CA2994143C - Muscarinic agonists - Google Patents
Muscarinic agonists Download PDFInfo
- Publication number
- CA2994143C CA2994143C CA2994143A CA2994143A CA2994143C CA 2994143 C CA2994143 C CA 2994143C CA 2994143 A CA2994143 A CA 2994143A CA 2994143 A CA2994143 A CA 2994143A CA 2994143 C CA2994143 C CA 2994143C
- Authority
- CA
- Canada
- Prior art keywords
- carboxylate
- ethyl
- azaspiro
- compound according
- piperidin
- Prior art date
- 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.)
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- 239000000472 muscarinic agonist Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 284
- 150000003839 salts Chemical class 0.000 claims abstract description 46
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 65
- 239000001257 hydrogen Substances 0.000 claims description 65
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 50
- 229910052757 nitrogen Inorganic materials 0.000 claims description 48
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 46
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 37
- 125000005842 heteroatom Chemical group 0.000 claims description 37
- 229910052731 fluorine Inorganic materials 0.000 claims description 36
- 239000011737 fluorine Chemical group 0.000 claims description 35
- 125000001153 fluoro group Chemical group F* 0.000 claims description 35
- -1 Methyl 6-[4-(1-methyl-1H-imidazol-2-yl)piperidin-1-yl]-2-azaspiro[3.3]heptane-carboxylate Chemical compound 0.000 claims description 34
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 33
- 229910052717 sulfur Inorganic materials 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 29
- 208000002193 Pain Diseases 0.000 claims description 27
- 208000010877 cognitive disease Diseases 0.000 claims description 24
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 23
- 239000000460 chlorine Chemical group 0.000 claims description 23
- 229910052801 chlorine Inorganic materials 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 23
- 150000007942 carboxylates Chemical class 0.000 claims description 21
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 18
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 18
- 229910052794 bromium Inorganic materials 0.000 claims description 18
- 208000024827 Alzheimer disease Diseases 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 208000004296 neuralgia Diseases 0.000 claims description 12
- 150000002431 hydrogen Chemical group 0.000 claims description 11
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 208000028017 Psychotic disease Diseases 0.000 claims description 7
- 201000000980 schizophrenia Diseases 0.000 claims description 7
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- 208000021722 neuropathic pain Diseases 0.000 claims description 6
- 206010065390 Inflammatory pain Diseases 0.000 claims description 5
- 208000005298 acute pain Diseases 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- 208000000094 Chronic Pain Diseases 0.000 claims description 4
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical group O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 4
- 206010067889 Dementia with Lewy bodies Diseases 0.000 claims description 3
- 201000002832 Lewy body dementia Diseases 0.000 claims description 3
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 6
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 3
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 2
- 125000004043 oxo group Chemical group O=* 0.000 claims 2
- LATDEOLLBNPFQH-UHFFFAOYSA-N ethyl 6-(4-pyrazol-1-ylpiperidin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate Chemical compound N1(N=CC=C1)C1CCN(CC1)C1CC2(CN(C2)C(=O)OCC)C1 LATDEOLLBNPFQH-UHFFFAOYSA-N 0.000 claims 1
- USGJBXUOLYQEEA-UHFFFAOYSA-N ethyl 6-(4-pyrazol-1-ylpiperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate Chemical compound N1(N=CC=C1)C1CCN(CC1)C1CC2(CN(C2)C(=O)OCC)CC1 USGJBXUOLYQEEA-UHFFFAOYSA-N 0.000 claims 1
- WVWBOXRKEOPBOX-UHFFFAOYSA-N ethyl 6-[4-(1-methylimidazol-2-yl)piperidin-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate Chemical compound CN1C(=NC=C1)C1CCN(CC1)C1CC2(CN(C2)C(=O)OCC)C1 WVWBOXRKEOPBOX-UHFFFAOYSA-N 0.000 claims 1
- LSFIJFJLLLJISW-UHFFFAOYSA-N ethyl 6-[4-(1-methylimidazol-2-yl)piperidin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate Chemical compound CN1C(=NC=C1)C1CCN(CC1)C1CC2(CN(C2)C(=O)OCC)CC1 LSFIJFJLLLJISW-UHFFFAOYSA-N 0.000 claims 1
- GKODYOLWAJKWOR-OAHLLOKOSA-N ethyl 6-[4-[(2R)-2-ethyl-5-oxopyrrolidin-1-yl]piperidin-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate Chemical compound C(C)[C@H]1N(C(CC1)=O)C1CCN(CC1)C1CC2(CN(C2)C(=O)OCC)C1 GKODYOLWAJKWOR-OAHLLOKOSA-N 0.000 claims 1
