ES2894637T3 - Agonistas muscarínicos - Google Patents

Agonistas muscarínicos Download PDF

Info

Publication number: ES2894637T3
Authority: ES; Spain
Prior art keywords: compound; ethyl; hydrogen; hydrocarbon group; carboxylate
Prior art date: 2015-08-03
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Active

Application number

ES16750222T

Other languages

English (en)

Spanish (es)

Inventor

Giles Albert Brown

Julie Cansfield

Mark Pickworth

Benjamin Gerald Tehan

Barry John Teobald

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Nxera Pharma UK Ltd

Original Assignee

Heptares Therapeutics Ltd

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2015-08-03

Filing date

2016-08-03

Publication date

2022-02-15

2016-08-03 Application filed by Heptares Therapeutics Ltd filed Critical Heptares Therapeutics Ltd

2022-02-15 Application granted granted Critical

2022-02-15 Publication of ES2894637T3 publication Critical patent/ES2894637T3/es

Status Active legal-status Critical Current

2036-08-03 Anticipated expiration legal-status Critical

Links

239000000472 muscarinic agonist Substances 0.000 title description 7
150000001875 compounds Chemical class 0.000 claims abstract description 261
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 63
239000001257 hydrogen Substances 0.000 claims abstract description 63
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 46
239000011737 fluorine Chemical group 0.000 claims abstract description 39
229910052731 fluorine Inorganic materials 0.000 claims abstract description 39
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 37
229910052757 nitrogen Inorganic materials 0.000 claims abstract description 37
125000001153 fluoro group Chemical group F* 0.000 claims abstract description 31
150000003839 salts Chemical class 0.000 claims abstract description 31
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 16
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 15
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 14
125000002393 azetidinyl group Chemical group 0.000 claims abstract description 9
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-1 Ethyl -{4-[(2R)-2-(methoxycarbonyl)azetidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate Chemical compound 0.000 claims description 30
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RYOMVDCRMPHGJS-FVWXCPNNSA-N ethyl 2-[4-[(2S)-2-ethyl-4-oxoazetidin-1-yl]piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate Chemical compound C(C)[C@@H]1N(C(C1)=O)C1CCN(CC1)C1CC2(C1)CN(CC2)C(=O)OCC RYOMVDCRMPHGJS-FVWXCPNNSA-N 0.000 claims description 2
UXOIDSVCLHGUML-UHFFFAOYSA-N ethyl 2-[4-(2-oxoazetidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate Chemical compound O=C1N(CC1)C1CCN(CC1)C1CC2(C1)CN(CC2)C(=O)OCC UXOIDSVCLHGUML-UHFFFAOYSA-N 0.000 claims 1
UWFOROPKXCXBQG-UHFFFAOYSA-N ethyl 2-[4-(3,3-difluoroazetidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate Chemical compound FC1(CN(C1)C1CCN(CC1)C1CC2(C1)CN(CC2)C(=O)OCC)F UWFOROPKXCXBQG-UHFFFAOYSA-N 0.000 claims 1
LJKKMFZWOISLNQ-ICXUMSERSA-N ethyl 2-[4-[(2R)-2-methyl-4-oxoazetidin-1-yl]piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate Chemical compound C[C@H]1N(C(C1)=O)C1CCN(CC1)C1CC2(C1)CN(CC2)C(=O)OCC LJKKMFZWOISLNQ-ICXUMSERSA-N 0.000 claims 1
LJKKMFZWOISLNQ-ASFAAARLSA-N ethyl 2-[4-[(2S)-2-methyl-4-oxoazetidin-1-yl]piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate Chemical compound C[C@@H]1N(C(C1)=O)C1CCN(CC1)C1CC2(C1)CN(CC2)C(=O)OCC LJKKMFZWOISLNQ-ASFAAARLSA-N 0.000 claims 1
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Classifications

- 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
- 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

