ES2894855T3 - Agonistas muscarínicos - Google Patents

Info

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

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.)

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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
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• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 24
• 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 24
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• 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
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• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
• 229910052799 carbon Inorganic materials 0.000 description 16
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• 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
• 239000002253 acid Substances 0.000 description 15
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• 229910052938 sodium sulfate Inorganic materials 0.000 description 15
• 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
• 125000000623 heterocyclic group Chemical group 0.000 description 13
• 239000012321 sodium triacetoxyborohydride Substances 0.000 description 13
• 101100533874 Hypocrea jecorina (strain QM6a) sor5 gene Proteins 0.000 description 12
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 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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