CN106029639B - 治疗阿尔茨海默病的bace1抑制剂的2-氨基-3，5，5-三氟-3，4，5，6-四氢吡啶 - Google Patents
治疗阿尔茨海默病的bace1抑制剂的2-氨基-3，5，5-三氟-3，4，5，6-四氢吡啶 Download PDFInfo
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Classifications
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- 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
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D227/00—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00
- C07D227/02—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00 with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D227/06—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00 with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D227/10—Nitrogen atoms not forming part of a nitro radical
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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
- C07D401/02—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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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| JO3458B1 (ar) | 2014-11-10 | 2020-07-05 | H Lundbeck As | 2- أمينو-6- (دايفلوروميثيل) – 5، 5- ديفلورو-6-فينيل-3،4، 5، 6-تيتراهيدروبيريدين كمثبطات bace1 |
| MA40941A (fr) | 2014-11-10 | 2017-09-19 | H Lundbeck As | 2-amino-5,5-difluoro-6-(fluorométhyl)-6-phényl-3,4,5,6-tétrahydropyridines comme inhibiteurs de bace1 |
| CR20170187A (es) * | 2014-11-10 | 2018-02-01 | H Lundbeck As | 2-Amino-3,5-difluoro-6-metil-6-fenil-3,4,5,6-tetrahidropiridinas en calidad de inhibidores de BACE1 para el tratamiento de la enfermedad de Alzheimer |
| JO3627B1 (ar) | 2015-04-30 | 2020-08-27 | H Lundbeck As | إيميدازو بيرازينونات على هيئة مثبطات pde1 |
| TW201717948A (zh) | 2015-08-10 | 2017-06-01 | Ｈ 朗德貝克公司 | 包括給予２－胺基－３，５，５－三氟－３，４，５，６－四氫吡啶的聯合治療 |
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| EP3347486A4 (en) * | 2015-09-09 | 2019-06-19 | The Trustees of Columbia University in the City of New York | REDUCTION OF ER-MAM-LOCALIZED APP-C99 AND METHOD FOR THE TREATMENT OF ALZHEIMER DISEASE |
| TW201726651A (zh) * | 2015-09-23 | 2017-08-01 | 健生藥品公司 | ２，３，４，５－四氫吡啶－６－胺衍生物 |
| US10034861B2 (en) | 2016-07-04 | 2018-07-31 | H. Lundbeck A/S | 1H-pyrazolo[4,3-b]pyridines as PDE1 inhibitors |
| JP2020500841A (ja) | 2016-10-28 | 2020-01-16 | ハー・ルンドベック・アクチエゼルスカベット | イミダゾピラジノンの投与を含む併用療法 |
| EP3532064B1 (en) | 2016-10-28 | 2020-07-29 | H. Lundbeck A/S | Combination treatments comprising imidazopyrazinones for the treatment of psychiatric and/or cognitive disorders |
| TW201829394A (zh) | 2016-12-21 | 2018-08-16 | 丹麥商Ｈ 朗德貝克公司 | 作為ｂａｃｅ１抑制劑之６-胺基-５-氟-５-（氟甲基）-２，３，４，５-四氫吡啶-２-基-苯基-５-（甲氧基-ｄ）-吡-２-甲醯胺及其氟化衍生物 |
| CN111601593B (zh) | 2017-10-05 | 2022-04-15 | 弗尔康医疗公司 | P38激酶抑制剂降低dux4和下游基因表达以用于治疗fshd |
| US10342786B2 (en) | 2017-10-05 | 2019-07-09 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD |
| AR113926A1 (es) | 2017-12-14 | 2020-07-01 | H Lundbeck As | Derivados de 1h-pirazolo[4,3-b]piridinas |
| CN111465410B (zh) | 2017-12-14 | 2022-10-25 | H.隆德贝克有限公司 | 包括施用1h-吡唑并[4,3-b]吡啶的组合治疗 |
| EP3728250A1 (en) | 2017-12-20 | 2020-10-28 | H. Lundbeck A/S | PYRAZOLO[3,4-beta]PYRIDINES AND IMIDAZO[1,5-beta]PYRIDAZINES AS PDE1 INHIBITORS |
| KR102507861B1 (ko) | 2018-04-19 | 2023-03-09 | 삼성에스디에스 주식회사 | 부채널 공격에 안전한 연산 장치 및 방법 |
| KR102510077B1 (ko) | 2018-04-24 | 2023-03-14 | 삼성에스디에스 주식회사 | 부채널 공격에 안전한 연산 장치 및 방법 |
