NZ555994A - Tetrahydroquinoline analogues as muscarinic agonists - Google Patents
Tetrahydroquinoline analogues as muscarinic agonistsInfo
- Publication number
- NZ555994A NZ555994A NZ555994A NZ55599405A NZ555994A NZ 555994 A NZ555994 A NZ 555994A NZ 555994 A NZ555994 A NZ 555994A NZ 55599405 A NZ55599405 A NZ 55599405A NZ 555994 A NZ555994 A NZ 555994A
- Authority
- NZ
- New Zealand
- Prior art keywords
- optionally substituted
- mmol
- branched
- straight
- chain
- Prior art date
Links
- 239000000472 muscarinic agonist Substances 0.000 title claims description 9
- 125000000147 tetrahydroquinolinyl group Chemical class N1(CCCC2=CC=CC=C12)* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 489
- 108010009685 Cholinergic Receptors Proteins 0.000 claims abstract description 62
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 claims abstract description 44
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 claims abstract description 44
- 208000028698 Cognitive impairment Diseases 0.000 claims abstract description 11
- 208000010877 cognitive disease Diseases 0.000 claims abstract description 11
- 102000034337 acetylcholine receptors Human genes 0.000 claims abstract 8
- 150000003839 salts Chemical class 0.000 claims description 90
- -1 substituted Chemical class 0.000 claims description 82
- 238000000034 method Methods 0.000 claims description 73
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 63
- 229910052739 hydrogen Inorganic materials 0.000 claims description 59
- 239000001257 hydrogen Substances 0.000 claims description 58
- 125000000217 alkyl group Chemical group 0.000 claims description 50
- 229910052736 halogen Inorganic materials 0.000 claims description 50
- 150000002367 halogens Chemical group 0.000 claims description 50
- 230000000694 effects Effects 0.000 claims description 47
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 44
- 208000035475 disorder Diseases 0.000 claims description 37
- 108020003175 receptors Proteins 0.000 claims description 34
- 102000005962 receptors Human genes 0.000 claims description 33
- 125000003118 aryl group Chemical group 0.000 claims description 29
- 201000010099 disease Diseases 0.000 claims description 26
- 230000008484 agonism Effects 0.000 claims description 24
- 125000000623 heterocyclic group Chemical group 0.000 claims description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims description 24
- 125000001424 substituent group Chemical group 0.000 claims description 24
- 230000004044 response Effects 0.000 claims description 21
- 208000024891 symptom Diseases 0.000 claims description 20
- 241000124008 Mammalia Species 0.000 claims description 19
- 230000003551 muscarinic effect Effects 0.000 claims description 18
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 17
- 230000009286 beneficial effect Effects 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 17
- 150000002148 esters Chemical class 0.000 claims description 16
- 229940002612 prodrug Drugs 0.000 claims description 16
- 239000000651 prodrug Substances 0.000 claims description 16
- 230000008485 antagonism Effects 0.000 claims description 15
- 125000004122 cyclic group Chemical group 0.000 claims description 15
- 230000006735 deficit Effects 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
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- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
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- 201000000980 schizophrenia Diseases 0.000 claims description 13
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 12
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 11
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- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 208000024827 Alzheimer disease Diseases 0.000 claims description 9
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- 101150060249 CHRM3 gene Proteins 0.000 claims description 9
- 125000001118 alkylidene group Chemical group 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 206010012289 Dementia Diseases 0.000 claims description 8
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 8
- 208000000044 Amnesia Diseases 0.000 claims description 7
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- 201000010374 Down Syndrome Diseases 0.000 claims description 7
