JP6843114B2 - ムスカリン作動薬 - Google Patents
ムスカリン作動薬 Download PDFInfo
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- JP6843114B2 JP6843114B2 JP2018504992A JP2018504992A JP6843114B2 JP 6843114 B2 JP6843114 B2 JP 6843114B2 JP 2018504992 A JP2018504992 A JP 2018504992A JP 2018504992 A JP2018504992 A JP 2018504992A JP 6843114 B2 JP6843114 B2 JP 6843114B2
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- 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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- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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| GB1513743.3 | 2015-08-03 | ||
| PCT/GB2016/052385 WO2017021729A1 (en) | 2015-08-03 | 2016-08-03 | Muscarinic agonists |
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| GB201513740D0 (en) | 2015-08-03 | 2015-09-16 | Heptares Therapeutics Ltd | Muscarinic agonist |
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| AU2018352828A1 (en) | 2017-10-17 | 2020-04-23 | Vanderbilt University | Antagonists of the muscarinic acetylcholine receptor M4 |
| AR115015A1 (es) * | 2018-03-23 | 2020-11-18 | Pfizer | Derivados de azaespiro piperazina |
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| US4369184A (en) | 1980-01-24 | 1983-01-18 | Janssen Pharmaceutica N.V. | 1-(Cyclohexyl)-4-aryl-4-piperidinecarboxylic acid derivatives |
| JPS56110674A (en) | 1980-01-24 | 1981-09-01 | Janssen Pharmaceutica Nv | Novel 11*cyclohexyl**44aryll44piperidine carboxylic acid derivative |
| US5852029A (en) | 1990-04-10 | 1998-12-22 | Israel Institute For Biological Research | Aza spiro compounds acting on the cholinergic system with muscarinic agonist activity |
| GB9300194D0 (en) | 1993-01-06 | 1993-03-03 | Wyeth John & Brother Ltd | Piperazine derivatives |
| US5446051A (en) | 1994-05-31 | 1995-08-29 | Eli Lilly And Company | Aryl-spaced decahydroisoquinoline-3-carboxylic acids as excitatory amino acid receptor antagonists |
| EP0786997A4 (en) | 1994-10-27 | 1998-03-11 | Merck & Co Inc | MUSCARINE ANTAGONISTS |
| US5889006A (en) | 1995-02-23 | 1999-03-30 | Schering Corporation | Muscarinic antagonists |
| IL117149A0 (en) | 1995-02-23 | 1996-06-18 | Schering Corp | Muscarinic antagonists |
| WO1997016187A1 (en) | 1995-10-31 | 1997-05-09 | Merck & Co., Inc. | Muscarine antagonists |
| US5854245A (en) | 1996-06-28 | 1998-12-29 | Merck & Co., Inc. | Fibrinogen receptor antagonists |
| US6664258B1 (en) | 1996-08-26 | 2003-12-16 | Pfizer Inc | Spirocyclic dopamine receptor subtype ligands |
| CA2293408A1 (en) | 1997-06-18 | 1998-12-23 | Merck & Co., Inc. | Alpha 1a adrenergic receptor antagonists |
| GB9715892D0 (en) | 1997-07-29 | 1997-10-01 | Zeneca Ltd | Heterocyclic compounds |
| AU2307899A (en) | 1997-12-23 | 1999-07-12 | Alcon Laboratories, Inc. | Muscarinic agents and use thereof to treat glaucoma, myopia and various other conditions |
| WO1999032489A1 (en) | 1997-12-23 | 1999-07-01 | Alcon Laboratories, Inc. | Muscarinic agents and use thereof to treat glaucoma, myopia and various other conditions |
| AU2307999A (en) | 1997-12-23 | 1999-07-12 | Alcon Laboratories, Inc. | Muscarinic agents and use thereof to treat glaucoma, myopia and various other conditions |
| WO1999032479A1 (en) | 1997-12-23 | 1999-07-01 | Alcon Laboratories, Inc. | Phthalimide-piperidine, -pyrrolidine and -azepine derivatives, their preparation and their use as muscarinic receptor (ant-)agonists |