| US12042492B2 (en) | 2020-10-09 | 2024-07-23 | Texas Tech University System | BACE1 inhibitory ligand molecules against amyloid beta-induced synaptic and mitochondrial toxicities |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012147763A1 (ja) * | 2011-04-26 | 2012-11-01 | 塩野義製薬株式会社 | オキサジン誘導体およびそれを含有するｂａｃｅ１阻害剤 |
| WO2012168164A1 (en) * | 2011-06-07 | 2012-12-13 | F. Hoffmann-La Roche Ag | Halogen-alkyl-1,3 oxazines as bace1 and/or bace2 inhibitors |
| US8338413B1 (en) * | 2012-03-07 | 2012-12-25 | Novartis Ag | Oxazine derivatives and their use in the treatment of neurological disorders |
| CN102933564A (zh) * | 2010-06-09 | 2013-02-13 | 詹森药业有限公司 | 用作β-分泌酶(BACE)抑制剂的5，6-二氢-2H-[1，4]噁嗪-3-基-胺衍生物 |
| WO2013027188A1 (en) * | 2011-08-25 | 2013-02-28 | Novartis Ag | 2 -amino-4 - (pyridin- 2 -yl) - 5, 6 -dihydro-4h- 1, 3 -oxazine derivatives and their use as bace-1 and/or bace - 2 inhibitors |
| CN103261199A (zh) * | 2010-10-29 | 2013-08-21 | 盐野义制药株式会社 | 萘啶衍生物 |
| CN103403001A (zh) * | 2011-01-13 | 2013-11-20 | 诺瓦提斯公司 | 新的杂环衍生物及其在神经性疾病治疗中的应用 |
| CN103429589A (zh) * | 2011-01-12 | 2013-12-04 | 诺瓦提斯公司 | 噁嗪衍生物及其在治疗神经障碍中的用途 |
| CN103502227A (zh) * | 2011-04-11 | 2014-01-08 | 霍夫曼-拉罗奇有限公司 | 作为bace1和／或bace2抑制剂的1,3噁嗪类 |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1395257A1 (en) * | 2001-06-12 | 2004-03-10 | Elan Pharmaceuticals, Inc. | Macrocycles useful in the treatment of alzheimer's disease |
| GB0124928D0 (en) * | 2001-10-17 | 2001-12-05 | Glaxo Group Ltd | Chemical compounds |
| WO2003068747A1 (en) * | 2002-02-12 | 2003-08-21 | Smithkline Beecham Corporation | Nicotinamide derivates useful as p38 inhibitors |
| TWI431004B (zh) * | 2008-05-02 | 2014-03-21 | Lilly Co Eli | Ｂａｃｅ抑制劑 |
| US9493485B2 (en) | 2012-03-20 | 2016-11-15 | Imago Pharmaceuticals, Inc. | Spirocyclic dihydro-thiazine and dihydro-oxazine BACE inhibitors, and compositions and uses thereof |
| WO2014056816A1 (en) | 2012-10-10 | 2014-04-17 | F. Hoffmann-La Roche Ag | COMBINATION OF AN Aβ ANTIBODY AND A BACE INHIBITOR |
| US9540359B2 (en) | 2012-10-24 | 2017-01-10 | Shionogi & Co., Ltd. | Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity |
| TW201446758A (zh) | 2013-03-01 | 2014-12-16 | Amgen Inc | 作爲β－分泌酶抑制劑的全氟化５，６－二氫－４Ｈ－１，３－□－２－胺化合物及其用途 |
| PE20161225A1 (es) | 2014-02-19 | 2016-12-04 | H Lundbeck As | 2-amino-3,5,5-trifluoro-3,4,5,6-tetrahidropiridinas como inhibidores de bace1 para el tratamiento de la enfermedad de alzheimer |
| TW201623295A (zh) | 2014-04-11 | 2016-07-01 | 塩野義製藥股份有限公司 | 具有ｂａｃｅ１抑制活性之二氫噻及二氫衍生物 |
-
2015
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- 2015-02-17 GE GEAP201514248A patent/GEP20186892B/en unknown
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- 2015-02-17 TW TW104105281A patent/TW201609700A/zh unknown
- 2015-02-17 UA UAA201608414A patent/UA117695C2/uk unknown
- 2015-02-17 MX MX2016010777A patent/MX2016010777A/es unknown
- 2015-02-17 SG SG11201606812WA patent/SG11201606812WA/en unknown
- 2015-02-17 CR CR20160352A patent/CR20160352A/es unknown
- 2015-02-17 EP EP15707304.0A patent/EP3107897A1/en not_active Withdrawn
- 2015-02-17 EA EA201691447A patent/EA031132B1/ru not_active IP Right Cessation
- 2015-02-17 US US15/119,639 patent/US20170066741A1/en not_active Abandoned
- 2015-02-17 CN CN201580009034.XA patent/CN106029639B/zh not_active Expired - Fee Related
- 2015-02-17 WO PCT/EP2015/053327 patent/WO2015124576A1/en not_active Ceased
- 2015-02-17 AU AU2015220873A patent/AU2015220873A1/en not_active Abandoned
