ES2894855T3 - Agonistas muscarínicos - Google Patents
Agonistas muscarínicos Download PDFInfo
- Publication number
- ES2894855T3 ES2894855T3 ES16750221T ES16750221T ES2894855T3 ES 2894855 T3 ES2894855 T3 ES 2894855T3 ES 16750221 T ES16750221 T ES 16750221T ES 16750221 T ES16750221 T ES 16750221T ES 2894855 T3 ES2894855 T3 ES 2894855T3
- Authority
- ES
- Spain
- Prior art keywords
- carboxylate
- ethyl
- compound
- piperidin
- azaspiro
- 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.)
- Active
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- 239000000472 muscarinic agonist Substances 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 276
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 77
- 239000001257 hydrogen Substances 0.000 claims abstract description 77
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 60
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 53
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 41
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 40
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 39
- 239000011737 fluorine Chemical group 0.000 claims abstract description 39
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 39
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 38
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 37
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims abstract description 36
- 125000003118 aryl group Chemical group 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000000460 chlorine Chemical group 0.000 claims abstract description 27
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 27
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 22
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 8
- 125000002883 imidazolyl group Chemical group 0.000 claims abstract description 7
- 125000003226 pyrazolyl group Chemical group 0.000 claims abstract description 7
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical group O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims abstract description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract 4
- 238000011282 treatment Methods 0.000 claims description 36
- 208000010877 cognitive disease Diseases 0.000 claims description 31
- 208000002193 Pain Diseases 0.000 claims description 28
- 208000024827 Alzheimer disease Diseases 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 208000004296 neuralgia Diseases 0.000 claims description 12
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
- 208000028017 Psychotic disease Diseases 0.000 claims description 8
- 201000000980 schizophrenia Diseases 0.000 claims description 7
- 230000001154 acute effect Effects 0.000 claims description 6
- 208000021722 neuropathic pain Diseases 0.000 claims description 6
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 5
- 206010065390 Inflammatory pain Diseases 0.000 claims description 5
- 208000005298 acute pain Diseases 0.000 claims description 5
- 230000002981 neuropathic effect Effects 0.000 claims description 5
- 208000000094 Chronic Pain Diseases 0.000 claims description 4
- 230000001684 chronic effect Effects 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
- 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 3
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 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
- SAYVKJWUIPTRJC-GOSISDBHSA-N ethyl 6-[4-[(2R)-2-(1,3-oxazol-5-yl)pyrrolidin-1-yl]piperidin-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate Chemical compound O1C=NC=C1[C@@H]1N(CCC1)C1CCN(CC1)C1CC2(CN(C2)C(=O)OCC)C1 SAYVKJWUIPTRJC-GOSISDBHSA-N 0.000 claims 1
- DGQFGULKRJZZGJ-MUMRKEEXSA-N ethyl 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)OCC)CC1 DGQFGULKRJZZGJ-MUMRKEEXSA-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
- PIAGNFVSQQDWNF-MRXNPFEDSA-N ethyl 6-[4-[(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidin-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate Chemical compound FC1(C[C@@H](N(C1)C1CCN(CC1)C1CC2(CN(C2)C(=O)OCC)C1)CO)F PIAGNFVSQQDWNF-MRXNPFEDSA-N 0.000 claims 1
- FBKKBOBKZJREGD-ZYMOGRSISA-N ethyl 6-[4-[(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate Chemical compound FC1(C[C@@H](N(C1)C1CCN(CC1)C1CC2(CN(C2)C(=O)OCC)CC1)CO)F FBKKBOBKZJREGD-ZYMOGRSISA-N 0.000 claims 1
- IJNRAMNTZRXLRL-KRWDZBQOSA-N ethyl 6-[4-[(2S)-1-(methylcarbamoyl)pyrrolidin-2-yl]piperidin-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate Chemical compound CNC(=O)N1[C@@H](CCC1)C1CCN(CC1)C1CC2(CN(C2)C(=O)OCC)C1 IJNRAMNTZRXLRL-KRWDZBQOSA-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
- AVRKLTUMTKSLCK-AWEZNQCLSA-N ethyl 6-[4-[(2S)-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-AWEZNQCLSA-N 0.000 claims 1
- FNPNRGQANRLYMU-MYJWUSKBSA-N ethyl 6-[4-[(2S)-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-MYJWUSKBSA-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
- PUDRFJJFRBCOJD-UHFFFAOYSA-N methyl 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)OC)C1 PUDRFJJFRBCOJD-UHFFFAOYSA-N 0.000 claims 1
- PEXOJKVNRZCLMG-UHFFFAOYSA-N methyl 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)OC)CC1 PEXOJKVNRZCLMG-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
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 150
- 239000002904 solvent Substances 0.000 description 80
- 238000000034 method Methods 0.000 description 79
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 72
- 150000002430 hydrocarbons Chemical group 0.000 description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 58
- 239000011541 reaction mixture Substances 0.000 description 57
- 239000000243 solution Substances 0.000 description 43
