ES2984420T3 - Compuestos con puente como agonistas del receptor muscarínico M1 y/o M4 - Google Patents
Compuestos con puente como agonistas del receptor muscarínico M1 y/o M4 Download PDFInfo
- Publication number
- ES2984420T3 ES2984420T3 ES19734492T ES19734492T ES2984420T3 ES 2984420 T3 ES2984420 T3 ES 2984420T3 ES 19734492 T ES19734492 T ES 19734492T ES 19734492 T ES19734492 T ES 19734492T ES 2984420 T3 ES2984420 T3 ES 2984420T3
- Authority
- ES
- Spain
- Prior art keywords
- oxa
- carboxylate
- nonane
- piperidin
- ethyl
- 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
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 210
- 239000000556 agonist Substances 0.000 title abstract description 21
- 102000017924 CHRM4 Human genes 0.000 title 1
- 102000007207 Muscarinic M1 Receptor Human genes 0.000 title 1
- 108010008406 Muscarinic M1 Receptor Proteins 0.000 title 1
- 101100107916 Xenopus laevis chrm4 gene Proteins 0.000 title 1
- 238000011282 treatment Methods 0.000 claims abstract description 32
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims description 53
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 48
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 45
- 229910052757 nitrogen Inorganic materials 0.000 claims description 43
- 125000005842 heteroatom Chemical group 0.000 claims description 41
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 41
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- 229910052760 oxygen Inorganic materials 0.000 claims description 40
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 39
- 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 39
- 229910052736 halogen Inorganic materials 0.000 claims description 38
- 150000002367 halogens Chemical class 0.000 claims description 38
- 125000003545 alkoxy group Chemical group 0.000 claims description 36
- 125000004043 oxo group Chemical group O=* 0.000 claims description 36
- 125000001424 substituent group Chemical group 0.000 claims description 36
- 125000002950 monocyclic group Chemical group 0.000 claims description 34
- -1 7-[4-(Azepan-1-ylcarbonyl )piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound 0.000 claims description 32
- 208000002193 Pain Diseases 0.000 claims description 30
- 229910052717 sulfur Inorganic materials 0.000 claims description 29
- 208000010877 cognitive disease Diseases 0.000 claims description 28
- 208000024827 Alzheimer disease Diseases 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 24
- 125000001153 fluoro group Chemical group F* 0.000 claims description 23
- 125000002619 bicyclic group Chemical group 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 208000004296 neuralgia Diseases 0.000 claims description 13
- 125000004429 atom Chemical group 0.000 claims description 11
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
- 101100440695 Dictyostelium discoideum corB gene Proteins 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 208000028017 Psychotic disease Diseases 0.000 claims description 8
- 230000001154 acute effect Effects 0.000 claims description 7
- 208000021722 neuropathic pain Diseases 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 230000009467 reduction Effects 0.000 claims description 7
- 206010065390 Inflammatory pain Diseases 0.000 claims description 6
- 208000005298 acute pain Diseases 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
- 230000002981 neuropathic effect Effects 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 208000000094 Chronic Pain Diseases 0.000 claims description 5
- 230000001684 chronic effect Effects 0.000 claims description 5
- IEGMMVRYAIOIEL-UHFFFAOYSA-N ethyl 7-[4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound CC1(CCC1)NC(=O)C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OCC IEGMMVRYAIOIEL-UHFFFAOYSA-N 0.000 claims description 5
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 3
- 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 description 3
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Chemical group 0.000 claims description 3
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
- YBYQRKYENNYSNL-UHFFFAOYSA-N ethyl 7-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound O=C1OC2(CN1)CCN(CC2)C1CC2COCC(C1)N2C(=O)OCC YBYQRKYENNYSNL-UHFFFAOYSA-N 0.000 claims description 2
- 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 description 2
- ALJDKHLQTDIEMO-UHFFFAOYSA-N ethyl 7-(4-ethyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound C(C)C1NC(OC11CCN(CC1)C1CC2COCC(C1)N2C(=O)OCC)=O ALJDKHLQTDIEMO-UHFFFAOYSA-N 0.000 claims description 2
- WAFXBAHRKGAQOT-UHFFFAOYSA-N ethyl 7-(6-azaspiro[2.5]octan-6-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound C1CC11CCN(CC1)C1CC2COCC(C1)N2C(=O)OCC WAFXBAHRKGAQOT-UHFFFAOYSA-N 0.000 claims description 2
- 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 description 2
- FOSFTTMRKSRARO-UHFFFAOYSA-N ethyl 7-[4-(2-oxoazepan-1-yl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound O=C1N(CCCCC1)C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OCC FOSFTTMRKSRARO-UHFFFAOYSA-N 0.000 claims description 2
- MTSCQCYMOJHZFC-UHFFFAOYSA-N ethyl 7-[4-(2-oxopiperidin-1-yl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound O=C1N(CCCC1)C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OCC MTSCQCYMOJHZFC-UHFFFAOYSA-N 0.000 claims description 2
- 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 description 2
- 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 description 2
- QBFNZPHDAKIINO-UHFFFAOYSA-N ethyl 7-[4-(azepane-1-carbonyl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound N1(CCCCCC1)C(=O)C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OCC QBFNZPHDAKIINO-UHFFFAOYSA-N 0.000 claims description 2
- IPLSEPARNLUXCV-UHFFFAOYSA-N ethyl 7-[4-(cyclobutylmethylcarbamoyl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound C1(CCC1)CNC(=O)C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OCC IPLSEPARNLUXCV-UHFFFAOYSA-N 0.000 claims description 2
- HSMIFTMWZWYZHU-UHFFFAOYSA-N ethyl 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)OCC)CC(C)(C)C HSMIFTMWZWYZHU-UHFFFAOYSA-N 0.000 claims description 2
