JP5853035B2 - β−セクレターゼ（ＢＡＣＥ）の阻害剤として有用な３，４−ジヒドロ−ピロロ［１，２−ａ］ピラジン−１−イルアミン誘導体 - Google Patents
β−セクレターゼ（ＢＡＣＥ）の阻害剤として有用な３，４−ジヒドロ−ピロロ［１，２−ａ］ピラジン−１−イルアミン誘導体 Download PDFInfo
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- JP5853035B2 JP5853035B2 JP2013557074A JP2013557074A JP5853035B2 JP 5853035 B2 JP5853035 B2 JP 5853035B2 JP 2013557074 A JP2013557074 A JP 2013557074A JP 2013557074 A JP2013557074 A JP 2013557074A JP 5853035 B2 JP5853035 B2 JP 5853035B2
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- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
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- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
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| CN101346357B (zh) | 2005-10-25 | 2014-04-02 | 盐野义制药株式会社 | 氨基二氢噻嗪衍生物 |
| EP2689780A1 (en) | 2007-04-24 | 2014-01-29 | Shionogi & Co., Ltd. | Intermediates for aminodihydrothiazine derivatives substituted with a cyclic group |
| JP5383483B2 (ja) | 2007-04-24 | 2014-01-08 | 塩野義製薬株式会社 | アルツハイマー症治療用医薬組成物 |
| KR101324426B1 (ko) | 2008-06-13 | 2013-10-31 | 시오노기세야쿠 가부시키가이샤 | β 세크레타제 저해 작용을 갖는 황 함유 복소환 유도체 |
| CN102186841A (zh) | 2008-10-22 | 2011-09-14 | 盐野义制药株式会社 | 具有bace1抑制活性的2-氨基嘧啶-4-酮及2-氨基吡啶衍生物 |
| KR20120104570A (ko) | 2009-12-11 | 2012-09-21 | 시오노기세야쿠 가부시키가이샤 | 옥사진 유도체 |
| KR101730937B1 (ko) | 2010-06-09 | 2017-04-27 | 얀센 파마슈티카 엔.브이. | 베타-세크레타아제(ｂａｃｅ) 저해제로 유용한 5,6-디하이드로-2ｈ-[1,4]옥사진-3-일-아민 유도체 |
| EP2634188A4 (en) | 2010-10-29 | 2014-05-07 | Shionogi & Co | FUSIONED AMINODIHYDROPYRIMIDINE DERIVATIVE |
| CN103261199A (zh) | 2010-10-29 | 2013-08-21 | 盐野义制药株式会社 | 萘啶衍生物 |
| BR112013015430A2 (pt) | 2010-12-22 | 2016-09-20 | Janssen Pharmaceutica Nv | derivados de 5,6-diidro-imidazo[1,2-a]pirazin-8-ilamina úteis como inibidores de beta-secretase (bace) |
| CN103415519B (zh) | 2011-03-01 | 2016-03-02 | 詹森药业有限公司 | 作为β-分泌酶(BACE)抑制剂有用的6，7-二氢-吡唑[1，5-a]吡嗪-4-基胺衍生物 |
| PH12013501805A1 (en) | 2011-03-09 | 2013-11-18 | Janssen Pharmaceutica Nv | 3,4-DIHYDRO-PYRROLO[1,2-a]PYRAZIN-1-YLAMINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE (BACE) |
| CN103608345A (zh) | 2011-04-26 | 2014-02-26 | 盐野义制药株式会社 | 噁嗪衍生物和含有该噁嗪衍生物的bace1抑制剂 |
| WO2014065434A1 (en) | 2012-10-24 | 2014-05-01 | Shionogi & Co., Ltd. | Dihydrooxazine or oxazepine derivatives having bace1 inhibitory activity |
| WO2014198851A1 (en) * | 2013-06-12 | 2014-12-18 | Janssen Pharmaceutica Nv | 4-amino-6-phenyl-5,6-dihydroimidazo[1,5-a]pyrazin-3(2h)-one derivatives as inhibitors of beta-secretase (bace) |
| CN105283457B (zh) * | 2013-06-12 | 2018-09-18 | 詹森药业有限公司 | 作为β-分泌酶(BACE)抑制剂的4-氨基-6-苯基-5,6-二氢咪唑并[1,5-A]吡嗪衍生物 |
| US9751886B2 (en) | 2013-06-12 | 2017-09-05 | Janssen Pharmaceutica Nv | 4-amino-6-phenyl-6,7-dihydro[1,2,3]triazolo[1,5-A]pyrazine derivatives as inhibitors of beta-secretase (BACE) |
| RU2572076C2 (ru) * | 2014-03-26 | 2015-12-27 | Федеральное государственное бюджетное научное учреждение "Научно-исследовательский институт фармакологии имени В.В. Закусова" | 1-арилпирроло[1,2-a]пиразин-3-карбоксамиды с нейропсихотропной активностью |
