1 (en) * | 2000-11-21 | 2002-02-19 | American Home Products Corporation | Ethers of o-desmethyl venlafaxine |
| ATE327993T1 (de) * | 2000-03-16 | 2006-06-15 | Mitsubishi Pharma Corp | Amid-verbindung und deren verwendung |
| AU2001236006A1 (en) * | 2000-03-31 | 2001-10-15 | Mitsubishi Pharma Corporation | Preventives/remedies for kidney diseases |
| JPWO2002100833A1 (ja) * | 2001-06-12 | 2004-09-24 | 住友製薬株式会社 | Ｒｈｏキナーゼ阻害剤 |
| US7094789B2 (en) * | 2002-07-22 | 2006-08-22 | Asahi Kasei Pharma Corporation | 5-substituted isoquinoline derivatives |
| CA2496197A1 (en) * | 2002-08-20 | 2004-03-04 | Neurogen Corporation | 5-substituted-2-arylpyrazines as modulators of crf receptors |
| GB2400101A (en) * | 2003-03-28 | 2004-10-06 | Biofocus Discovery Ltd | Compounds capable of binding to the active site of protein kinases |
| EP1678160A1 (en) * | 2003-10-27 | 2006-07-12 | Astellas Pharma Inc. | Pyrazine derivatives and pharmaceutical use thereof |
| WO2005058876A1 (en) * | 2003-12-16 | 2005-06-30 | Gpc Biotech Ag | Pyrazine derivatives as effective compounds against infectious diseases |
| WO2005095384A1 (en) * | 2004-04-01 | 2005-10-13 | Astellas Pharma Inc. | Pyrazine derivatives and pharmaceutical use thereof as adenosine antagonists |
-
2005
- 2005-12-14 CA CA2590261A patent/CA2590261C/en not_active Expired - Fee Related
- 2005-12-14 EP EP05854156A patent/EP1830853B1/en not_active Expired - Lifetime
- 2005-12-14 MX MX2007007797A patent/MX2007007797A/es active IP Right Grant
- 2005-12-14 PL PL383491A patent/PL383491A1/pl not_active Application Discontinuation
- 2005-12-14 ZA ZA200704959A patent/ZA200704959B/xx unknown
- 2005-12-14 CN CN200580046786XA patent/CN101102773B/zh not_active Expired - Fee Related
- 2005-12-14 ES ES05854156T patent/ES2368338T3/es not_active Expired - Lifetime
- 2005-12-14 WO PCT/US2005/045384 patent/WO2006071548A2/en not_active Ceased
- 2005-12-14 AT AT05854156T patent/ATE519488T1/de not_active IP Right Cessation
- 2005-12-14 US US11/302,825 patent/US20080269249A2/en not_active Abandoned
- 2005-12-14 AU AU2005322338A patent/AU2005322338B2/en not_active Ceased
- 2005-12-14 KR KR1020077017035A patent/KR100994173B1/ko not_active Expired - Fee Related
- 2005-12-14 JP JP2007548311A patent/JP2008525453A/ja active Pending
- 2005-12-14 BR BRPI0519508-0A patent/BRPI0519508A2/pt not_active IP Right Cessation
- 2005-12-23 TW TW094146211A patent/TW200633709A/zh unknown
- 2005-12-26 AR ARP050105535A patent/AR053110A1/es not_active Application Discontinuation
-
2010
- 2010-05-05 US US12/774,399 patent/US20100216777A1/en not_active Abandoned
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003045924A1 (en) * | 2001-11-21 | 2003-06-05 | Pharmacia & Upjohn Company | Substituted aryl 1,4-pyrazine derivatives |
| WO2003051870A1 (en) * | 2001-12-18 | 2003-06-26 | Astrazeneca Ab | Novel compounds |
| WO2004018473A2 (en) * | 2002-08-23 | 2004-03-04 | Institute Of Experimental Botany Ascr | Azapurine derivatives |
| WO2004084824A2 (en) * | 2003-03-24 | 2004-10-07 | Merck & Co., Inc. | Biaryl substituted 6-membered heterocyles as sodium channel blockers |
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009179644A (ja) * | 2005-05-20 | 2009-08-13 | Vertex Pharmaceut Inc | プロテインキナーゼ阻害剤として有用なピロロピリジン化合物 |