- 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 description 2
- 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 description 2
- 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 description 2
- CHXPFCSEQOCARC-UHFFFAOYSA-N ethyl 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)OCC)CC1(CC1)C CHXPFCSEQOCARC-UHFFFAOYSA-N 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 14
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 4
- 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
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 abstract description 29
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 abstract description 29
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 22
- 201000010099 disease Diseases 0.000 abstract description 14
- 230000001225 therapeutic effect Effects 0.000 abstract description 7
- 230000001404 mediated effect Effects 0.000 abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 141
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 111
- 238000000034 method Methods 0.000 description 108
- 239000012071 phase Substances 0.000 description 82
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 81
- 239000002904 solvent Substances 0.000 description 79
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 72
- 238000000746 purification Methods 0.000 description 59
- 238000006243 chemical reaction Methods 0.000 description 55
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 46
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 44
- 150000002430 hydrocarbons Chemical group 0.000 description 41
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 40
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 37
- 239000000543 intermediate Substances 0.000 description 35
- 239000000203 mixture Substances 0.000 description 35
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- 239000002253 acid Substances 0.000 description 29
- 150000001412 amines Chemical class 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 102000005962 receptors Human genes 0.000 description 27
- 108020003175 receptors Proteins 0.000 description 27
- 238000004128 high performance liquid chromatography Methods 0.000 description 26
- 238000004808 supercritical fluid chromatography Methods 0.000 description 25
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- 229910021529 ammonia Inorganic materials 0.000 description 23
- 235000019439 ethyl acetate Nutrition 0.000 description 23
- 125000006239 protecting group Chemical group 0.000 description 23
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 22
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 22
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 22
- 239000001099 ammonium carbonate Substances 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- 230000000694 effects Effects 0.000 description 20
- 239000007788 liquid Substances 0.000 description 20
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 239000002585 base Substances 0.000 description 19
- 238000002360 preparation method Methods 0.000 description 19
- 239000011541 reaction mixture Substances 0.000 description 18
- 229910052799 carbon Inorganic materials 0.000 description 15
- 239000003814 drug Substances 0.000 description 15
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 15
- 230000003287 optical effect Effects 0.000 description 15
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 14
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 150000001408 amides Chemical class 0.000 description 12
- 150000001721 carbon Chemical group 0.000 description 12
- 239000003054 catalyst Substances 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- 238000006268 reductive amination reaction Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 239000012453 solvate Substances 0.000 description 12
- 239000011734 sodium Substances 0.000 description 11
- 150000002431 hydrogen Chemical group 0.000 description 10
- 150000002576 ketones Chemical class 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 9
- 208000028698 Cognitive impairment Diseases 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 238000004296 chiral HPLC Methods 0.000 description 8
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 8
- 208000035475 disorder Diseases 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 229910052763 palladium Inorganic materials 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 7
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 7
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 7
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 7
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 239000000472 muscarinic agonist Substances 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 239000000651 prodrug Substances 0.000 description 7
- 229940002612 prodrug Drugs 0.000 description 7
- 201000000980 schizophrenia Diseases 0.000 description 7
- JOLJIIDDOBNFHW-UHFFFAOYSA-N xanomeline Chemical compound CCCCCCOC1=NSN=C1C1=CCCN(C)C1 JOLJIIDDOBNFHW-UHFFFAOYSA-N 0.000 description 7
- 229950006755 xanomeline Drugs 0.000 description 7
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 7
- 239000011592 zinc chloride Substances 0.000 description 7
- 235000005074 zinc chloride Nutrition 0.000 description 7
- 206010012289 Dementia Diseases 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 230000008878 coupling Effects 0.000 description 6
- 238000010168 coupling process Methods 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- 230000003551 muscarinic effect Effects 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- SXAMGRAIZSSWIH-UHFFFAOYSA-N 2-[3-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,2,4-oxadiazol-5-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NOC(=N1)CC(=O)N1CC2=C(CC1)NN=N2 SXAMGRAIZSSWIH-UHFFFAOYSA-N 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- 229940121743 Muscarinic receptor agonist Drugs 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 230000001713 cholinergic effect Effects 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 230000002093 peripheral effect Effects 0.000 description 5