- ZVYGUQXJVNRSMW-PYUWXLGESA-N ethyl 6-[4-[(2R)-2-ethyl-5-oxopyrrolidin-1-yl]piperidin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate Chemical compound C(C)[C@H]1N(C(CC1)=O)C1CCN(CC1)C1CC2(CN(C2)C(=O)OCC)CC1 ZVYGUQXJVNRSMW-PYUWXLGESA-N 0.000 claims 1
- AVRKLTUMTKSLCK-CQSZACIVSA-N ethyl 6-[4-[(2R)-2-methyl-5-oxopyrrolidin-1-yl]piperidin-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate Chemical compound C[C@H]1N(C(CC1)=O)C1CCN(CC1)C1CC2(CN(C2)C(=O)OCC)C1 AVRKLTUMTKSLCK-CQSZACIVSA-N 0.000 claims 1
- FNPNRGQANRLYMU-LDCVWXEPSA-N ethyl 6-[4-[(2R)-2-methyl-5-oxopyrrolidin-1-yl]piperidin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate Chemical compound C[C@H]1N(C(CC1)=O)C1CCN(CC1)C1CC2(CN(C2)C(=O)OCC)CC1 FNPNRGQANRLYMU-LDCVWXEPSA-N 0.000 claims 1
- DJPAKIGZZAJNBO-ZVAWYAOSSA-N ethyl 6-[4-[(2S)-1-(methylcarbamoyl)pyrrolidin-2-yl]piperidin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate Chemical compound CNC(=O)N1[C@@H](CCC1)C1CCN(CC1)C1CC2(CN(C2)C(=O)OCC)CC1 DJPAKIGZZAJNBO-ZVAWYAOSSA-N 0.000 claims 1
- GKODYOLWAJKWOR-HNNXBMFYSA-N ethyl 6-[4-[(2S)-2-ethyl-5-oxopyrrolidin-1-yl]piperidin-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate Chemical compound C(C)[C@@H]1N(C(CC1)=O)C1CCN(CC1)C1CC2(CN(C2)C(=O)OCC)C1 GKODYOLWAJKWOR-HNNXBMFYSA-N 0.000 claims 1
- ZVYGUQXJVNRSMW-ATNAJCNCSA-N ethyl 6-[4-[(2S)-2-ethyl-5-oxopyrrolidin-1-yl]piperidin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate Chemical compound C(C)[C@@H]1N(C(CC1)=O)C1CCN(CC1)C1CC2(CN(C2)C(=O)OCC)CC1 ZVYGUQXJVNRSMW-ATNAJCNCSA-N 0.000 claims 1
- VPHRMANYIUAQNV-UHFFFAOYSA-N ethyl 6-[4-[2-(1,2-oxazol-3-yl)pyrrolidin-1-yl]piperidin-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate Chemical compound O1N=C(C=C1)C1N(CCC1)C1CCN(CC1)C1CC2(CN(C2)C(=O)OCC)C1 VPHRMANYIUAQNV-UHFFFAOYSA-N 0.000 claims 1
- DVZYRUCGRJANBZ-QRWMCTBCSA-N methyl 6-[4-[(2R)-2-(1,3-oxazol-5-yl)pyrrolidin-1-yl]piperidin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate Chemical compound O1C=NC=C1[C@@H]1N(CCC1)C1CCN(CC1)C1CC2(CN(C2)C(=O)OC)CC1 DVZYRUCGRJANBZ-QRWMCTBCSA-N 0.000 claims 1
- WSRWHKRSNQJSAT-LDCVWXEPSA-N methyl 6-[4-[(2R)-2-ethyl-5-oxopyrrolidin-1-yl]piperidin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate Chemical compound C(C)[C@H]1N(C(CC1)=O)C1CCN(CC1)C1CC2(CN(C2)C(=O)OC)CC1 WSRWHKRSNQJSAT-LDCVWXEPSA-N 0.000 claims 1
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- 230000001404 mediated effect Effects 0.000 abstract description 6
- 108010008414 Muscarinic M4 Receptor Proteins 0.000 abstract description 2
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- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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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
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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
- C07D401/14—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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Epidemiology (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
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| WO2017107089A1 (en) | 2015-12-23 | 2017-06-29 | Merck Sharp & Dohme Corp. | 3- (1h-pyrazol-4-yl) pyridineallosteric modulators of the m4 muscarinic acetylcholine receptor |
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| WO2018112843A1 (en) | 2016-12-22 | 2018-06-28 | Merck Sharp & Dohme Corp. | Heteroaryl piperidine ether allosteric modulators of the m4 muscarinic acetylcholine receptor |
| EP3732163A4 (en) * | 2017-12-20 | 2021-07-14 | Vanderbilt University | MUSCARIN M4 ACETYLCHOLIN RECEPTOR ANTAGONISTS |
| PT3768669T (pt) | 2018-03-23 | 2023-04-24 | Pfizer | Derivados de piperazina azaspiro |
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| 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 |
| ES2983860T3 (es) | 2019-12-06 | 2024-10-25 | Neurocrine Biosciences Inc | Antagonistas del receptor muscarínico 4 y métodos de uso |
| EP4100410A1 (en) * | 2020-02-05 | 2022-12-14 | Neurocrine Biosciences, Inc. | Muscarinic receptor 4 antagonists and methods of use |
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| WO2025030095A1 (en) * | 2023-08-03 | 2025-02-06 | Neurocrine Biosciences, Inc. | Methods of synthesis |
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| WO2007100664A2 (en) | 2006-02-22 | 2007-09-07 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
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| 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 |
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