- 201000011240 Frontotemporal dementia Diseases 0.000 claims description 7
- 208000023105 Huntington disease Diseases 0.000 claims description 7
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- 208000024571 Pick disease Diseases 0.000 claims description 7
- 208000034972 Sudden Infant Death Diseases 0.000 claims description 7
- 206010042440 Sudden infant death syndrome Diseases 0.000 claims description 7
- 230000007000 age related cognitive decline Effects 0.000 claims description 7
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 7
- 125000001188 haloalkyl group Chemical group 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 7
- 230000006984 memory degeneration Effects 0.000 claims description 7
- 206010027175 memory impairment Diseases 0.000 claims description 7
- 208000023060 memory loss Diseases 0.000 claims description 7
- 208000019116 sleep disease Diseases 0.000 claims description 7
- 230000016776 visual perception Effects 0.000 claims description 7
- 208000000323 Tourette Syndrome Diseases 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 5
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 4
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 4
- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 claims description 4
- 125000005819 alkenylalkoxy group Chemical group 0.000 claims description 4
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 claims description 4
- 230000004770 neurodegeneration Effects 0.000 claims description 4
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 4
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 102000007205 Muscarinic M2 Receptor Human genes 0.000 claims description 3
- 108010008407 Muscarinic M2 Receptor Proteins 0.000 claims description 3
- 102000007216 Muscarinic M4 Receptor Human genes 0.000 claims description 3
- 108010008414 Muscarinic M4 Receptor Proteins 0.000 claims description 3
- 206010044688 Trisomy 21 Diseases 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 3
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 9
- 239000000556 agonist Substances 0.000 abstract description 26
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 216
- 235000019439 ethyl acetate Nutrition 0.000 description 207
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 192
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 186
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 186
- XEKAWZARUWARND-UHFFFAOYSA-N 6h-oxazin-3-one Chemical compound O=C1NOCC=C1 XEKAWZARUWARND-UHFFFAOYSA-N 0.000 description 179
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 175
- 238000005481 NMR spectroscopy Methods 0.000 description 168
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 155
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 152
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 143
- 239000005695 Ammonium acetate Substances 0.000 description 143
- 235000019257 ammonium acetate Nutrition 0.000 description 143
- 229940043376 ammonium acetate Drugs 0.000 description 143
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 138
- 239000000047 product Substances 0.000 description 133
- 229910001868 water Inorganic materials 0.000 description 127
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 124
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 123
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 113
- 229910052681 coesite Inorganic materials 0.000 description 104
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- 229910052682 stishovite Inorganic materials 0.000 description 104
- 229910052905 tridymite Inorganic materials 0.000 description 104
- 229910000027 potassium carbonate Inorganic materials 0.000 description 102
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 91
- 239000011541 reaction mixture Substances 0.000 description 89
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 86
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- 235000015320 potassium carbonate Nutrition 0.000 description 75
- XIQSPCJCAJVNJL-UHFFFAOYSA-N 4-butylpiperidine Chemical compound CCCCC1CCNCC1 XIQSPCJCAJVNJL-UHFFFAOYSA-N 0.000 description 70
- 239000012044 organic layer Substances 0.000 description 69
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- 230000002829 reductive effect Effects 0.000 description 47