- 150000003053 piperidines Chemical class 0.000 description 5
- 238000000634 powder X-ray diffraction Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 201000002832 Lewy body dementia Diseases 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- 208000004550 Postoperative Pain Diseases 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- GPDHNZNLPKYHCN-DZOOLQPHSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-morpholin-4-ylmethylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.CCOC(=O)C(\C#N)=N/OC(=[N+](C)C)N1CCOCC1 GPDHNZNLPKYHCN-DZOOLQPHSA-N 0.000 description 4
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 230000006399 behavior Effects 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 229960003920 cocaine Drugs 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- IJJKMHXLBQWNNT-UHFFFAOYSA-N ethyl 7-[4-(2-oxo-1H-pyridin-3-yl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound O=C1NC=CC=C1C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OCC IJJKMHXLBQWNNT-UHFFFAOYSA-N 0.000 description 4
- OSUORQACBNGDKQ-UHFFFAOYSA-N ethyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound O=C1CC2COCC(C1)N2C(=O)OCC OSUORQACBNGDKQ-UHFFFAOYSA-N 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 239000010936 titanium Substances 0.000 description 4
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 3
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 3
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 3
- 208000008035 Back Pain Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 208000000003 Breakthrough pain Diseases 0.000 description 3
- 206010058019 Cancer Pain Diseases 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 208000006561 Cluster Headache Diseases 0.000 description 3
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 3
- 206010013774 Dry eye Diseases 0.000 description 3
- 244000166102 Eucalyptus leucoxylon Species 0.000 description 3
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 3
- 208000010412 Glaucoma Diseases 0.000 description 3
- 206010019233 Headaches Diseases 0.000 description 3
- 208000023105 Huntington disease Diseases 0.000 description 3
- 208000004404 Intractable Pain Diseases 0.000 description 3
- 208000009829 Lewy Body Disease Diseases 0.000 description 3
- 206010026749 Mania Diseases 0.000 description 3
- 208000019695 Migraine disease Diseases 0.000 description 3
- 206010028836 Neck pain Diseases 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 208000001294 Nociceptive Pain Diseases 0.000 description 3
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 3
- 206010059604 Radicular pain Diseases 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 208000008765 Sciatica Diseases 0.000 description 3
- 208000021386 Sjogren Syndrome Diseases 0.000 description 3
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 3
- 229960004373 acetylcholine Drugs 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 125000002015 acyclic group Chemical group 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 238000010640 amide synthesis reaction Methods 0.000 description 3
- 229940025084 amphetamine Drugs 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000003542 behavioural effect Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000006172 buffering agent Substances 0.000 description 3
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- WUTYZMFRCNBCHQ-PSASIEDQSA-N cevimeline Chemical compound C1S[C@H](C)O[C@]21C(CC1)CCN1C2 WUTYZMFRCNBCHQ-PSASIEDQSA-N 0.000 description 3
- 229960001314 cevimeline Drugs 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 230000006735 deficit Effects 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 206010013781 dry mouth Diseases 0.000 description 3
- 238000002825 functional assay Methods 0.000 description 3
- 210000003128 head Anatomy 0.000 description 3
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 3
- 210000001320 hippocampus Anatomy 0.000 description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000004410 intraocular pressure Effects 0.000 description 3
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 3
- 230000000155 isotopic effect Effects 0.000 description 3
- 150000003951 lactams Chemical group 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 206010027599 migraine Diseases 0.000 description 3
- YMMXHEYLRHNXAB-RMKNXTFCSA-N milameline Chemical compound CO\N=C\C1=CCCN(C)C1 YMMXHEYLRHNXAB-RMKNXTFCSA-N 0.000 description 3
- 229950004373 milameline Drugs 0.000 description 3
- 210000001577 neostriatum Anatomy 0.000 description 3
- 230000003349 osteoarthritic effect Effects 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 239000000049 pigment Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 3
- 230000002285 radioactive effect Effects 0.000 description 3
- 238000004007 reversed phase HPLC Methods 0.000 description 3
- IQWCBYSUUOFOMF-QTLFRQQHSA-N sabcomeline Chemical compound C1CC2[C@@H](C(/C#N)=N/OC)CN1CC2 IQWCBYSUUOFOMF-QTLFRQQHSA-N 0.000 description 3
- 229950000425 sabcomeline Drugs 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 206010044652 trigeminal neuralgia Diseases 0.000 description 3
- 238000001665 trituration Methods 0.000 description 3
- 208000009935 visceral pain Diseases 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- PHOZOHFUXHPOCK-QMMMGPOBSA-N (2s)-2-ethyl-8-methyl-1-thia-4,8-diazaspiro[4.5]decan-3-one Chemical compound N1C(=O)[C@H](CC)SC11CCN(C)CC1 PHOZOHFUXHPOCK-QMMMGPOBSA-N 0.000 description 2
- XGQOKMZIBPVSRL-UHFFFAOYSA-N 2-methoxy-6-piperidin-4-ylpyridine hydrochloride Chemical compound Cl.COc1cccc(n1)C1CCNCC1 XGQOKMZIBPVSRL-UHFFFAOYSA-N 0.000 description 2
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 2
- LSDUNIXJMHJKRQ-UHFFFAOYSA-N 3-oxa-9-azabicyclo[3.3.1]nonan-7-one 2,2,2-trifluoroacetic acid Chemical compound FC(C(=O)O)(F)F.C12COCC(CC(C1)=O)N2 LSDUNIXJMHJKRQ-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 206010001497 Agitation Diseases 0.000 description 2
- 208000000044 Amnesia Diseases 0.000 description 2
- 208000031091 Amnestic disease Diseases 0.000 description 2