| ES2768823T3 (es) | 2014-12-18 | 2020-06-23 | Janssen Pharmaceutica Nv | Derivados de 2,3,4,5-tetrahidropiridin-6-amina y 3,4-dihidro-2H-pirrol-5-amina útiles como inhibidores de beta-secretasa |
| WO2018165520A1 (en) | 2017-03-10 | 2018-09-13 | Vps-3, Inc. | Metalloenzyme inhibitor compounds |
| CN114727974A (zh) | 2019-07-30 | 2022-07-08 | 艾科尼佐治疗股份有限公司 | Hdac6抑制剂及其用途 |
| CN117471007B (zh) * | 2023-10-31 | 2024-08-09 | 广东省中医院（广州中医药大学第二附属医院、广州中医药大学第二临床医学院、广东省中医药科学院） | 一种血浆β-淀粉样蛋白检测方法 |
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| US4188389A (en) | 1978-11-03 | 1980-02-12 | Ayerst Mckenna & Harrison, Inc. | 1,2,3,4-Tetrahydropyrrolo(1,2-A)pyrazines |
| TW224974B (enExample) | 1991-07-02 | 1994-06-11 | Hoffmann La Roche | |
| CA2293408A1 (en) | 1997-06-18 | 1998-12-23 | Merck & Co., Inc. | Alpha 1a adrenergic receptor antagonists |
| JP2005530739A (ja) | 2002-04-19 | 2005-10-13 | セルラー ジェノミクス，インコーポレーテッド | イミダゾ［１，２−ａ］ピラジン−８−イルアミン、生成方法、および使用方法 |
| JP4799864B2 (ja) | 2002-09-23 | 2011-10-26 | シェーリング コーポレイション | サイクリン依存性キナーゼインヒビターとしてのイミダゾピラジン |
| WO2004058176A2 (en) | 2002-12-20 | 2004-07-15 | Pharmacia Corporation | Acyclic pyrazole compounds |
| PT1678172E (pt) | 2003-10-15 | 2010-03-03 | Targacept Inc | Composições farmacêuticas e métodos para alívio da dor e tratamento de perturbações do sistema nervoso central |
| EP1740573A1 (en) | 2004-04-22 | 2007-01-10 | Eli Lilly And Company | Amides as bace inhibitors |
| ATE444962T1 (de) | 2004-06-16 | 2009-10-15 | Wyeth Corp | Amino-5,5-diphenylimidazolon-derivate zur beta- sekretase-hemmung |
| SV2006002232A (es) | 2004-09-21 | 2006-05-25 | Lilly Co Eli | Inhibidores bace ref. x-16940 |
| EP2264036A1 (en) * | 2005-01-14 | 2010-12-22 | Wyeth LLC (Formerly Known As Wyeth) | Amino-imidazolones for the inhibition of beta-secretase |
| CN2781924Y (zh) | 2005-01-21 | 2006-05-24 | 厦门革新塑胶制品有限公司 | 折叠床中部支脚 |
| US20070005404A1 (en) | 2005-06-09 | 2007-01-04 | Drive Diagnostics Ltd. | System and method for providing driving insurance |
| EP1896032B1 (en) | 2005-06-14 | 2012-10-31 | Merck Sharp & Dohme Corp. | The preparation and use of compounds as protease inhibitors |
| JP2009500329A (ja) | 2005-06-30 | 2009-01-08 | ワイス | アミノ−５−（６員）ヘテロアリールイミダゾロン化合物およびβ−セレクターゼ調節のためのその使用 |
| CN101346357B (zh) | 2005-10-25 | 2014-04-02 | 盐野义制药株式会社 | 氨基二氢噻嗪衍生物 |
| TW200804290A (en) | 2005-11-15 | 2008-01-16 | Astrazeneca Ab | Compounds and uses thereof |
| CN101460480A (zh) | 2006-04-05 | 2009-06-17 | 阿斯利康(瑞典)有限公司 | 2-氨基嘧啶-4-酮类化合物及其用于治疗或预防Aβ相关病理的用途 |
| GB2443654A (en) | 2006-05-30 | 2008-05-14 | Matthew Emmerson Allen | System for detecting and testing drivers who show abnormal driving behaviour. |
| US20080051420A1 (en) | 2006-06-14 | 2008-02-28 | Astrazeneca Ab | New Compounds 317 |
| EP2689780A1 (en) | 2007-04-24 | 2014-01-29 | Shionogi & Co., Ltd. | Intermediates for aminodihydrothiazine derivatives substituted with a cyclic group |