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Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Biomedical Technology (AREA)
Neurology (AREA)
Neurosurgery (AREA)
General Chemical & Material Sciences (AREA)
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Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Veterinary Medicine (AREA)
Pharmacology & Pharmacy (AREA)
Chemical Kinetics & Catalysis (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
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ES16750222T 2015-08-03 2016-08-03 Agonistas muscarínicos Active ES2894637T3 (es)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
GBGB1513743.3A GB201513743D0 (en)	2015-08-03	2015-08-03	Muscarinic agonists
PCT/GB2016/052385 WO2017021729A1 (en)	2015-08-03	2016-08-03	Muscarinic agonists

Publications (1)

Publication Number	Publication Date
ES2894637T3 true ES2894637T3 (es)	2022-02-15

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Application Number	Title	Priority Date	Filing Date
ES16750222T Active ES2894637T3 (es)	2015-08-03	2016-08-03	Agonistas muscarínicos

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US (3)	US10738029B2 (2)
EP (1)	EP3331529B1 (2)
JP (1)	JP6843114B2 (2)
CN (1)	CN108025004B (2)
AU (1)	AU2016304387B2 (2)
CA (1)	CA2994203C (2)
DK (1)	DK3331529T3 (2)
ES (1)	ES2894637T3 (2)
GB (1)	GB201513743D0 (2)
WO (1)	WO2017021729A1 (2)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP2780015B1 (en)	2011-11-18	2017-01-04	Heptares Therapeutics Limited	Muscarinic m1 receptor agonists
GB201404922D0 (en)	2014-03-19	2014-04-30	Heptares Therapeutics Ltd	Pharmaceutical compounds
GB201513743D0 (en)	2015-08-03	2015-09-16	Heptares Therapeutics Ltd	Muscarinic agonists
GB201513740D0 (en) *	2015-08-03	2015-09-16	Heptares Therapeutics Ltd	Muscarinic agonist
GB201519352D0 (en)	2015-11-02	2015-12-16	Heptares Therapeutics Ltd	Pharmaceutical compounds
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
AU2018300980A1 (en)	2017-07-12	2020-01-02	Vanderbilt University	Antagonists of the muscarinic acetylcholine receptor M4
AU2018352828A1 (en) *	2017-10-17	2020-04-23	Vanderbilt University	Antagonists of the muscarinic acetylcholine receptor M4
IL273924B2 (en)	2017-10-20	2024-07-01	Univ Vanderbilt	Antagonists of the muscarinic acetylcholine receptor m4
PT3768669T (pt) *	2018-03-23	2023-04-24	Pfizer	Derivados de piperazina azaspiro
GB201810245D0 (en)	2018-06-22	2018-08-08	Heptares Therapeutics Ltd	Pharmaceutical compounds
GB201810239D0 (en)	2018-06-22	2018-08-08	Heptares Therapeutics Ltd	Pharmaceutical compounds
GB201819961D0 (en)	2018-12-07	2019-01-23	Heptares Therapeutics Ltd	Pharmaceutical compounds
GB201819960D0 (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
WO2021070090A1 (en) *	2019-10-09	2021-04-15	Novartis Ag	2-azaspiro[3.4]octane derivatives as m4 agonists
CN119390705A (zh)	2019-10-09	2025-02-07	诺华股份有限公司	作为m4激动剂的5-氧杂-2-氮杂螺[3.4]辛烷衍生物