- 2015-02-17 RU RU2016133626A patent/RU2016133626A/ru not_active Application Discontinuation
- 2015-02-17 KR KR1020167021930A patent/KR20160115936A/ko not_active Withdrawn
- 2015-02-17 MA MA39225A patent/MA39225A1/fr unknown
- 2015-02-17 AP AP2016009370A patent/AP2016009370A0/en unknown
- 2015-02-18 AR ARP150100475A patent/AR099489A1/es unknown
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- 2016-07-21 IL IL246875A patent/IL246875A0/en unknown
- 2016-07-28 DO DO2016000194A patent/DOP2016000194A/es unknown
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- 2016-08-17 CL CL2016002072A patent/CL2016002072A1/es unknown
- 2016-09-09 EC ECIEPI201672941A patent/ECSP16072941A/es unknown
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102933564A (zh) * | 2010-06-09 | 2013-02-13 | 詹森药业有限公司 | 用作β-分泌酶(BACE)抑制剂的5，6-二氢-2H-[1，4]噁嗪-3-基-胺衍生物 |
| CN103261199A (zh) * | 2010-10-29 | 2013-08-21 | 盐野义制药株式会社 | 萘啶衍生物 |
| CN103429589A (zh) * | 2011-01-12 | 2013-12-04 | 诺瓦提斯公司 | 噁嗪衍生物及其在治疗神经障碍中的用途 |
| CN103403001A (zh) * | 2011-01-13 | 2013-11-20 | 诺瓦提斯公司 | 新的杂环衍生物及其在神经性疾病治疗中的应用 |
| CN103502227A (zh) * | 2011-04-11 | 2014-01-08 | 霍夫曼-拉罗奇有限公司 | 作为bace1和／或bace2抑制剂的1,3噁嗪类 |
| WO2012147763A1 (ja) * | 2011-04-26 | 2012-11-01 | 塩野義製薬株式会社 | オキサジン誘導体およびそれを含有するｂａｃｅ１阻害剤 |
| WO2012168164A1 (en) * | 2011-06-07 | 2012-12-13 | F. Hoffmann-La Roche Ag | Halogen-alkyl-1,3 oxazines as bace1 and/or bace2 inhibitors |
| WO2013027188A1 (en) * | 2011-08-25 | 2013-02-28 | Novartis Ag | 2 -amino-4 - (pyridin- 2 -yl) - 5, 6 -dihydro-4h- 1, 3 -oxazine derivatives and their use as bace-1 and/or bace - 2 inhibitors |
| US8338413B1 (en) * | 2012-03-07 | 2012-12-25 | Novartis Ag | Oxazine derivatives and their use in the treatment of neurological disorders |
Non-Patent Citations (3)
| Title |
|---|
| BACE1 inhibitors: A head group scan on a series of amides;Thomas J. Woltering et al.;《Bioorganic & Medicinal Chemistry Letters》;20130518;第23卷;4239-4243 * |
| Small-molecule BACE1 inhibitors: a patent literature review(2006-2011);Gary Probst et al.;《Expert Opin. Ther. Patents》;20121231;第22卷(第5期);511-540 * |
| β-Secretase (BACE1) Inhibitors with High in Vivo Efficacy Suitable for Clinical Evaluation in Alzheimer′s Disease;Hans Hilpert et al.;《J. Med. Chem.》;20130416;第56卷;3980-3995 * |
Also Published As
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| UA117695C2 (uk) | 2018-09-10 |
| ECSP16072941A (es) | 2017-02-24 |
| DOP2016000194A (es) | 2016-09-30 |
| EA031132B1 (ru) | 2018-11-30 |
| AP2016009370A0 (en) | 2016-08-31 |
| SG11201606812WA (en) | 2016-09-29 |
| KR20160115936A (ko) | 2016-10-06 |
| AU2015220873A1 (en) | 2016-08-11 |
| MA39225A1 (fr) | 2017-04-28 |
| EA201691447A1 (ru) | 2016-12-30 |
| JP2017506237A (ja) | 2017-03-02 |
| AR099489A1 (es) | 2016-07-27 |
| PE20161225A1 (es) | 2016-12-04 |
| PH12016501600A1 (en) | 2017-02-06 |
| TW201609700A (zh) | 2016-03-16 |
| CN106029639A (zh) | 2016-10-12 |
| JP6483146B2 (ja) | 2019-03-13 |
| CA2940028A1 (en) | 2015-08-27 |
| IL246875A0 (en) | 2016-08-31 |
| CL2016002072A1 (es) | 2017-01-20 |
| EP3107897A1 (en) | 2016-12-28 |
| RU2016133626A (ru) | 2018-03-20 |
| GEP20186892B (en) | 2018-09-10 |
| US9353084B2 (en) | 2016-05-31 |
| CR20160352A (es) | 2016-10-20 |
| WO2015124576A1 (en) | 2015-08-27 |
| US20150232449A1 (en) | 2015-08-20 |
| US20170066741A1 (en) | 2017-03-09 |
| RU2016133626A3 (enExample) | 2018-09-25 |
| MX2016010777A (es) | 2016-10-26 |
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