| TW200902499A (en) * | 2007-05-15 | 2009-01-16 | Astrazeneca Ab | New compounds |
| AU2008319310A1 (en) | 2007-10-30 | 2009-05-07 | Arena Pharmaceuticals, Inc. | Biphenyl derivatives as modulators of the histamine-H3 receptor useful for the treatment of disorders related thereto |
| CA2713998A1 (en) | 2008-01-28 | 2009-08-06 | Janssen Pharmaceutica N.V. | 6-substituted-thio-2-amino-quinoline derivatives useful as inhibitors of.beta.-secretase (bace) |
| EP2252617A1 (en) | 2008-02-13 | 2010-11-24 | CGI Pharmaceuticals, Inc. | 6-aryl-imidaz0[l, 2-a]pyrazine derivatives, method of making, and method of use thereof |
| TWI431004B (zh) | 2008-05-02 | 2014-03-21 | Lilly Co Eli | Ｂａｃｅ抑制劑 |
| WO2011002409A1 (en) | 2009-07-02 | 2011-01-06 | Astrazeneca Ab | 5h-pyrrolo[3,4-£>]pyrazin-7-amine derivatives inhibitors of beta-secretase |
| 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 |
| UY32799A (es) | 2009-07-24 | 2011-02-28 | Novartis Ag | Derivados de oxazina y su uso en el tratamiento de trastornos neurológicos |
| US8188079B2 (en) | 2009-08-19 | 2012-05-29 | Hoffman-La Roche Inc. | 3-amino-5-phenyl-5,6-dihydro-2H-[1,4]oxazines |
| CN102686584A (zh) | 2009-11-13 | 2012-09-19 | 盐野义制药株式会社 | 具有氨基连接基的氨基噻嗪或氨基噁嗪衍生物 |
| UA103272C2 (uk) | 2009-12-11 | 2013-09-25 | Ф. Хоффманн-Ля Рош Аг | 2-аміно-5,5-дифтор-5,6-дигідро-4h-оксазини як інгібітори bace1 і/або bace2 |
| KR20120104570A (ko) | 2009-12-11 | 2012-09-21 | 시오노기세야쿠 가부시키가이샤 | 옥사진 유도체 |
| EP2518059A4 (en) | 2009-12-24 | 2013-05-29 | Shionogi & Co | 4-AMINO-1,3-THIAZINE OR OXAZINE DERIVATIVE |
| US20120277244A1 (en) | 2009-12-31 | 2012-11-01 | Novartis Ag | Pyrazine derivatives and their use in the treatment of neurological disorders |
| KR101730937B1 (ko) | 2010-06-09 | 2017-04-27 | 얀센 파마슈티카 엔.브이. | 베타-세크레타아제(ｂａｃｅ) 저해제로 유용한 5,6-디하이드로-2ｈ-[1,4]옥사진-3-일-아민 유도체 |
| ES2459593T3 (es) | 2010-06-09 | 2014-05-09 | Janssen Pharmaceutica, N.V. | Derivados de 5-amino-3,6-dihidro-1H-pirazin-2-ona útiles como inhibidores de beta-secretasa (BACE) |
| EA201291413A1 (ru) | 2010-06-28 | 2013-05-30 | Янссен Фармацевтика Нв | Производные 3-амино-5,6-дигидро-1h-пиразин-2-она, применимые для лечения болезни альцгеймера и других форм деменции |
| NZ606848A (en) | 2010-09-22 | 2015-01-30 | Janssen Pharmaceutica Nv | 4,7-dihydro-pyrazolo[1,5-a]pyrazin-6-ylamine derivatives useful as inhibitors of beta-secretase (bace) |
| EP2634188A4 (en) | 2010-10-29 | 2014-05-07 | Shionogi & Co | FUSIONED AMINODIHYDROPYRIMIDINE DERIVATIVE |
| BR112013015430A2 (pt) | 2010-12-22 | 2016-09-20 | Janssen Pharmaceutica Nv | derivados de 5,6-diidro-imidazo[1,2-a]pirazin-8-ilamina úteis como inibidores de beta-secretase (bace) |
| KR20140051822A (ko) | 2011-01-12 | 2014-05-02 | 노파르티스 아게 | 옥사진 유도체 및 신경계 장애의 치료에서의 그의 용도 |
| JP2012147763A (ja) | 2011-01-17 | 2012-08-09 | Toshitaka Kobayashi | 乾物穿孔具 |