| CZ286152B6 (cs) | 1998-03-13 | 2000-01-12 | Miroslav Ing. Csc. Vlček | Transparentní a semitransparentní difrakční prvky |
| DE69922186T2 (de) | 1998-04-28 | 2005-05-04 | Dainippon Pharmaceutical Co., Ltd. | 1-(1-subst.-4-piperidinyl)methyl]-4-piperidin-derivate, verafhren zu deren herstellung, pharmazeutische mixturen und intermediate zu deren herstellung |
| US6387930B1 (en) | 1999-05-04 | 2002-05-14 | Schering Corporation | Piperidine derivatives useful as CCR5 antagonists |
| MXPA01011116A (es) | 1999-05-04 | 2002-06-04 | Schering Corp | Terapia de hiv de combinacion de antagonista ccr5 - interferon alfa pegilado. |
| KR100439357B1 (ko) | 1999-05-04 | 2004-07-07 | 쉐링 코포레이션 | Ｃｃｒ５ 길항제로서 유용한 피페리딘 유도체 |
| US6420364B1 (en) | 1999-09-13 | 2002-07-16 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compound useful as reversible inhibitors of cysteine proteases |
| ATE244235T1 (de) | 1999-09-13 | 2003-07-15 | Boehringer Ingelheim Pharma | Heterocyclische verbindungen als reversible inhibitoren von cysteinproteasen |
| US6921763B2 (en) | 1999-09-17 | 2005-07-26 | Abbott Laboratories | Pyrazolopyrimidines as therapeutic agents |
| DE60013464T2 (de) | 1999-10-13 | 2005-09-15 | Banyu Pharmaceutical Co., Ltd. | Substituierte imidazolin-derivate |
| US7163938B2 (en) | 2000-11-28 | 2007-01-16 | Eli Lilly And Company | Substituted carboxamides |
| US7164024B2 (en) | 2001-04-20 | 2007-01-16 | Banyu Pharmaceutical Co., Ltd. | Benzimidazolone derivatives |
| CA2450167A1 (en) | 2001-06-12 | 2002-12-19 | Elan Pharmaceuticals, Inc. | Macrocycles useful in the treatment of alzheimer's disease |
| WO2004089942A2 (en) | 2001-10-02 | 2004-10-21 | Acadia Pharmaceuticals Inc. | Benzimidazolidinone derivatives as muscarinic agents |
| GB0128378D0 (en) | 2001-11-27 | 2002-01-16 | Smithkline Beecham Plc | Novel Compounds |
| US7550459B2 (en) | 2001-12-28 | 2009-06-23 | Acadia Pharmaceuticals, Inc. | Tetrahydroquinoline analogues as muscarinic agonists |
| WO2003057672A2 (en) | 2001-12-28 | 2003-07-17 | Acadia Pharmaceuticals, Inc. | Tetrahydroquinoline analogues as muscarinic agonists |
| US20040171614A1 (en) | 2002-02-06 | 2004-09-02 | Schering-Plough Corporation | Novel gamma secretase inhibitors |
| US7256186B2 (en) | 2002-02-06 | 2007-08-14 | Schering Corporation | Gamma secretase inhibitors |
| AU2003221178B2 (en) | 2002-03-28 | 2006-06-15 | Tanabe Seiyaku Co., Ltd. | Benzofuran derivative |
| WO2003104230A1 (ja) | 2002-06-07 | 2003-12-18 | 協和醱酵工業株式会社 | 二環性ピリミジン誘導体 |
| DE60226906D1 (de) | 2002-07-31 | 2008-07-10 | Ranbaxy Lab Ltd | 3,6-disubstituierte azabicyclo ä3.1.0ühexanderivate, die sich als muscarinrezeptorantagonisten eignen |
| KR20050062575A (ko) | 2002-09-30 | 2005-06-23 | 뉴로서치 에이/에스 | 신규한 1,4-디아자바이사이클로알칸 유도체, 이의 제법 및용도 |
| MXPA05005425A (es) | 2002-11-22 | 2005-11-23 | Japan Tobacco Inc | Heterociclos que contienen nitrogeno, biciclicos, fusionados. |
| GEP20115290B (en) | 2002-11-27 | 2011-09-26 | Incyte Corp | 3-aminopyrrolidine derivatives as modulators of chemokine receptors |
| WO2004069828A1 (ja) | 2003-02-04 | 2004-08-19 | Mitsubishi Pharma Corporation | ピペリジン化合物およびその医薬用途 |
| CN1835948B (zh) | 2003-07-17 | 2010-05-26 | 安斯泰来制药有限公司 | 2-酰基氨基噻唑衍生物或其盐 |
| EP1679069A4 (en) | 2003-10-21 | 2009-05-13 | Dainippon Sumitomo Pharma Co | NEW PIPERIDINE DERIVATIVE |
| JP2007520556A (ja) | 2004-02-05 | 2007-07-26 | シェーリング コーポレイション | Ｃｃｒ３アンタゴニストとして有用なピペリジン誘導体 |
