TWI822803B - 醫藥化合物 - Google Patents
醫藥化合物 Download PDFInfo
- Publication number
- TWI822803B TWI822803B TW108122030A TW108122030A TWI822803B TW I822803 B TWI822803 B TW I822803B TW 108122030 A TW108122030 A TW 108122030A TW 108122030 A TW108122030 A TW 108122030A TW I822803 B TWI822803 B TW I822803B
- Authority
- TW
- Taiwan
- Prior art keywords
- oxa
- nonane
- azabicyclo
- carboxylic acid
- optionally substituted
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 239
- 238000011282 treatment Methods 0.000 claims abstract description 28
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims description 65
- 150000001412 amines Chemical class 0.000 claims description 52
- -1 7-{4-[(1-methylcyclo Butyl)aminomethyl]piperidin-1-yl}-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ethyl ester Chemical compound 0.000 claims description 51
- 229910052760 oxygen Inorganic materials 0.000 claims description 47
- 229910052757 nitrogen Inorganic materials 0.000 claims description 44
- 125000003118 aryl group Chemical group 0.000 claims description 41
- 125000005842 heteroatom Chemical group 0.000 claims description 41
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 36
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 34
- 125000002950 monocyclic group Chemical group 0.000 claims description 33
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 29
- 208000010877 cognitive disease Diseases 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 150000002367 halogens Chemical class 0.000 claims description 28
- 229910052717 sulfur Inorganic materials 0.000 claims description 27
- 208000024827 Alzheimer disease Diseases 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 125000001424 substituent group Chemical group 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 21
- 125000002619 bicyclic group Chemical group 0.000 claims description 19
- 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 description 18
- 239000003814 drug Substances 0.000 claims description 17
- 125000001153 fluoro group Chemical group F* 0.000 claims description 16
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 15
- 125000004429 atom Chemical group 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 230000000694 effects Effects 0.000 claims description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 13
- 229940079593 drug Drugs 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 11
- 239000001301 oxygen Substances 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 125000003277 amino group Chemical group 0.000 claims description 9
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 230000001154 acute effect Effects 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 206010065390 Inflammatory pain Diseases 0.000 claims description 5
- 201000002832 Lewy body dementia Diseases 0.000 claims description 5
- 206010067889 Dementia with Lewy bodies Diseases 0.000 claims description 4
- 150000001555 benzenes Chemical group 0.000 claims description 4
- 230000001684 chronic effect Effects 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 208000020016 psychiatric disease Diseases 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- 239000000359 muscarinic M1 receptor agonist Substances 0.000 claims description 3
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 3
- KZKRRZFCAYOXQE-UHFFFAOYSA-N 1$l^{2}-azinane Chemical group C1CC[N]CC1 KZKRRZFCAYOXQE-UHFFFAOYSA-N 0.000 claims 1
- 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 claims 1
- 208000012902 Nervous system disease Diseases 0.000 claims 1
- 208000025966 Neurological disease Diseases 0.000 claims 1
- 241000009298 Trigla lyra Species 0.000 claims 1
- YIMUUIIWAQMRPG-UHFFFAOYSA-N ethyl 7-(4-cyano-4-pyridin-2-ylpiperidin-1-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound C(#N)C1(CCN(CC1)C1CC2COCC(C1)N2C(=O)OCC)C1=NC=CC=C1 YIMUUIIWAQMRPG-UHFFFAOYSA-N 0.000 claims 1
- SSCJIESACTYSJE-UHFFFAOYSA-N ethyl 7-(4-pyrazol-1-ylpiperidin-1-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound N1(N=CC=C1)C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OCC SSCJIESACTYSJE-UHFFFAOYSA-N 0.000 claims 1
- YMUHNWBHSHBUNZ-UHFFFAOYSA-N ethyl 7-[4-(2-methoxypyridin-3-yl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound COC1=NC=CC=C1C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OCC YMUHNWBHSHBUNZ-UHFFFAOYSA-N 0.000 claims 1
- WGFNUZDIMNZIFF-UHFFFAOYSA-N ethyl 7-[4-(2-methylpropylcarbamoyl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound CC(CNC(=O)C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OCC)C WGFNUZDIMNZIFF-UHFFFAOYSA-N 0.000 claims 1
- PJXXKNRDGUJOOX-UHFFFAOYSA-N ethyl 7-[4-(4-chloropyrazol-1-yl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound ClC=1C=NN(C=1)C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OCC PJXXKNRDGUJOOX-UHFFFAOYSA-N 0.000 claims 1
- UNQPZORTUWGIBX-UHFFFAOYSA-N ethyl 7-[4-(4-methylpyrazol-1-yl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound CC=1C=NN(C=1)C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OCC UNQPZORTUWGIBX-UHFFFAOYSA-N 0.000 claims 1
- FISQGOWXCDDBIA-UHFFFAOYSA-N ethyl 7-[4-(6-methoxypyridin-2-yl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound COC1=CC=CC(=N1)C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OCC FISQGOWXCDDBIA-UHFFFAOYSA-N 0.000 claims 1
- KFVGELDEEISAQT-VHYNJHTPSA-N ethyl 7-[4-[(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound FC1(C[C@@H](N(C1)C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OCC)CO)F KFVGELDEEISAQT-VHYNJHTPSA-N 0.000 claims 1