- 102000009091 Amyloidogenic Proteins Human genes 0.000 description 2
- 108010048112 Amyloidogenic Proteins Proteins 0.000 description 2
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 2
- KBJNLAGTJNWEAN-UHFFFAOYSA-N C1=C(OC)N=C(C2CCN(C(=O)OC(C)(C)C)CC2)C=C1 Chemical compound C1=C(OC)N=C(C2CCN(C(=O)OC(C)(C)C)CC2)C=C1 KBJNLAGTJNWEAN-UHFFFAOYSA-N 0.000 description 2
- XIDZCEXJMVMNMY-UHFFFAOYSA-N COc1cccc(n1)C1=CCN(CC1)C(=O)OC(C)(C)C Chemical compound COc1cccc(n1)C1=CCN(CC1)C(=O)OC(C)(C)C XIDZCEXJMVMNMY-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- UCSAUQVHCUPHAG-UHFFFAOYSA-N Cl.N1CCC(CC1)N1C(CCCCC1)=O Chemical compound Cl.N1CCC(CC1)N1C(CCCCC1)=O UCSAUQVHCUPHAG-UHFFFAOYSA-N 0.000 description 2
- 208000024254 Delusional disease Diseases 0.000 description 2
- 206010012335 Dependence Diseases 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 201000010374 Down Syndrome Diseases 0.000 description 2
- 206010013654 Drug abuse Diseases 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 2
- 201000011240 Frontotemporal dementia Diseases 0.000 description 2
- 102000034354 Gi proteins Human genes 0.000 description 2
- 108091006101 Gi proteins Proteins 0.000 description 2
- 208000004547 Hallucinations Diseases 0.000 description 2
- 208000008454 Hyperhidrosis Diseases 0.000 description 2
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 2
- 208000026139 Memory disease Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 206010039424 Salivary hypersecretion Diseases 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 2
- 208000000323 Tourette Syndrome Diseases 0.000 description 2
- 208000016620 Tourette disease Diseases 0.000 description 2
- 201000004810 Vascular dementia Diseases 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- AXJDEHNQPMZKOS-UHFFFAOYSA-N acetylazanium;chloride Chemical compound [Cl-].CC([NH3+])=O AXJDEHNQPMZKOS-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- 230000016571 aggressive behavior Effects 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000003942 amyloidogenic effect Effects 0.000 description 2
- 230000007450 amyloidogenic pathway Effects 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 2
- 229910002056 binary alloy Inorganic materials 0.000 description 2
- 230000036471 bradycardia Effects 0.000 description 2
- 208000006218 bradycardia Diseases 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000004067 bulking agent Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000000544 cholinesterase inhibitor Substances 0.000 description 2
- 230000007278 cognition impairment Effects 0.000 description 2
- 230000003920 cognitive function Effects 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- MXFYYFVVIIWKFE-UHFFFAOYSA-N dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane Chemical group CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 MXFYYFVVIIWKFE-UHFFFAOYSA-N 0.000 description 2
- 238000000113 differential scanning calorimetry Methods 0.000 description 2
- 238000002050 diffraction method Methods 0.000 description 2
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 230000003291 dopaminomimetic effect Effects 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 238000003821 enantio-separation Methods 0.000 description 2
- QXQWTWXSWMSQTN-UHFFFAOYSA-N ethyl 7-(4-ethoxycarbonylpiperidin-1-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound C(C)OC(=O)C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OCC QXQWTWXSWMSQTN-UHFFFAOYSA-N 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 230000005176 gastrointestinal motility Effects 0.000 description 2
- 238000010914 gene-directed enzyme pro-drug therapy Methods 0.000 description 2
- 239000003979 granulating agent Substances 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 208000003532 hypothyroidism Diseases 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 208000027061 mild cognitive impairment Diseases 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 2
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 208000002851 paranoid schizophrenia Diseases 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 210000002442 prefrontal cortex Anatomy 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000000979 retarding effect Effects 0.000 description 2
- 230000000698 schizophrenic effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 208000011117 substance-related disease Diseases 0.000 description 2
- 150000003459 sulfonic acid esters Chemical class 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 239000007916 tablet composition Substances 0.000 description 2
- PJNMRNNWNFOFKB-UHFFFAOYSA-N tert-butyl 4-(2,2-dimethylpropylamino)piperidine-1-carboxylate Chemical compound CC(C)(C)CNC1CCN(C(=O)OC(C)(C)C)CC1 PJNMRNNWNFOFKB-UHFFFAOYSA-N 0.000 description 2
- XTHUDKQRZVVDNY-UHFFFAOYSA-N tert-butyl 4-(2-methylpropylamino)piperidine-1-carboxylate Chemical compound CC(C)CNC1CCN(C(=O)OC(C)(C)C)CC1 XTHUDKQRZVVDNY-UHFFFAOYSA-N 0.000 description 2
- SJEWIMADHVXYKP-UHFFFAOYSA-N tert-butyl 4-(2-oxoazepan-1-yl)piperidine-1-carboxylate Chemical compound O=C1N(CCCCC1)C1CCN(CC1)C(=O)OC(C)(C)C SJEWIMADHVXYKP-UHFFFAOYSA-N 0.000 description 2
- CTACWDCVZVSWGQ-UHFFFAOYSA-N tert-butyl 4-(6-bromohexanoylamino)piperidine-1-carboxylate Chemical compound BrCCCCCC(=O)NC1CCN(CC1)C(=O)OC(C)(C)C CTACWDCVZVSWGQ-UHFFFAOYSA-N 0.000 description 2
- JACADNGWVNRDON-UHFFFAOYSA-N tert-butyl 4-[acetyl(2,2-dimethylpropyl)amino]piperidine-1-carboxylate Chemical compound C(CN(C(=O)C)C1CCN(CC1)C(=O)OC(C)(C)C)(C)(C)C JACADNGWVNRDON-UHFFFAOYSA-N 0.000 description 2
- OHZUYKMSDAVYJH-UHFFFAOYSA-N tert-butyl 4-[acetyl(2-methylpropyl)amino]piperidine-1-carboxylate Chemical compound C(C)(=O)N(C1CCN(CC1)C(=O)OC(C)(C)C)CC(C)C OHZUYKMSDAVYJH-UHFFFAOYSA-N 0.000 description 2
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 2
- 210000001103 thalamus Anatomy 0.000 description 2
- 238000002411 thermogravimetry Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 230000000451 tissue damage Effects 0.000 description 2
- 231100000827 tissue damage Toxicity 0.000 description 2
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000008733 trauma Effects 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 2