- 239000012074 organic phase Substances 0.000 description 40
- 150000002431 hydrogen Chemical group 0.000 description 39
- 239000003921 oil Substances 0.000 description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 36
- GAGAICHLGQDUTL-UHFFFAOYSA-N 4h-thiazin-3-one Chemical compound O=C1CC=CSN1 GAGAICHLGQDUTL-UHFFFAOYSA-N 0.000 description 35
- 238000005341 cation exchange Methods 0.000 description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 30
- VOWMRECKIQVVPP-UHFFFAOYSA-N 4-propoxypiperidine Chemical compound CCCOC1CCNCC1 VOWMRECKIQVVPP-UHFFFAOYSA-N 0.000 description 28
- 229910000104 sodium hydride Inorganic materials 0.000 description 28
- SFOYQZYQTQDRIY-UHFFFAOYSA-N 1-chloro-3-iodopropane Chemical compound ClCCCI SFOYQZYQTQDRIY-UHFFFAOYSA-N 0.000 description 27
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- 238000000746 purification Methods 0.000 description 18
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
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- A61P25/00—Drugs for disorders of the nervous system
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- C—CHEMISTRY; METALLURGY
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- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
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| PCT/US2005/045313 WO2006068904A1 (en) | 2004-12-21 | 2005-12-15 | Tetrahydroquinoline analogues as muscarinic agonists |
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| US7550459B2 (en) * | 2001-12-28 | 2009-06-23 | Acadia Pharmaceuticals, Inc. | Tetrahydroquinoline analogues as muscarinic agonists |
| EP1900732A4 (en) | 2005-06-24 | 2009-11-18 | Toyama Chemical Co Ltd | NEW NITROGENATED HETEROCYCLIC COMPOUND AND SALT THEREOF |
| US7678363B2 (en) * | 2005-08-26 | 2010-03-16 | Braincells Inc | Methods of treating psychiatric conditions comprising administration of muscarinic agents in combination with SSRIs |
| EP2258358A3 (en) | 2005-08-26 | 2011-09-07 | Braincells, Inc. | Neurogenesis with acetylcholinesterase inhibitor |
| EP2377530A3 (en) | 2005-10-21 | 2012-06-20 | Braincells, Inc. | Modulation of neurogenesis by PDE inhibition |
| EP1942879A1 (en) | 2005-10-31 | 2008-07-16 | Braincells, Inc. | Gaba receptor mediated modulation of neurogenesis |
| US20100216734A1 (en) | 2006-03-08 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
| WO2007134136A2 (en) | 2006-05-09 | 2007-11-22 | Braincells, Inc. | Neurogenesis by modulating angiotensin |
| US7678808B2 (en) | 2006-05-09 | 2010-03-16 | Braincells, Inc. | 5 HT receptor mediated neurogenesis |
| AU2007292848A1 (en) | 2006-09-08 | 2008-03-13 | Braincells, Inc. | Combinations containing a 4-acylaminopyridine derivative |
| US20100184806A1 (en) | 2006-09-19 | 2010-07-22 | Braincells, Inc. | Modulation of neurogenesis by ppar agents |
| WO2009106534A1 (en) * | 2008-02-26 | 2009-09-03 | H. Lundbeck A/S | Novel heterocyclic carboxamides as m1 agonists |
| US20100216805A1 (en) | 2009-02-25 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis using d-cycloserine combinations |
| AU2012338581B2 (en) | 2011-11-18 | 2016-12-08 | Nxera Pharma Uk Limited | Muscarinic M1 receptor agonists |
| MX2015012043A (es) * | 2013-03-15 | 2016-03-17 | Acadia Pharm Inc | Agonistas muscarinicos. |
| CN103242230B (zh) * | 2013-05-02 | 2015-02-18 | 陕西步长高新制药有限公司 | 一种喹啉酮衍生物及其制备方法 |
| 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 |
| 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 |
| GB201810239D0 (en) | 2018-06-22 | 2018-08-08 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| US11066404B2 (en) | 2018-10-11 | 2021-07-20 | Incyte Corporation | Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors |
| 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 |
| WO2020168197A1 (en) | 2019-02-15 | 2020-08-20 | Incyte Corporation | Pyrrolo[2,3-d]pyrimidinone compounds as cdk2 inhibitors |
| US11472791B2 (en) | 2019-03-05 | 2022-10-18 | Incyte Corporation | Pyrazolyl pyrimidinylamine compounds as CDK2 inhibitors |
| WO2020205560A1 (en) | 2019-03-29 | 2020-10-08 | Incyte Corporation | Sulfonylamide compounds as cdk2 inhibitors |
| GB202020191D0 (en) | 2020-12-18 | 2021-02-03 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| US11447494B2 (en) | 2019-05-01 | 2022-09-20 | Incyte Corporation | Tricyclic amine compounds as CDK2 inhibitors |