| AU2005211499A1 (en) | 2004-02-10 | 2005-08-18 | F. Hoffmann-La Roche Ag | Chemokine CCR5 receptor modulators |
| US7504424B2 (en) | 2004-07-16 | 2009-03-17 | Schering Corporation | Compounds for the treatment of inflammatory disorders |
| US7488745B2 (en) | 2004-07-16 | 2009-02-10 | Schering Corporation | Compounds for the treatment of inflammatory disorders |
| US7786141B2 (en) | 2004-08-19 | 2010-08-31 | Vertex Pharmaceuticals Incorporated | Dihydrospiroindene modulators of muscarinic receptors |
| EP1817032A2 (en) | 2004-11-29 | 2007-08-15 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
| JP4774995B2 (ja) | 2005-01-12 | 2011-09-21 | アステラス製薬株式会社 | アシルアミノチアゾール誘導体を有効成分とする医薬組成物 |
| EP1863490A2 (en) | 2005-03-28 | 2007-12-12 | Vertex Pharmaceuticals Incorporated | Muscarinic modulators |
| WO2006137485A1 (ja) | 2005-06-24 | 2006-12-28 | Toyama Chemical Co., Ltd. | 新規な含窒素複素環化合物およびその塩 |
| RU2008130094A (ru) | 2005-12-22 | 2010-01-27 | Вертекс Фармасьютикалз Инкорпорейтед (Us) | Модуляторы мускариновых рецепторов |
| TW201307354A (zh) | 2005-12-29 | 2013-02-16 | Abbott Lab | 蛋白質激酶抑制劑 |
| ATE517106T1 (de) * | 2006-02-22 | 2011-08-15 | Vertex Pharma | Kondensierte spiropiperidine als modulatoren muskarinartiger rezeptoren |
| EP1988892A2 (en) | 2006-02-22 | 2008-11-12 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
| EP2051712A2 (en) | 2006-08-15 | 2009-04-29 | Vertex Pharmceuticals Incorporated | Modulators of muscarinic receptors |
| CN101610761A (zh) | 2006-12-22 | 2009-12-23 | 诺瓦提斯公司 | 作为ddp-iv抑制剂的1-氨基甲基-l-苯基-环己烷衍生物 |
| WO2008117229A1 (en) | 2007-03-23 | 2008-10-02 | Ranbaxy Laboratories Limited | Muscarinic receptor antagonists |
| US8119661B2 (en) | 2007-09-11 | 2012-02-21 | Astrazeneca Ab | Piperidine derivatives and their use as muscarinic receptor modulators |
| US20090221567A1 (en) | 2008-02-28 | 2009-09-03 | Astrazeneca Ab | Muscarinic receptor agonists, compositions, methods of treatment thereof, and processes for preparation thereof 177 |
| WO2009118370A1 (en) | 2008-03-27 | 2009-10-01 | Janssen Pharmaceutica Nv | Aza-bicyclohexyl substituted indolyl alkyl amino derivatives as novel inhibitors of histone deacetylase |
| AU2009309988A1 (en) | 2008-10-29 | 2010-05-06 | Grunenthal Gmbh | Substituted spiroamines |
| KR101754698B1 (ko) | 2008-12-19 | 2017-07-26 | 센트렉시온 테라퓨틱스 코포레이션 | 염증, 천식 및 ｃｏｐｄ 치료용 ｃｃｒ2 수용체 길항제로서의 사이클릭 피리미딘-4-카복스아미드 |
| AU2010236346B2 (en) | 2009-04-17 | 2015-01-22 | Janssen Pharmaceutica Nv | 4-azetidinyl-1-phenyl-cyclohexane antagonists of CCR2 |
| FR2945531A1 (fr) | 2009-05-12 | 2010-11-19 | Sanofi Aventis | Derives de 7-aza-spiro°3,5!nonane-7-carboxylates, leur preparation et leur application en therapeutique |
| WO2011112825A2 (en) | 2010-03-10 | 2011-09-15 | Vanderbilt University | Heterocyclyl-azabicyclo[3.2.1]octane analogs as selective m1 agonists and methods of making and using same |
| JP2013525370A (ja) | 2010-04-22 | 2013-06-20 | ヤンセン ファーマシューティカ エヌ．ベー． | ケトヘキソキナーゼ阻害剤として有用なインダゾール化合物 |
| WO2011137012A1 (en) | 2010-04-27 | 2011-11-03 | Merck Sharp & Dohme Corp. | Prolylcarboxypeptidase inhibitors |
| US9365539B2 (en) | 2010-05-11 | 2016-06-14 | Merck Sharp & Dohme Corp. | Prolylcarboxypeptidase inhibitors |
| CN102918031A (zh) | 2010-05-28 | 2013-02-06 | 通用电气健康护理有限公司 | 放射标记的化合物及其方法 |
| JP2013537234A (ja) | 2010-09-17 | 2013-09-30 | アレイ バイオファーマ、インコーポレイテッド | Ｇｐｒ１１９モジュレーターとしてのピペリジニル置換ラクタム |
| US20140005165A1 (en) | 2011-03-17 | 2014-01-02 | Anilkumar G. Nair | Substituted 3-azabicyclo[3.1.0]hexane derivatives useful as ccr2 antagonists |
