JP5993875B2 - 縮合アミノジヒドロチアジン誘導体の合成に有用な方法および化合物 - Google Patents
縮合アミノジヒドロチアジン誘導体の合成に有用な方法および化合物 Download PDFInfo
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- JP5993875B2 JP5993875B2 JP2013550622A JP2013550622A JP5993875B2 JP 5993875 B2 JP5993875 B2 JP 5993875B2 JP 2013550622 A JP2013550622 A JP 2013550622A JP 2013550622 A JP2013550622 A JP 2013550622A JP 5993875 B2 JP5993875 B2 JP 5993875B2
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/22—Nitrogen atoms not forming part of a nitro radical
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- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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- Hydrogenated Pyridines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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| MY148233A (en) | 2003-12-15 | 2013-03-29 | Merck Sharp & Dohme | Heterocyclic aspartyl protease inhibitors |
| WO2005097767A1 (en) | 2004-03-30 | 2005-10-20 | Merck & Co., Inc. | 2-aminothiazole compounds useful as aspartyl protease inhibitors |
| PE20060664A1 (es) | 2004-09-15 | 2006-08-04 | Novartis Ag | Amidas biciclicas como inhibidores de cinasa |
| JP2008516945A (ja) | 2004-10-15 | 2008-05-22 | アストラゼネカ・アクチエボラーグ | 置換されたアミノ化合物およびそれらの使用 |
| JP2008516946A (ja) | 2004-10-15 | 2008-05-22 | アストラゼネカ・アクチエボラーグ | 置換されたアミノ−ピリミドンおよびそれらの使用 |
| US8338614B2 (en) | 2005-01-19 | 2012-12-25 | Merck, Sharp & Dohme Corp. | Tertiary carbinamines having substituted heterocycles which are active as β-secretase inhibitors for the treatment of alzheimer's disease |
| RU2008100165A (ru) | 2005-06-14 | 2009-07-20 | Шеринг Корпорейшн (US) | Ингибиторы аспартильных протеаз |
| JP2009502786A (ja) | 2005-07-18 | 2009-01-29 | メルク エンド カムパニー インコーポレーテッド | アルツハイマー病を治療するためのスピロピペリジンβ−セクレターゼ阻害剤 |
| ES2476027T3 (es) | 2005-10-25 | 2014-07-11 | Shionogi & Co., Ltd. | Derivados de aminodihidrotriazina |
| US20090099217A1 (en) | 2006-04-05 | 2009-04-16 | Astex Therapeutics Ltd. | 2-Aminopyrimidin-4-Ones And Their Use For Treating Or Preventing Alpha Beta-Related Pathologies |
| AU2007268507B2 (en) | 2006-05-31 | 2012-01-19 | Daiichi Sankyo Company, Limited | Seven-membered ring compound, production method thereof and pharmaceutical use thereof |
| JP2010512389A (ja) | 2006-12-12 | 2010-04-22 | シェーリング コーポレイション | アスパルチルプロテアーゼ阻害剤 |
| WO2008133273A1 (ja) | 2007-04-24 | 2008-11-06 | Shionogi & Co., Ltd. | アルツハイマー症治療用医薬組成物 |
| KR20100017255A (ko) | 2007-04-24 | 2010-02-16 | 시오노기 앤드 컴파니, 리미티드 | 환식기로 치환된 아미노다이하이드로싸이아진 유도체 |
| ES2419239T3 (es) | 2007-05-29 | 2013-08-20 | Santen Pharmaceutical Co., Ltd | Nuevo derivado de 1,2,3,4-tetrahidroquinoxalina que tiene como sustituyente un grupo fenilo con una estructura de éster de ácido sulfónico o una estructura de amida de ácido sulfónico introducida en el mismo y que tienen una actividad de unión al receptor de glucocorticoides |
| PE20091236A1 (es) | 2007-11-22 | 2009-09-16 | Astrazeneca Ab | Derivados de pirimidina como immunomoduladores de tlr7 |
| HRP20151030T1 (hr) * | 2008-01-18 | 2015-11-06 | Eisai R&D Management Co., Ltd. | Kondenzirani derivat aminodihidrotiazina |