| JP2008545660A (ja) * | 2005-05-20 | 2008-12-18 | バーテックス ファーマシューティカルズ インコーポレイテッド | プロテインキナーゼ阻害剤として有用なピロロピリジン化合物 |
| US9701674B2 (en) | 2008-12-19 | 2017-07-11 | Vertex Pharmaceuticals Incorporated | Substituted pyrazines as ATR kinase inhibitors |
| US10479784B2 (en) | 2008-12-19 | 2019-11-19 | Vertex Pharmaceuticals Incorporated | Substituted pyrazin-2-amines as inhibitors of ATR kinase |
| US9365557B2 (en) | 2008-12-19 | 2016-06-14 | Vertex Pharmaceuticals Incorporated | Substituted pyrazin-2-amines as inhibitors of ATR kinase |
| US10961232B2 (en) | 2008-12-19 | 2021-03-30 | Vertex Pharmaceuticals Incorporated | Substituted pyrazines as ATR kinase inhibitors |
| JP2013509424A (ja) * | 2009-10-30 | 2013-03-14 | ヤンセン ファーマシューティカ エヌ．ベー． | デルタオピオイド受容体調節因子としてのピラジン |
| US9630956B2 (en) | 2010-05-12 | 2017-04-25 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of ATR kinase |
| US9334244B2 (en) | 2010-05-12 | 2016-05-10 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of ATR kinase |
| JP2013529200A (ja) * | 2010-05-12 | 2013-07-18 | バーテックス ファーマシューティカルズ インコーポレイテッド | Ａｔｒキナーゼ阻害剤として有用な化合物 |
| US10822331B2 (en) | 2011-09-30 | 2020-11-03 | Vertex Pharmaceuticals Incorporated | Processes for preparing ATR inhibitors |
| US9862709B2 (en) | 2011-09-30 | 2018-01-09 | Vertex Pharmaceuticals Incorporated | Processes for making compounds useful as inhibitors of ATR kinase |
| US10208027B2 (en) | 2011-09-30 | 2019-02-19 | Vertex Pharmaceuticals Incorporated | Processes for preparing ATR inhibitors |
| US10813929B2 (en) | 2011-09-30 | 2020-10-27 | Vertex Pharmaceuticals Incorporated | Treating cancer with ATR inhibitors |
| US10478430B2 (en) | 2012-04-05 | 2019-11-19 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of ATR kinase and combination therapies thereof |
| US11110086B2 (en) | 2012-04-05 | 2021-09-07 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of ATR kinase and combination therapies thereof |
| US9791456B2 (en) | 2012-10-04 | 2017-10-17 | Vertex Pharmaceuticals Incorporated | Method for measuring ATR inhibition mediated increases in DNA damage |
| US11464774B2 (en) | 2015-09-30 | 2022-10-11 | Vertex Pharmaceuticals Incorporated | Method for treating cancer using a combination of DNA damaging agents and ATR inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| US20100216777A1 (en) | 2010-08-26 |
| WO2006071548A3 (en) | 2006-09-08 |
| CN101102773A (zh) | 2008-01-09 |
| ZA200704959B (en) | 2009-04-29 |
| EP1830853B1 (en) | 2011-08-10 |
| PL383491A1 (pl) | 2008-03-17 |
| AU2005322338B2 (en) | 2011-06-09 |
| CA2590261A1 (en) | 2006-07-06 |
| US20080269249A2 (en) | 2008-10-30 |
| BRPI0519508A2 (pt) | 2009-03-17 |
| US20060142307A1 (en) | 2006-06-29 |
| WO2006071548A2 (en) | 2006-07-06 |
| CA2590261C (en) | 2011-08-16 |
| KR100994173B1 (ko) | 2010-11-15 |
| HK1104222A1 (en) | 2008-01-11 |
| KR20070100952A (ko) | 2007-10-15 |
| AU2005322338A1 (en) | 2006-07-06 |
| ES2368338T3 (es) | 2011-11-16 |
| EP1830853A2 (en) | 2007-09-12 |
| MX2007007797A (es) | 2007-08-23 |
| TW200633709A (en) | 2006-10-01 |
| AR053110A1 (es) | 2007-04-25 |
| CN101102773B (zh) | 2010-10-27 |
| ATE519488T1 (de) | 2011-08-15 |
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