| US9242943B2 (en) | 2011-01-18 | 2016-01-26 | Siena Biotech S.P.A. | 1,4 oxazines as BACE1 and/or BACE2 inhibitors |
| CN103415519B (zh) | 2011-03-01 | 2016-03-02 | 詹森药业有限公司 | 作为β-分泌酶(BACE)抑制剂有用的6，7-二氢-吡唑[1，5-a]吡嗪-4-基胺衍生物 |
| PH12013501805A1 (en) * | 2011-03-09 | 2013-11-18 | Janssen Pharmaceutica Nv | 3,4-DIHYDRO-PYRROLO[1,2-a]PYRAZIN-1-YLAMINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE (BACE) |
| CN103608345A (zh) | 2011-04-26 | 2014-02-26 | 盐野义制药株式会社 | 噁嗪衍生物和含有该噁嗪衍生物的bace1抑制剂 |
| EP2766358B1 (en) | 2011-10-13 | 2016-06-22 | Novartis AG | Novel oxazine derivatives and their use in the treatment of disease |
| UA111749C2 (uk) | 2011-12-05 | 2016-06-10 | Янссен Фармацевтика Нв | Похідні 6-дифторметил-5,6-дигідро-2h-[1,4]оксазин-3-аміну |
| CA2853891C (en) | 2011-12-06 | 2020-03-10 | Janssen Pharmaceutica Nv | 5-(3-aminophenyl)-5-alkyl-5,6-dihydro-2h-[1,4]oxazin-3-amine derivatives |
| AU2013363151A1 (en) | 2012-12-20 | 2015-06-04 | Merck Sharp & Dohme Corp. | C5, C6 oxacyclic-fused iminothiazine dioxide compounds as BACE inhibitors |
| CN105283457B (zh) | 2013-06-12 | 2018-09-18 | 詹森药业有限公司 | 作为β-分泌酶(BACE)抑制剂的4-氨基-6-苯基-5,6-二氢咪唑并[1,5-A]吡嗪衍生物 |
| WO2014198851A1 (en) | 2013-06-12 | 2014-12-18 | Janssen Pharmaceutica Nv | 4-amino-6-phenyl-5,6-dihydroimidazo[1,5-a]pyrazin-3(2h)-one derivatives as inhibitors of beta-secretase (bace) |
| US9751886B2 (en) | 2013-06-12 | 2017-09-05 | Janssen Pharmaceutica Nv | 4-amino-6-phenyl-6,7-dihydro[1,2,3]triazolo[1,5-A]pyrazine derivatives as inhibitors of beta-secretase (BACE) |
| ES2768823T3 (es) | 2014-12-18 | 2020-06-23 | Janssen Pharmaceutica Nv | Derivados de 2,3,4,5-tetrahidropiridin-6-amina y 3,4-dihidro-2H-pirrol-5-amina útiles como inhibidores de beta-secretasa |
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| Publication number | Publication date |
|---|---|
| HK1189223A1 (zh) | 2014-05-30 |
| KR102012675B1 (ko) | 2019-08-21 |
| EA201391296A1 (ru) | 2014-01-30 |
| PH12013501805A1 (en) | 2013-11-18 |
| IL228239A (en) | 2016-06-30 |
| CA2825620A1 (en) | 2012-09-13 |
| ES2534973T3 (es) | 2015-04-30 |
| AU2012224632A1 (en) | 2013-08-01 |
| BR112013022917A2 (pt) | 2016-12-06 |
| US9845326B2 (en) | 2017-12-19 |
| CN103415521B (zh) | 2016-01-06 |
| KR20140019332A (ko) | 2014-02-14 |
| US20130345228A1 (en) | 2013-12-26 |
| SG193342A1 (en) | 2013-10-30 |
| UA109687C2 (xx) | 2015-09-25 |
| NZ615720A (en) | 2014-08-29 |
| MY163346A (en) | 2017-09-15 |
| WO2012120023A1 (en) | 2012-09-13 |
| MX2013010280A (es) | 2013-10-01 |
| AU2012224632B2 (en) | 2016-06-16 |
| CL2013002511A1 (es) | 2014-01-24 |
| MX340031B (es) | 2016-06-21 |
| CO6751283A2 (es) | 2013-09-16 |
| JP2014507455A (ja) | 2014-03-27 |
| ZA201306719B (en) | 2015-04-29 |
| EP2683721B1 (en) | 2015-01-28 |
| EP2683721A1 (en) | 2014-01-15 |
| CA2825620C (en) | 2019-04-23 |
| CN103415521A (zh) | 2013-11-27 |
| EA023824B1 (ru) | 2016-07-29 |
| IL228239A0 (en) | 2013-11-25 |
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