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 238000002424 x-ray crystallography Methods 0.000 description 2
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 2
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 1
- WMJNKBXKYHXOHC-PMACEKPBSA-N (2S,3S)-2,3-dihydroxy-2,3-bis(2-methylbenzoyl)butanedioic acid Chemical compound C=1(C(=CC=CC1)C(=O)[C@]([C@](C(=O)O)(O)C(=O)C=1C(=CC=CC1)C)(O)C(=O)O)C WMJNKBXKYHXOHC-PMACEKPBSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N 1,1'-Carbonyldiimidazole Substances C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- JMAQUGPYTWILQY-UHFFFAOYSA-N 1-methylcyclobutan-1-amine;hydrochloride Chemical compound Cl.CC1(N)CCC1 JMAQUGPYTWILQY-UHFFFAOYSA-N 0.000 description 1
- XDIAMRVROCPPBK-UHFFFAOYSA-N 2,2-dimethylpropan-1-amine Chemical compound CC(C)(C)CN XDIAMRVROCPPBK-UHFFFAOYSA-N 0.000 description 1
- ZMTZHYATPMNUJR-UHFFFAOYSA-N 2-iodo-6-methoxypyridine Chemical compound COC1=CC=CC(I)=N1 ZMTZHYATPMNUJR-UHFFFAOYSA-N 0.000 description 1
- IWTFOFMTUOBLHG-UHFFFAOYSA-N 2-methoxypyridine Chemical class COC1=CC=CC=N1 IWTFOFMTUOBLHG-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- NWVSHHSCDXUYRS-UHFFFAOYSA-N 2-piperidin-4-ylacetamide Chemical compound NC(=O)CC1CCNCC1 NWVSHHSCDXUYRS-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- DPBWFNDFMCCGGJ-UHFFFAOYSA-N 4-Piperidine carboxamide Chemical class NC(=O)C1CCNCC1 DPBWFNDFMCCGGJ-UHFFFAOYSA-N 0.000 description 1
- WGNPNAOPVBYTKD-UHFFFAOYSA-N 4-pyrazol-1-ylpiperidine Chemical compound C1CNCCC1N1N=CC=C1 WGNPNAOPVBYTKD-UHFFFAOYSA-N 0.000 description 1
- FLDSMVTWEZKONL-AWEZNQCLSA-N 5,5-dimethyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1,4,7,8-tetrahydrooxepino[4,5-c]pyrazole-3-carboxamide Chemical compound CC1(CC2=C(NN=C2C(=O)N[C@@H]2C(N(C3=C(OC2)C=CC=C3)C)=O)CCO1)C FLDSMVTWEZKONL-AWEZNQCLSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- HBPVGJGBRWIVSX-UHFFFAOYSA-N 6-bromohexanoyl chloride Chemical compound ClC(=O)CCCCCBr HBPVGJGBRWIVSX-UHFFFAOYSA-N 0.000 description 1
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 1
- 206010065040 AIDS dementia complex Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010002942 Apathy Diseases 0.000 description 1
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
- 208000036574 Behavioural and psychiatric symptoms of dementia Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010008027 Cerebellar atrophy Diseases 0.000 description 1
- 206010008428 Chemical poisoning Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010012218 Delirium Diseases 0.000 description 1
- 206010012239 Delusion Diseases 0.000 description 1
- 206010067889 Dementia with Lewy bodies Diseases 0.000 description 1
- 206010012468 Dermatitis herpetiformis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010013142 Disinhibition Diseases 0.000 description 1
- 208000017701 Endocrine disease Diseases 0.000 description 1
- 208000030644 Esophageal Motility disease Diseases 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 206010015535 Euphoric mood Diseases 0.000 description 1
- 208000026097 Factitious disease Diseases 0.000 description 1
- 208000024412 Friedreich ataxia Diseases 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 206010017999 Gastrointestinal pain Diseases 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 1
- 206010020651 Hyperkinesia Diseases 0.000 description 1
- 208000000269 Hyperkinesis Diseases 0.000 description 1
- 206010021067 Hypopituitarism Diseases 0.000 description 1
- 208000012704 Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome Diseases 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 206010021518 Impaired gastric emptying Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 201000007493 Kallmann syndrome Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000020358 Learning disease Diseases 0.000 description 1
- 102000019149 MAP kinase activity proteins Human genes 0.000 description 1
- 108040008097 MAP kinase activity proteins Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000016285 Movement disease Diseases 0.000 description 1
- 208000005314 Multi-Infarct Dementia Diseases 0.000 description 1
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 1
- 208000009668 Neurobehavioral Manifestations Diseases 0.000 description 1
- 108090000189 Neuropeptides Proteins 0.000 description 1
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 1
- 206010053142 Olfacto genital dysplasia Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 206010034277 Pemphigoid Diseases 0.000 description 1
- 201000011152 Pemphigus Diseases 0.000 description 1
- 208000000609 Pick Disease of the Brain Diseases 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 206010036631 Presenile dementia Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 102000007568 Proto-Oncogene Proteins c-fos Human genes 0.000 description 1
- 108010071563 Proto-Oncogene Proteins c-fos Proteins 0.000 description 1
- 206010052276 Pseudodementia Diseases 0.000 description 1
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 1
- 208000020114 Schizophrenia and other psychotic disease Diseases 0.000 description 1
- 208000020186 Schizophreniform disease Diseases 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 208000008630 Sialorrhea Diseases 0.000 description 1
- 208000028979 Skull fracture Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 206010043118 Tardive Dyskinesia Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000005386 Transient Global Amnesia Diseases 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000007000 age related cognitive decline Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 238000003016 alphascreen Methods 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000006986 amnesia Effects 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 238000010913 antigen-directed enzyme pro-drug therapy Methods 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 1
- 229960004046 apomorphine Drugs 0.000 description 1
- 230000004594 appetite change Effects 0.000 description 1