| TWI431004B (zh) | 2008-05-02 | 2014-03-21 | Lilly Co Eli | Ｂａｃｅ抑制劑 |
| WO2010013302A1 (ja) | 2008-07-28 | 2010-02-04 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | スピロアミノジヒドロチアジン誘導体 |
| AU2009277485B2 (en) | 2008-07-28 | 2013-05-02 | Eisai R&D Management Co., Ltd. | Spiroaminodihydrothiazine derivatives |
| WO2010038686A1 (ja) | 2008-09-30 | 2010-04-08 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 新規な縮合アミノジヒドロチアジン誘導体 |
| AR077277A1 (es) | 2009-07-09 | 2011-08-17 | Lilly Co Eli | Compuestos de biciclo (1,3)tiazin-2-amina formulacion farmaceutica que lo comprende y su uso para la manufactura de un medicamento util para el tratamiento de la enfermedad de alzheimer |
| GB0912777D0 (en) | 2009-07-22 | 2009-08-26 | Eisai London Res Lab Ltd | Fused aminodihydropyrimidone derivatives |
| GB0912778D0 (en) | 2009-07-22 | 2009-08-26 | Eisai London Res Lab Ltd | Fused aminodihydro-oxazine derivatives |
| JP2013530238A (ja) | 2010-07-01 | 2013-07-25 | アムジエン・インコーポレーテツド | Ｐｉ３ｋ活性の阻害剤としての複素環化合物及びその使用 |
| GB201101140D0 (en) | 2011-01-21 | 2011-03-09 | Eisai Ltd | Fused aminodihydrothiazine derivatives |
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- 2012-01-20 SG SG10201601516QA patent/SG10201601516QA/en unknown
- 2012-01-20 CN CN201610875412.9A patent/CN106632401B/zh not_active Expired - Fee Related
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- 2012-01-20 JP JP2013550622A patent/JP5993875B2/ja not_active Expired - Fee Related
- 2012-01-20 BR BR112013016241A patent/BR112013016241A2/pt not_active IP Right Cessation
- 2012-01-20 RU RU2013138226/04A patent/RU2013138226A/ru not_active Application Discontinuation
- 2012-01-20 ES ES12702690.4T patent/ES2624288T3/es active Active
- 2012-01-20 CN CN201280004193.7A patent/CN103502231A/zh active Pending
- 2012-01-20 SG SG2013027461A patent/SG191710A1/en unknown
- 2012-01-20 WO PCT/US2012/022053 patent/WO2012100179A1/en not_active Ceased
- 2012-01-20 CA CA2814014A patent/CA2814014A1/en not_active Abandoned
- 2012-01-20 EP EP12702690.4A patent/EP2665716B1/en active Active
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| Publication number | Publication date |
|---|---|
| MX2013005115A (es) | 2013-06-03 |
| ES2624288T3 (es) | 2017-07-13 |
| EP2665716B1 (en) | 2017-03-08 |
| CN106632401A (zh) | 2017-05-10 |
| US20120190848A1 (en) | 2012-07-26 |
| CA2814014A1 (en) | 2012-07-26 |
| JP6087005B2 (ja) | 2017-03-01 |
| CN103502231A (zh) | 2014-01-08 |
| WO2012100179A1 (en) | 2012-07-26 |
| IL226405A0 (en) | 2013-07-31 |
| EP2665716A1 (en) | 2013-11-27 |
| US8426584B2 (en) | 2013-04-23 |
| US8962858B2 (en) | 2015-02-24 |
| SG191710A1 (en) | 2013-08-30 |
| US20140309429A1 (en) | 2014-10-16 |
| JP2014503001A (ja) | 2014-02-06 |
| CN106632401B (zh) | 2020-12-29 |
| BR112013016241A2 (pt) | 2016-07-12 |
| US20130197244A1 (en) | 2013-08-01 |
| SG10201601516QA (en) | 2016-03-30 |
| RU2013138226A (ru) | 2015-02-27 |
| US8802871B2 (en) | 2014-08-12 |
| JP2016121177A (ja) | 2016-07-07 |
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