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 42
- 239000000203 mixture Substances 0.000 description 41
- -1 xanomelin Chemical class 0.000 description 40
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 34
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- 239000000543 intermediate Substances 0.000 description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
- 235000019439 ethyl acetate Nutrition 0.000 description 28
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 28
- 238000002360 preparation method Methods 0.000 description 28
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 27
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 24
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 24
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
- 125000004432 carbon atom Chemical group C* 0.000 description 22
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- 239000007787 solid Substances 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 229910052799 carbon Inorganic materials 0.000 description 16
- 239000012071 phase Substances 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000007832 Na2SO4 Substances 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
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- 235000011152 sodium sulphate Nutrition 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- 239000000556 agonist Substances 0.000 description 14
- 150000001721 carbon Chemical group 0.000 description 13
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- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 13
- 101100533874 Hypocrea jecorina (strain QM6a) sor5 gene Proteins 0.000 description 12
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- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 10
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- 150000003053 piperidines Chemical class 0.000 description 10
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- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 9
- 0 CC(C*(CC1)C(OC*)=O)C1*(C[C@@]1C2)CC(C)CC1C2(*(*)(N)S=*)I=C Chemical compound CC(C*(CC1)C(OC*)=O)C1*(C[C@@]1C2)CC(C)CC1C2(*(*)(N)S=*)I=C 0.000 description 9
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- 102000017926 CHRM2 Human genes 0.000 description 6
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- 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
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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
- A61P25/14—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
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- 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)
- Engineering & Computer Science (AREA)
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- Epidemiology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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| GBGB1513740.9A GB201513740D0 (en) | 2015-08-03 | 2015-08-03 | Muscarinic agonist |
| PCT/GB2016/052384 WO2017021728A1 (en) | 2015-08-03 | 2016-08-03 | Muscarinic agonists |
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| ES2894855T3 true ES2894855T3 (es) | 2022-02-16 |
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| EP (1) | EP3331528B1 (enExample) |
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| ES (1) | ES2894855T3 (enExample) |
| GB (1) | GB201513740D0 (enExample) |
| WO (1) | WO2017021728A1 (enExample) |
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| 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 |
| 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 |
| TW201726675A (zh) | 2015-12-23 | 2017-08-01 | 默沙東藥廠 | M4毒蕈鹼乙醯膽鹼受體之異位調節劑6,7-二氫-5h-吡咯并[3,4-b]吡啶-5-酮 |
| GB201617454D0 (en) | 2016-10-14 | 2016-11-30 | Heptares Therapeutics Limited | Pharmaceutical compounds |
| WO2018112842A1 (en) | 2016-12-22 | 2018-06-28 | Merck Sharp & Dohme Corp. | 6,6-fused heteroaryl piperidine ether allosteric modulators of m4 muscarinic acetylcholine receptor |
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| IL273924B2 (en) | 2017-10-20 | 2024-07-01 | Univ Vanderbilt | Antagonists of the muscarinic acetylcholine receptor m4 |
| WO2019126559A1 (en) | 2017-12-20 | 2019-06-27 | Vanderbilt University | Antagonists of the muscarinic acetylcholine receptor m4 |
| PT3768669T (pt) * | 2018-03-23 | 2023-04-24 | Pfizer | Derivados de piperazina azaspiro |
| GB201810239D0 (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 |
| MX2022002881A (es) * | 2019-09-25 | 2022-06-08 | Oncoarendi Therapeutics Sa | Proceso para la produccion de 5-(4-((2s,5s)-5-(4-clorobencil)-2-me tilmorfolino)piperidin-1-il)-1h-1,2,4-triazol-3-amina. |
| 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 |
| US12486250B2 (en) | 2019-12-06 | 2025-12-02 | Neurocrine Biosciences, Inc. | Muscarinic receptor 4 antagonists and methods of use |
| JP7707176B2 (ja) * | 2020-02-05 | 2025-07-14 | ニューロクライン バイオサイエンシーズ，インコーポレイテッド | ムスカリン性受容体４アンタゴニストおよび使用方法 |
| WO2023114224A1 (en) | 2021-12-13 | 2023-06-22 | Sage Therapeutics, Inc. | Combination of muscarinic receptor positive modulators and nmda positive allosteric modulators |
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| 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 |
| MX2011004340A (es) | 2008-10-29 | 2011-05-23 | Gruenenthal Gmbh | Espiroaminas sustituidas. |
| 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 |
| 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Ｈｅｐｔａｒｅｓ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｌｉｍｉｔｅｄ | 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 |
| 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 |
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