- 238000002820 assay format Methods 0.000 description 1
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 1
- 230000006472 autoimmune response Effects 0.000 description 1
- JPNZKPRONVOMLL-UHFFFAOYSA-N azane;octadecanoic acid Chemical class [NH4+].CCCCCCCCCCCCCCCCCC([O-])=O JPNZKPRONVOMLL-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 229940023913 cation exchange resins Drugs 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 210000002932 cholinergic neuron Anatomy 0.000 description 1
- 208000019902 chronic diarrheal disease Diseases 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 230000009194 climbing Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 230000006999 cognitive decline Effects 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 230000003931 cognitive performance Effects 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229920006037 cross link polymer Polymers 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- ARUKYTASOALXFG-UHFFFAOYSA-N cycloheptylcycloheptane Chemical compound C1CCCCCC1C1CCCCCC1 ARUKYTASOALXFG-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- NLUNLVTVUDIHFE-UHFFFAOYSA-N cyclooctylcyclooctane Chemical compound C1CCCCCCC1C1CCCCCCC1 NLUNLVTVUDIHFE-UHFFFAOYSA-N 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 231100000868 delusion Toxicity 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 208000013219 diaphoresis Diseases 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- 229960003530 donepezil Drugs 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 210000004002 dopaminergic cell Anatomy 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 201000011191 dyskinesia of esophagus Diseases 0.000 description 1
- 230000000142 dyskinetic effect Effects 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 238000002635 electroconvulsive therapy Methods 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 208000030172 endocrine system disease Diseases 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- IFMHTLPQKAWQQV-UHFFFAOYSA-N ethyl 7-(3-oxo-2,8-diazaspiro[4.5]decan-8-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound O=C1NCC2(C1)CCN(CC2)C1CC2COCC(C1)N2C(=O)OCC IFMHTLPQKAWQQV-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- RUJPPJYDHHAEEK-UHFFFAOYSA-N ethyl piperidine-4-carboxylate Chemical compound CCOC(=O)C1CCNCC1 RUJPPJYDHHAEEK-UHFFFAOYSA-N 0.000 description 1
- 210000003499 exocrine gland Anatomy 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 238000010304 firing Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 230000007661 gastrointestinal function Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 208000001288 gastroparesis Diseases 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000003400 hallucinatory effect Effects 0.000 description 1
- 210000005003 heart tissue Anatomy 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000002989 hypothyroidism Effects 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 230000030214 innervation Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- SYJRVVFAAIUVDH-UHFFFAOYSA-N ipa isopropanol Chemical compound CC(C)O.CC(C)O SYJRVVFAAIUVDH-UHFFFAOYSA-N 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 201000003723 learning disability Diseases 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 240000004308 marijuana Species 0.000 description 1
- 241001515942 marmosets Species 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000015654 memory Effects 0.000 description 1
- 230000006984 memory degeneration Effects 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 208000023060 memory loss Diseases 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- XEVHNOWPVLZQDR-UHFFFAOYSA-N methyl 7-[4-(azepane-1-carbonyl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate Chemical compound N1(CCCCCC1)C(=O)C1CCN(CC1)C1CC2COCC(C1)N2C(=O)OC XEVHNOWPVLZQDR-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 150000002780 morpholines Chemical class 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- ADAMEOZKZQRNKP-UHFFFAOYSA-N n'-propylmethanediimine Chemical compound CCCN=C=N ADAMEOZKZQRNKP-UHFFFAOYSA-N 0.000 description 1
- 201000003631 narcolepsy Diseases 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000001722 neurochemical effect Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 239000002581 neurotoxin Substances 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 210000001009 nucleus accumben Anatomy 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 230000008533 pain sensitivity Effects 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 201000001976 pemphigus vulgaris Diseases 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 208000022821 personality disease Diseases 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 210000000063 presynaptic terminal Anatomy 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 210000004129 prosencephalon Anatomy 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000009993 protective function Effects 0.000 description 1
- 230000006337 proteolytic cleavage Effects 0.000 description 1
- 230000002385 psychotomimetic effect Effects 0.000 description 1
- 210000002637 putamen Anatomy 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000003014 reinforcing effect Effects 0.000 description 1
- 238000009256 replacement therapy Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 208000026451 salivation Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 208000022610 schizoaffective disease Diseases 0.000 description 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 206010040882 skin lesion Diseases 0.000 description 1
- 231100000444 skin lesion Toxicity 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000006886 spatial memory Effects 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 210000000106 sweat gland Anatomy 0.000 description 1
- 230000035900 sweating Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000015883 synaptic transmission, dopaminergic Effects 0.000 description 1
- 206010042772 syncope Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006068 taste-masking agent Substances 0.000 description 1