| JP2013010719A (ja) | 2011-06-30 | 2013-01-17 | Dainippon Sumitomo Pharma Co Ltd | ベンズイミダゾロンおよびオキシインドール誘導体ならびにそれらの医薬用途 |
| IN2014KN01075A (enExample) | 2011-11-18 | 2015-10-09 | Heptares Therapeutics Ltd | |
| BR112015006029B1 (pt) * | 2012-09-18 | 2022-01-25 | Heptares Therapeutics Limited | Compostos aza bicíclicos como agonistas de receptor m1 muscarínicos, composição farmacêutica compreendendo ditos compostos e uso dos mesmos para tratar um distúrbio cognitivo ou distúrbio psicótico ou para tratar ou reduzir a gravidade de dores agudas, crônicas, neuropáticas ou inflamatórias |
| WO2014122474A1 (en) | 2013-02-07 | 2014-08-14 | Takeda Pharmaceutical Company Limited | Piperidin-1 -yl and azepin-1 -yl carboxylates as muscarinic m4 receptor agonists |
| SMT202400446T1 (it) | 2014-02-06 | 2024-11-15 | Nxera Pharma Uk Ltd | Composti aza biciclici come agonisti del recettore muscarinico |
| GB201404922D0 (en) | 2014-03-19 | 2014-04-30 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| CN107406434B (zh) | 2015-02-13 | 2020-09-11 | 苏文生命科学有限公司 | 作为5-ht4受体激动剂的酰胺化合物 |
| GB201504675D0 (en) * | 2015-03-19 | 2015-05-06 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| GB201513740D0 (en) | 2015-08-03 | 2015-09-16 | Heptares Therapeutics Ltd | Muscarinic agonist |
| GB201513743D0 (en) * | 2015-08-03 | 2015-09-16 | Heptares Therapeutics Ltd | Muscarinic agonists |
| GB201513742D0 (en) | 2015-08-03 | 2015-09-16 | Heptares Therapeutics Ltd | Muscarinic agonists |
| GB201519352D0 (en) | 2015-11-02 | 2015-12-16 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| US10259787B2 (en) | 2016-10-14 | 2019-04-16 | Heptares Therapeutics Limited | Substituted cyclohexanes as muscarinic M1 receptor and/or M4 receptor agonists |
| GB201617454D0 (en) | 2016-10-14 | 2016-11-30 | Heptares Therapeutics Limited | Pharmaceutical compounds |
| GB201709652D0 (en) | 2017-06-16 | 2017-08-02 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| US10501483B2 (en) | 2017-10-24 | 2019-12-10 | Allergan, Inc. | Enamines and diastereo-selective reduction of enamines |
| GB201810239D0 (en) | 2018-06-22 | 2018-08-08 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| GB201810245D0 (en) * | 2018-06-22 | 2018-08-08 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| GB201819960D0 (en) | 2018-12-07 | 2019-01-23 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| GB201819961D0 (en) | 2018-12-07 | 2019-01-23 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| GB202020191D0 (en) | 2020-12-18 | 2021-02-03 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| GB202103211D0 (en) | 2021-03-08 | 2021-04-21 | Heptares Therapeutics Ltd | Pharmaceutical compounds for use in therapy |
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| US11254656B2 (en) | 2022-02-22 |
| AU2016304387A1 (en) | 2018-02-22 |
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| GB201513743D0 (en) | 2015-09-16 |
| CN108025004B (zh) | 2021-07-09 |
| CA2994203A1 (en) | 2017-02-09 |
| CN108025004A (zh) | 2018-05-11 |
| US20230002354A1 (en) | 2023-01-05 |
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| US20180222885A1 (en) | 2018-08-09 |
| EP3331529B1 (en) | 2021-09-29 |
| HK1250138A1 (en) | 2018-11-30 |
| US10738029B2 (en) | 2020-08-11 |
| US20200354339A1 (en) | 2020-11-12 |
| US12024499B2 (en) | 2024-07-02 |
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