- YPSXWVCCWCEVPH-UHFFFAOYSA-N ethyl 7-[4-[acetyl(2-methylpropyl)amino]piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound C(C)(=O)N(C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OCC)CC(C)C YPSXWVCCWCEVPH-UHFFFAOYSA-N 0.000 claims 1
- LVRRZLMHKHBMPT-UHFFFAOYSA-N ethyl 7-[4-[acetyl(benzyl)amino]piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound C(C)(=O)N(C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OCC)CC1=CC=CC=C1 LVRRZLMHKHBMPT-UHFFFAOYSA-N 0.000 claims 1
- WBGKJZYLIYFTHY-UHFFFAOYSA-N ethyl 7-[4-[acetyl-[(1-methylcyclobutyl)methyl]amino]piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound C(C)(=O)N(C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OCC)CC1(CCC1)C WBGKJZYLIYFTHY-UHFFFAOYSA-N 0.000 claims 1
- 238000002483 medication Methods 0.000 claims 1
- XBNXAVPXXMWMRZ-UHFFFAOYSA-N methyl 7-(4-pyrazol-1-ylpiperidin-1-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound N1(N=CC=C1)C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OC XBNXAVPXXMWMRZ-UHFFFAOYSA-N 0.000 claims 1
- FYVWZFOWZFWJNT-UHFFFAOYSA-N methyl 7-(6-azaspiro[2.5]octan-6-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound COC(=O)N1C2COCC1CC(C2)N1CCC2(CC2)CC1 FYVWZFOWZFWJNT-UHFFFAOYSA-N 0.000 claims 1
- CCOSERKYOVYTLW-UHFFFAOYSA-N methyl 7-[4-(2-methoxypyridin-3-yl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound COC1=NC=CC=C1C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OC CCOSERKYOVYTLW-UHFFFAOYSA-N 0.000 claims 1
- ITPZJDRYYREJBG-UHFFFAOYSA-N methyl 7-[4-(4-chloropyrazol-1-yl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound ClC=1C=NN(C=1)C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OC ITPZJDRYYREJBG-UHFFFAOYSA-N 0.000 claims 1
- OCZBSOJHWHFJPD-UHFFFAOYSA-N methyl 7-[4-(4-methylpyrazol-1-yl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound CC=1C=NN(C=1)C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OC OCZBSOJHWHFJPD-UHFFFAOYSA-N 0.000 claims 1
- GZLWPGRDPOFZJM-UHFFFAOYSA-N methyl 7-[4-(6-methoxypyridin-2-yl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound COC1=CC=CC(=N1)C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OC GZLWPGRDPOFZJM-UHFFFAOYSA-N 0.000 claims 1
- YISWVCHTPYMFGD-VKFIQFPUSA-N methyl 7-[4-[(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound FC1(C[C@@H](N(C1)C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OC)CO)F YISWVCHTPYMFGD-VKFIQFPUSA-N 0.000 claims 1
- CZDWOKYDXBKUBV-UHFFFAOYSA-N methyl 7-[4-[acetyl(2,2-dimethylpropyl)amino]piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound C(C)(=O)N(C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OC)CC(C)(C)C CZDWOKYDXBKUBV-UHFFFAOYSA-N 0.000 claims 1
- IZGWXQMXVPBLGL-UHFFFAOYSA-N methyl 7-[4-[acetyl(2-methylpropyl)amino]piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound C(C)(=O)N(C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OC)CC(C)C IZGWXQMXVPBLGL-UHFFFAOYSA-N 0.000 claims 1
- ULNGUBXYYYKTBS-UHFFFAOYSA-N methyl 7-[4-[acetyl-[(1-methylcyclobutyl)methyl]amino]piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound C(C)(=O)N(C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OC)CC1(CCC1)C ULNGUBXYYYKTBS-UHFFFAOYSA-N 0.000 claims 1
- SYFAVJLHLAOBHA-UHFFFAOYSA-N methyl 7-[4-[acetyl-[(1-methylcyclopropyl)methyl]amino]piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound C(C)(=O)N(C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OC)CC1(CC1)C SYFAVJLHLAOBHA-UHFFFAOYSA-N 0.000 claims 1
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged 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
- A61P25/28—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
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Hospice & Palliative Care (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Psychiatry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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| GB1810239.2 | 2018-06-22 |
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| TWI822803B true TWI822803B (zh) | 2023-11-21 |
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| ES2619829T3 (es) | 2011-11-18 | 2017-06-27 | Heptares Therapeutics Limited | Agonistas del receptor muscarínico M1 |
| 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 |
| WO2018229542A1 (en) * | 2017-06-09 | 2018-12-20 | Adama Makhteshim Ltd. | Formulation for seed treatment comprising fluensulfone |
| GB201810239D0 (en) | 2018-06-22 | 2018-08-08 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
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| GB202020191D0 (en) * | 2020-12-18 | 2021-02-03 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
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| WO2008117229A1 (en) * | 2007-03-23 | 2008-10-02 | Ranbaxy Laboratories Limited | Muscarinic receptor antagonists |
| WO2014045031A1 (en) * | 2012-09-18 | 2014-03-27 | Heptares Therapeutics Limited | Bicyclic aza compounds as muscarinic m1 receptor agonists |
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| JPS56110674A (en) | 1980-01-24 | 1981-09-01 | Janssen Pharmaceutica Nv | Novel 11*cyclohexyl**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 |
| AU701127B2 (en) | 1994-10-27 | 1999-01-21 | 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 |
| DE69734774D1 (de) | 1996-08-26 | 2006-01-05 | Pfizer | Spirocyclische dopaminrezeptor-subtyp-liganden |
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| ES2984420T3 (es) | 2024-10-29 |
| GB201810239D0 (en) | 2018-08-08 |
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