Family Cites Families (96)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
JPS56110674A (en)	1980-01-24	1981-09-01	Janssen Pharmaceutica Nv	Novel 11cyclohexyl*44aryll44piperidine carboxylic acid derivative
US4369184A (en)	1980-01-24	1983-01-18	Janssen Pharmaceutica N.V.	1-(Cyclohexyl)-4-aryl-4-piperidinecarboxylic acid derivatives
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
JP2002515008A (ja)	1994-10-27	2002-05-21	メルクエンドカンパニーインコーポレーテッド	ムスカリン・アンタゴニスト
IL117149A0 (en)	1995-02-23	1996-06-18	Schering Corp	Muscarinic antagonists
US5889006A (en)	1995-02-23	1999-03-30	Schering Corporation	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
DE69734774D1 (de)	1996-08-26	2006-01-05	Pfizer	Spirocyclische dopaminrezeptor-subtyp-liganden
JP2002505684A (ja)	1997-06-18	2002-02-19	メルクエンドカンパニーインコーポレーテッド	α１ａアドレナリン受容体拮抗薬
GB9715892D0 (en)	1997-07-29	1997-10-01	Zeneca Ltd	Heterocyclic compounds
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
AU2307999A (en)	1997-12-23	1999-07-12	Alcon Laboratories, Inc.	Muscarinic agents and use thereof to treat glaucoma, myopia and various other conditions
WO1999032486A1 (en)	1997-12-23	1999-07-01	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
CZ286152B6 (cs)	1998-03-13	2000-01-12	Miroslav Ing. Csc. Vlček	Transparentní a semitransparentní difrakční prvky
WO1999055674A1 (en)	1998-04-28	1999-11-04	Dainippon Pharmaceutical Co., Ltd.	1-[(1-substituted-4-piperidinyl)methyl]-4-piperidine derivatives, process for producing the same, medicinal compositions containing the same and intermediates of these compounds
BR0010593A (pt)	1999-05-04	2002-02-13	Schering Corp	Terapia de combinação com antagonista de ccr5-interferon alfa peguilado para hiv
KR100439357B1 (ko)	1999-05-04	2004-07-07	쉐링 코포레이션	Ｃｃｒ５ 길항제로서 유용한 피페리딘 유도체
US6387930B1 (en)	1999-05-04	2002-05-14	Schering Corporation	Piperidine derivatives useful as CCR5 antagonists
ES2199856T3 (es)	1999-09-13	2004-03-01	Boehringer Ingelheim Pharmaceuticals, Inc.	Nuevos compuestos heterociclicos, utiles como inhibidores reversibles de cisteina proteasas.
US6420364B1 (en)	1999-09-13	2002-07-16	Boehringer Ingelheim Pharmaceuticals, Inc.	Compound useful as reversible inhibitors of cysteine proteases
US6921763B2 (en)	1999-09-17	2005-07-26	Abbott Laboratories	Pyrazolopyrimidines as therapeutic agents
US6699880B1 (en)	1999-10-13	2004-03-02	Banyu Pharmaceutical Co., Ltd.	Substituted imidazolidinone derivatives
US7163938B2 (en)	2000-11-28	2007-01-16	Eli Lilly And Company	Substituted carboxamides
JPWO2002085890A1 (ja)	2001-04-20	2004-08-12	萬有製薬株式会社	ベンズイミダゾロン誘導体
EP1395257A1 (en)	2001-06-12	2004-03-10	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
ES2251624T3 (es)	2001-12-28	2006-05-01	Acadia Pharmaceuticals Inc.	Analogos de la tetrahidroquinolina como los agonistas muscarinicos.
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
PT1489078E (pt)	2002-03-28	2010-02-24	Mitsubishi Tanabe Pharma Corp	Derivados de benzofurano
JPWO2003104230A1 (ja)	2002-06-07	2005-10-06	協和醗酵工業株式会社	二環性ピリミジン誘導体
HK1079787A1 (zh)	2002-07-31	2006-04-13	Ranbaxy Laboratories Limited	用作毒蕈碱受体拮抗剂的3，6-二取代的氮杂双环[3．1．0]己烷衍生物
JP4711391B2 (ja)	2002-09-30	2011-06-29	ニューロサーチ、アクティーゼルスカブ	新規１，４−ジアザビシクロアルカン誘導体及びその製造方法
RU2342388C2 (ru)	2002-11-22	2008-12-27	Джапан Тобакко Инк.	Конденсированные бициклические азотсодержащие гетероциклы, обладающие dgat ингибирующим действием
EP1565436B1 (en)	2002-11-27	2012-04-25	Incyte Corporation	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
MXPA06000441A (es)	2003-07-17	2006-04-05	Astellas Pharma Inc	Derivado de 2-acilaminotiazole o sal del mismo.
JPWO2005037269A1 (ja)	2003-10-21	2006-12-28	住友製薬株式会社	新規ピペリジン誘導体