- 102000013498 tau Proteins Human genes 0.000 description 1
- 108010026424 tau Proteins Proteins 0.000 description 1
- VVDCRJGWILREQH-UHFFFAOYSA-N tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC(B2OC(C)(C)C(C)(C)O2)=C1 VVDCRJGWILREQH-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 230000001515 vagal effect Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 230000001755 vocal effect Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000003936 working memory Effects 0.000 description 1
Classifications
-
- 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
-
- 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
-
- 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)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB1810239.2A GB201810239D0 (en) | 2018-06-22 | 2018-06-22 | Pharmaceutical compounds |
| PCT/GB2019/051780 WO2019243851A1 (en) | 2018-06-22 | 2019-06-24 | Bridged compounds as agonists of the muscarinic m1 and/or m4 receptor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2984420T3 true ES2984420T3 (es) | 2024-10-29 |
Family
ID=63042513
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES19734492T Active ES2984420T3 (es) | 2018-06-22 | 2019-06-24 | Compuestos con puente como agonistas del receptor muscarínico M1 y/o M4 |
Country Status (10)
| Country | Link |
|---|---|
| US (2) | US10787447B2 (enExample) |
| EP (1) | EP3810614B1 (enExample) |
| JP (1) | JP7317054B2 (enExample) |
| CN (1) | CN112585143B (enExample) |
| AU (1) | AU2019289217B2 (enExample) |
| CA (1) | CA3104222A1 (enExample) |
| ES (1) | ES2984420T3 (enExample) |
| GB (1) | GB201810239D0 (enExample) |
| TW (1) | TWI822803B (enExample) |
| WO (1) | WO2019243851A1 (enExample) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| GB202020191D0 (en) * | 2020-12-18 | 2021-02-03 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
Family Cites Families (94)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| AU734892B2 (en) | 1997-06-18 | 2001-06-28 | Merck & Co., Inc. | Alpha 1a adrenergic receptor antagonists |
| GB9715892D0 (en) | 1997-07-29 | 1997-10-01 | Zeneca Ltd | Heterocyclic compounds |
| AU2095099A (en) | 1997-12-23 | 1999-07-12 | Alcon Laboratories, Inc. | Phthalimide-piperidine, -pyrrolidine and -azepine derivatives, their preparationand their use as muscarinic receptor (ant-)agonists |
| AU2206699A (en) | 1997-12-23 | 1999-07-12 | Alcon Laboratories, Inc. | Muscarinic agents and use thereof to treat glaucoma, myopia and various other conditions |
| AU2307899A (en) | 1997-12-23 | 1999-07-12 | Alcon Laboratories, Inc. | Muscarinic agents and use thereof to treat glaucoma, myopia and various other conditions |
| WO1999032481A1 (en) | 1997-12-23 | 1999-07-01 | Alcon Laboratories, Inc. | Muscarinic agents and use thereof to treat glaucoma, myopia and various other conditions |
| CZ286152B6 (cs) | 1998-03-13 | 2000-01-12 | Miroslav Ing. Csc. Vlček | Transparentní a semitransparentní difrakční prvky |
| WO2000066141A2 (en) | 1999-05-04 | 2000-11-09 | Schering Corporation | Pegylated interferon alfa-ccr5 antagonist combination hiv therapy |
| PL203117B1 (pl) | 1999-05-04 | 2009-08-31 | Schering Corp | Piperydynopiperydynowa pochodna użyteczna jako antagonista CCR5, zawierająca ją kompozycja farmaceutyczna i jej zastosowanie |
| US6387930B1 (en) | 1999-05-04 | 2002-05-14 | Schering Corporation | Piperidine derivatives useful as CCR5 antagonists |
| HUP0302380A2 (hu) | 1999-09-13 | 2004-03-01 | Boehringer Ingelheim Pharmaceuticals, Inc. | Cisztein-proteázok reverzibilis inhibitoraiként alkalmazható új spiroheterociklusos vegyületek, eljárás az előállításukra és ezeket tartalmazó gyógyszerkészítmények |
| US6420364B1 (en) | 1999-09-13 | 2002-07-16 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compound useful as reversible inhibitors of cysteine proteases |
| US6921763B2 (en) | 1999-09-17 | 2005-07-26 | Abbott Laboratories | Pyrazolopyrimidines as therapeutic agents |
| ES2223588T3 (es) | 1999-10-13 | 2005-03-01 | Banyu Pharmaceutical Co., Ltd. | Derivados de imidazolidinona sustituidos. |
| AU2001297648A1 (en) | 2000-11-28 | 2002-08-28 | Eli Lilly And Company | Substituted carboxamides as inhibitors of factor xa |
| US7164024B2 (en) | 2001-04-20 | 2007-01-16 | Banyu Pharmaceutical Co., Ltd. | Benzimidazolone derivatives |
| EP1395257A1 (en) | 2001-06-12 | 2004-03-10 | Elan Pharmaceuticals, Inc. | Macrocycles useful in the treatment of alzheimer's disease |
| WO2004089942A2 (en) | 2001-10-02 | 2004-10-21 | Acadia Pharmaceuticals Inc. | Benzimidazolidinone derivatives as muscarinic agents |
| GB0128378D0 (en) | 2001-11-27 | 2002-01-16 | Smithkline Beecham Plc | Novel Compounds |
| US7550459B2 (en) | 2001-12-28 | 2009-06-23 | Acadia Pharmaceuticals, Inc. | Tetrahydroquinoline analogues as muscarinic agonists |
| AU2002359875B2 (en) | 2001-12-28 | 2009-01-08 | Acadia Pharmaceuticals Inc. | Tetrahydroquinoline analogues as muscarinic agonists |
| US7256186B2 (en) | 2002-02-06 | 2007-08-14 | Schering Corporation | Gamma secretase inhibitors |
| US20040171614A1 (en) | 2002-02-06 | 2004-09-02 | Schering-Plough Corporation | Novel gamma secretase inhibitors |
| IL163923A0 (en) | 2002-03-28 | 2005-12-18 | Tanabe Seiyaku Co | Benzofuran derivatives |
| AU2003242252A1 (en) | 2002-06-07 | 2003-12-22 | Kyowa Hakko Kogyo Co., Ltd. | Bicyclic pyrimidine derivatives |
| EP1546098B1 (en) | 2002-07-31 | 2008-05-28 | Ranbaxy Laboratories Limited | 3,6-disubstituted azabicyclo [3.1.0]hexane derivatives useful as muscarinic receptor antagonists |
| PT1551835E (pt) | 2002-09-30 | 2007-03-30 | Neurosearch As | Novos derivados de 1, 4-diazabicicloalcano, sua preparação e utilização |
| EP1562956A4 (en) | 2002-11-22 | 2007-10-10 | Japan Tobacco Inc | HETEROCYCLES CONTAINING FUSED BICYCLIC NITROGEN |
| WO2004050024A2 (en) | 2002-11-27 | 2004-06-17 | Incyte Corporation | 3-aminopyrrolidine derivatives as modulators of chemokine receptors |
| WO2004069828A1 (ja) | 2003-02-04 | 2004-08-19 | Mitsubishi Pharma Corporation | ピペリジン化合物およびその医薬用途 |
| JP4324791B2 (ja) | 2003-07-17 | 2009-09-02 | アステラス製薬株式会社 | ２−アシルアミノチアゾール誘導体又はその塩 |