| US11440914B2 (en) | 2019-05-01 | 2022-09-13 | Incyte Corporation | Tricyclic amine compounds as CDK2 inhibitors |
| BR112022002698A2 (pt) | 2019-08-14 | 2022-07-19 | Incyte Corp | Compostos de imidazolil pirimidinilamina como inibidores de cdk2 |
| AU2020364007A1 (en) | 2019-10-11 | 2022-04-28 | Incyte Corporation | Bicyclic amines as CDK2 inhibitors |
| CN115073370B (zh) * | 2021-03-10 | 2024-12-17 | 成都硕德药业有限公司 | 新型烷基氨类化合物或盐、异构体、其制备方法及用途 |
| US11981671B2 (en) | 2021-06-21 | 2024-05-14 | Incyte Corporation | Bicyclic pyrazolyl amines as CDK2 inhibitors |
| US11976073B2 (en) | 2021-12-10 | 2024-05-07 | Incyte Corporation | Bicyclic amines as CDK2 inhibitors |
| EP4447953A1 (en) | 2021-12-13 | 2024-10-23 | Sage Therapeutics, Inc. | Combination of muscarinic receptor positive modulators and nmda positive allosteric modulators |
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| US3365457A (en) * | 1964-05-08 | 1968-01-23 | Sterling Drug Inc | N [(1-, 2-, 3-indolyl)-lower alkyl]-1, 5-iminocycloalkane and-1, 5-iminocycloalkene derivatives |
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| US3364457A (en) * | 1966-05-13 | 1968-01-16 | Navy Usa | Electrical adapter |
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| CA2050264A1 (en) * | 1990-08-30 | 1992-03-01 | Raymond Baker | Substituted pyrazine and its salts, compositions containing them and their use in medicine |
| US5149815A (en) * | 1991-04-29 | 1992-09-22 | American Home Products Corporation | N-substituted-2-aminoquinolines |
| US5093333A (en) * | 1991-04-29 | 1992-03-03 | American Home Products Corporation | N-substituted-2-aminoquinolines useful for treating hypofunction of the cholinergic system |
| US5378698A (en) | 1991-10-21 | 1995-01-03 | Shionogi & Co., Ltd. | Benzothiazepine derivatives |
| JPH0673011A (ja) * | 1992-07-02 | 1994-03-15 | Sawai Seiyaku Kk | カルボスチリル誘導体および抗アレルギー剤 |
| US5457099A (en) * | 1992-07-02 | 1995-10-10 | Sawai Pharmaceutical Co., Ltd. | Carbostyril derivatives and antiallergic agent |
| DE4228095A1 (de) | 1992-08-24 | 1994-03-03 | Asta Medica Ag | Neue 4,5-Dihydro-4-oxo-pyrrolo[1,2-a]chinoxaline und entsprechende Aza-analoga und Verfahren zu deren Herstellung |
| IL110298A (en) * | 1993-07-13 | 1999-04-11 | Brann Mark Robert | Identification of ligands by selective amplification of cells transfected with receptors |
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| US5929247A (en) * | 1994-10-24 | 1999-07-27 | Eli Lilly And Company | Heterocyclic compounds and their preparation and use |
| US5510478A (en) * | 1994-11-30 | 1996-04-23 | American Home Products Corporation | 2-arylamidothiazole derivatives with CNS activity |
| US5468875A (en) * | 1994-12-22 | 1995-11-21 | American Home Products Corporation | 1-azabicycloheptane derivatives |
| EP0934932A4 (en) | 1996-08-22 | 2002-06-26 | Meiji Seika Kaisha | CHINOLINE DERIVATIVES AND PSYCHOTROPES MEDIUM |
| CA2326804C (en) | 1998-03-31 | 2006-05-02 | Acadia Pharmaceuticals Inc. | Compounds with activity on muscarinic receptors |
| EP1221443B1 (en) | 1999-10-13 | 2004-09-01 | Banyu Pharmaceutical Co., Ltd. | Substituted imidazolidinone derivatives |
| ES2302992T3 (es) | 1999-12-30 | 2008-08-01 | H. Lundbeck A/S | Derivados de 4-fenil-piperazinil, -piperidinil y tetrahidropiridil como antagonistas de dopamina d4. |
| ATE366249T1 (de) * | 2000-02-29 | 2007-07-15 | Mitsubishi Pharma Corp | Zyklische amid-derivate |
| CN1814596A (zh) | 2000-04-28 | 2006-08-09 | 阿卡蒂亚药品公司 | 毒蕈碱性激动剂 |
| US6951849B2 (en) * | 2001-10-02 | 2005-10-04 | Acadia Pharmaceuticals Inc. | Benzimidazolidinone derivatives as muscarinic agents |
| WO2004089942A2 (en) * | 2001-10-02 | 2004-10-21 | Acadia Pharmaceuticals Inc. | Benzimidazolidinone derivatives as muscarinic agents |
| US7550459B2 (en) | 2001-12-28 | 2009-06-23 | Acadia Pharmaceuticals, Inc. | Tetrahydroquinoline analogues as muscarinic agonists |
| ATE304533T1 (de) | 2001-12-28 | 2005-09-15 | Acadia Pharm Inc | Tetrahydrochinolinderivate als muscarinische agonisten |
| EP1613321A2 (en) | 2003-03-28 | 2006-01-11 | Acadia Pharmaceuticals Inc. | Muscarinic m1 receptor agonists for pain management |
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