CA2554465A1 (en)	2004-02-05	2005-08-25	Schering Corporation	Piperidine derivatives useful as ccr3 antagonists
RU2006132465A (ru)	2004-02-10	2008-03-20	Ф.Хоффманн-Ля Рош Аг (Ch)	Модуляторы хемокинового рецептора ccr5
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
JP2008521821A (ja)	2004-11-29	2008-06-26	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	ムスカリン受容体のモジュレーター
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
EP1900732A4 (en)	2005-06-24	2009-11-18	Toyama Chemical Co Ltd	NEW NITROGENATED HETEROCYCLIC COMPOUND AND SALT THEREOF
AU2006330866A1 (en)	2005-12-22	2007-07-05	Vertex Pharmaceuticals Incorporated	Modulators of muscarinic receptors
ES2545907T3 (es)	2005-12-29	2015-09-16	Abbvie Inc.	Inhibidores de proteína quinasa
KR20080098070A (ko) *	2006-02-22	2008-11-06	버텍스 파마슈티칼스 인코포레이티드	무스카린성 수용체의 조절제로서의 스피로 축합된 피페리딘
AU2007221214A1 (en)	2006-02-22	2007-09-07	Vertex Pharmaceuticals Incorporated	Modulators of muscarinic receptors
AU2007284548A1 (en)	2006-08-15	2008-02-21	Vertex Pharmaceuticals Incorporated	Modulators of muscarinic receptors
US20130012485A1 (en)	2006-12-22	2013-01-10	Baeschlin Daniel Kaspar	Organic compounds
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
UY31672A1 (es)	2008-02-28	2009-09-30		"agonistas de receptores muscarínicos composiciones farmacéuticas métodos de tratamiento de los mismos, y procedimientos para su preparación"
WO2009118370A1 (en)	2008-03-27	2009-10-01	Janssen Pharmaceutica Nv	Aza-bicyclohexyl substituted indolyl alkyl amino derivatives as novel inhibitors of histone deacetylase
MX2011004340A (es)	2008-10-29	2011-05-23	Gruenenthal Gmbh	Espiroaminas sustituidas.
CN102256963B (zh)	2008-12-19	2014-06-11	贝林格尔.英格海姆国际有限公司	作为ccr2受体拮抗剂用于治疗炎症、哮喘和copd的环状嘧啶-4-甲酰胺
EP2419419B1 (en)	2009-04-17	2014-12-03	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
US8822447B2 (en)	2010-04-22	2014-09-02	Janssen Pharmaceutica Nv	Indazole compounds useful as ketohexokinase inhibitors
EP2563127A4 (en)	2010-04-27	2013-11-06	Merck Sharp & Dohme	PROLYLCARBOXYPEPTIDASE INHIBITORS
EP2568812B1 (en)	2010-05-11	2016-10-26	Merck Sharp & Dohme Corp.	Novel prolylcarboxypeptidase inhibitors
JP2013528180A (ja)	2010-05-28	2013-07-08	ジーイー・ヘルスケア・リミテッド	放射性標識化合物及びその製造方法
EP2616074A1 (en)	2010-09-17	2013-07-24	Array Biopharma, Inc.	Piperidinyl-substituted lactams as gpr119 modulators
EP2685828A4 (en)	2011-03-17	2014-08-13	Merck Sharp & Dohme	SUBSTITUTED 3-AZABICYCLO [3,1,0-] HEXAN DERIVATIVES 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
EP2780015B1 (en)	2011-11-18	2017-01-04	Heptares Therapeutics Limited	Muscarinic m1 receptor agonists
CN107098899B (zh)	2012-09-18	2019-09-06	赫普泰雅治疗有限公司	作为毒蕈碱的m1受体激动剂的二环氮杂化合物
JP6478923B2 (ja)	2013-02-07	2019-03-06	ヘプタレスセラピューティクスリミテッドＨｅｐｔａｒｅｓＴｈｅｒａｐｅｕｔｉｃｓＬｉｍｉｔｅｄ	ムスカリンｍ４受容体アゴニストとしてのピペリジン−１−イル及びアゼピン−１−イルカルボキシレート
SG11201606269WA (en)	2014-02-06	2016-09-29	Heptares Therapeutics Ltd	Bicyclic aza compounds as muscarinic m1 receptor and/or m4 receptor agonists
GB201404922D0 (en)	2014-03-19	2014-04-30	Heptares Therapeutics Ltd	Pharmaceutical compounds
SG11201706501VA (en)	2015-02-13	2017-09-28	Suven Life Sciences Ltd	AMIDE COMPOUNDS AS 5-HT<sb>4</sb> RECEPTOR AGONISTS
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
GB201617454D0 (en)	2016-10-14	2016-11-30	Heptares Therapeutics Limited	Pharmaceutical compounds
US10259787B2 (en)	2016-10-14	2019-04-16	Heptares Therapeutics Limited	Substituted cyclohexanes as muscarinic M1 receptor and/or M4 receptor agonists
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
GB201819961D0 (en)	2018-12-07	2019-01-23	Heptares Therapeutics Ltd	Pharmaceutical compounds
GB201819960D0 (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

2015
- 2015-08-03 GB GBGB1513743.3A patent/GB201513743D0/en not_active Ceased
2016
- 2016-08-03 JP JP2018504992A patent/JP6843114B2/ja active Active
- 2016-08-03 AU AU2016304387A patent/AU2016304387B2/en active Active
- 2016-08-03 US US15/749,957 patent/US10738029B2/en active Active
- 2016-08-03 CA CA2994203A patent/CA2994203C/en active Active
- 2016-08-03 ES ES16750222T patent/ES2894637T3/es active Active
- 2016-08-03 CN CN201680045224.1A patent/CN108025004B/zh active Active
- 2016-08-03 WO PCT/GB2016/052385 patent/WO2017021729A1/en not_active Ceased
- 2016-08-03 DK DK16750222.8T patent/DK3331529T3/da active
- 2016-08-03 EP EP16750222.8A patent/EP3331529B1/en active Active
2020
- 2020-07-29 US US16/942,167 patent/US11254656B2/en active Active
2022
- 2022-02-15 US US17/672,302 patent/US12024499B2/en active Active

Also Published As

Publication number	Publication date
CN108025004A (zh)	2018-05-11
CA2994203C (en)	2023-11-28
US20200354339A1 (en)	2020-11-12
US11254656B2 (en)	2022-02-22
AU2016304387B2 (en)	2020-10-22
JP2018522033A (ja)	2018-08-09
HK1250138A1 (en)	2018-11-30
AU2016304387A1 (en)	2018-02-22
JP6843114B2 (ja)	2021-03-17
EP3331529A1 (en)	2018-06-13
DK3331529T3 (da)	2021-10-18
US10738029B2 (en)	2020-08-11
US20230002354A1 (en)	2023-01-05
US20180222885A1 (en)	2018-08-09
US12024499B2 (en)	2024-07-02
WO2017021729A1 (en)	2017-02-09
CN108025004B (zh)	2021-07-09
CA2994203A1 (en)	2017-02-09
EP3331529B1 (en)	2021-09-29
GB201513743D0 (en)	2015-09-16

Publication	Publication Date	Title
ES2894637T3 (es)	2022-02-15	Agonistas muscarínicos
ES2894855T3 (es)	2022-02-16	Agonistas muscarínicos
ES2986327T3 (es)	2024-11-11	Compuestos aza bicíclicos como agonistas del receptor muscarínico
ES2980578T3 (es)	2024-10-02	Agonistas muscarínicos
ES2804774T3 (es)	2021-02-09	Compuestos de oxima como agonistas del receptor muscarínico M1 y/o M4
ES2852753T3 (es)	2021-09-14	Compuestos espirocíclicos como agonistas del receptor muscarínico M1 y/o M4
ES2872378T3 (es)	2021-11-02	Agonistas de receptores muscarínicos
ES2619829T3 (es)	2017-06-27	Agonistas del receptor muscarínico M1
ES2984420T3 (es)	2024-10-29	Compuestos con puente como agonistas del receptor muscarínico M1 y/o M4
ES2976504T3 (es)	2024-08-02	Derivados de quinolinona y benzoxazina como agonistas de los receptores muscarínicos M1 y/o M4
BR112015006029B1 (pt)	2022-01-25	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
US11945801B2 (en)	2024-04-02	Bicyclic aza compounds as muscarinic M1 and/or M4 receptor agonists
HK1250138B (en)	2022-01-28	Muscarinic agonists
HK1253036B (en)	2021-01-22	Oxime compounds as agonists of the muscarinic m1 and/or m4 receptor
HK1250139B (en)	2022-01-21	Muscarinic agonists