| WO2005037269A1 (ja) | 2003-10-21 | 2005-04-28 | Dainippon Sumitomo Pharma Co., Ltd. | 新規ピペリジン誘導体 |
| EP1725235B1 (en) | 2004-02-05 | 2009-04-15 | Schering Corporation | Piperidine derivatives useful as ccr3 antagonists |
| EP1716156A2 (en) | 2004-02-10 | 2006-11-02 | F.Hoffmann-La Roche Ag | Chemokine ccr5 receptor modulators |
| US7488745B2 (en) | 2004-07-16 | 2009-02-10 | Schering Corporation | Compounds for the treatment of inflammatory disorders |
| US7504424B2 (en) | 2004-07-16 | 2009-03-17 | Schering Corporation | Compounds for the treatment of inflammatory disorders |
| US7786141B2 (en) | 2004-08-19 | 2010-08-31 | Vertex Pharmaceuticals Incorporated | Dihydrospiroindene modulators of muscarinic receptors |
| JP2008521821A (ja) | 2004-11-29 | 2008-06-26 | バーテックス ファーマシューティカルズ インコーポレイテッド | ムスカリン受容体のモジュレーター |
| JP4774995B2 (ja) | 2005-01-12 | 2011-09-21 | アステラス製薬株式会社 | アシルアミノチアゾール誘導体を有効成分とする医薬組成物 |
| US7786308B2 (en) | 2005-03-28 | 2010-08-31 | Vertex Pharmaceuticals Incorporated | Muscarinic modulators |
| EP2468743A1 (en) | 2005-06-24 | 2012-06-27 | Toyama Chemical Co., Ltd. | Nitrogen-containing bicyclic compounds useful as antibacterial agents |
| CA2634456A1 (en) | 2005-12-22 | 2007-07-05 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
| US7772231B2 (en) | 2005-12-29 | 2010-08-10 | Abbott Laboratories | Substituted pyrazolo[3,4-d]pyrimidines as protein kinase inhibitors |
| US8003660B2 (en) | 2006-02-22 | 2011-08-23 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
| RU2008137583A (ru) | 2006-02-22 | 2010-03-27 | Вертекс Фармасьютикалз Инкорпорейшн (Us) | Спиропиперидины в качестве модуляторов мускариновых рецепторов |
| CN101553231A (zh) | 2006-08-15 | 2009-10-07 | 弗特克斯药品有限公司 | 毒蕈碱受体调节剂 |
| EA200900821A1 (ru) | 2006-12-22 | 2010-02-26 | Новартис Аг | Производные 1-аминометил-l-фенилциклогексана как ингибиторы дпп-iv (дипептидилпептидазы-iv) |
| WO2008117229A1 (en) | 2007-03-23 | 2008-10-02 | Ranbaxy Laboratories Limited | Muscarinic receptor antagonists |
| US8119661B2 (en) | 2007-09-11 | 2012-02-21 | Astrazeneca Ab | Piperidine derivatives and their use as muscarinic receptor modulators |
| WO2009118370A1 (en) | 2008-03-27 | 2009-10-01 | Janssen Pharmaceutica Nv | Aza-bicyclohexyl substituted indolyl alkyl amino derivatives as novel inhibitors of histone deacetylase |
| AU2009309988A1 (en) | 2008-10-29 | 2010-05-06 | Grunenthal Gmbh | Substituted spiroamines |
| ES2551557T3 (es) | 2008-12-19 | 2015-11-19 | Boehringer Ingelheim International Gmbh | Pirimidin-4-carboxamidas cíclicas como antagonistas del receptor CCR2 para el tratamiento de inflamaciones, asma y EPOC |
| ES2528625T3 (es) | 2009-04-17 | 2015-02-11 | Janssen Pharmaceutica Nv | Antagonistas de 4-azetidinil-1-fenil-ciclohexano de CCR2 |
| 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 |
| US20130197027A1 (en) | 2010-03-10 | 2013-08-01 | Craig Lindsley | Heterocyclyl-azabicyclo[3.2.1]octane analogs as selective m1 agonists and methods of making and using same |
| US8822447B2 (en) | 2010-04-22 | 2014-09-02 | Janssen Pharmaceutica Nv | Indazole compounds useful as ketohexokinase inhibitors |
| WO2011137012A1 (en) | 2010-04-27 | 2011-11-03 | Merck Sharp & Dohme Corp. | Prolylcarboxypeptidase inhibitors |
| WO2011143057A1 (en) | 2010-05-11 | 2011-11-17 | Merck Sharp & Dohme Corp. | Novel prolylcarboxypeptidase inhibitors |
| JP2013528180A (ja) | 2010-05-28 | 2013-07-08 | ジーイー・ヘルスケア・リミテッド | 放射性標識化合物及びその製造方法 |
| CN103221046A (zh) | 2010-09-17 | 2013-07-24 | 阵列生物制药公司 | 作为gpr119调节剂的哌啶基取代的内酰胺 |
| EP2685828A4 (en) | 2011-03-17 | 2014-08-13 | Merck Sharp & Dohme | SUBSTITUTED 3-AZABICYCLO [3,1,0-] HEXAN DERIVATIVES AS CCR2 ANTAGONISTS |
| JP2013010719A (ja) | 2011-06-30 | 2013-01-17 | Dainippon Sumitomo Pharma Co Ltd | ベンズイミダゾロンおよびオキシインドール誘導体ならびにそれらの医薬用途 |
| ES2619829T3 (es) | 2011-11-18 | 2017-06-27 | Heptares Therapeutics Limited | Agonistas del receptor muscarínico M1 |
| EP2897948B1 (en) * | 2012-09-18 | 2016-08-31 | Heptares Therapeutics Limited | Bicyclic aza compounds as muscarinic m1 receptor agonists |
| US9593106B2 (en) | 2013-02-07 | 2017-03-14 | Heptares Therapeutics Limited | Piperidin-1-yl and azepin-1-yl carboxylates as muscarinic M4 receptor agonists |
| RU2685230C2 (ru) | 2014-02-06 | 2019-04-17 | Хептарес Терапьютикс Лимитед | Бициклические азотсодержащие соединения как агонисты М1 мускариновых рецепторов |
| GB201404922D0 (en) * | 2014-03-19 | 2014-04-30 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| CN107406434B (zh) | 2015-02-13 | 2020-09-11 | 苏文生命科学有限公司 | 作为5-ht4受体激动剂的酰胺化合物 |
| GB201504675D0 (en) * | 2015-03-19 | 2015-05-06 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| GB201513742D0 (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 |
| 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 |
| US10259787B2 (en) | 2016-10-14 | 2019-04-16 | Heptares Therapeutics Limited | Substituted cyclohexanes as muscarinic M1 receptor and/or M4 receptor agonists |
| GB201617454D0 (en) * | 2016-10-14 | 2016-11-30 | Heptares Therapeutics Limited | Pharmaceutical compounds |
| GB201709652D0 (en) * | 2017-06-16 | 2017-08-02 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| US10501483B2 (en) | 2017-10-24 | 2019-12-10 | Allergan, Inc. | Enamines and diastereo-selective reduction of enamines |
| GB201810239D0 (en) | 2018-06-22 | 2018-08-08 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| GB201810245D0 (en) | 2018-06-22 | 2018-08-08 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| 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 |
| GB202020191D0 (en) | 2020-12-18 | 2021-02-03 | Heptares Therapeutics Ltd | Pharmaceutical compounds |
| GB202103211D0 (en) | 2021-03-08 | 2021-04-21 | Heptares Therapeutics Ltd | Pharmaceutical compounds for use in therapy |
-
2018
- 2018-06-22 GB GBGB1810239.2A patent/GB201810239D0/en not_active Ceased
-
2019
- 2019-06-24 AU AU2019289217A patent/AU2019289217B2/en active Active
- 2019-06-24 EP EP19734492.2A patent/EP3810614B1/en active Active
- 2019-06-24 TW TW108122030A patent/TWI822803B/zh active
- 2019-06-24 JP JP2020571690A patent/JP7317054B2/ja active Active
- 2019-06-24 CN CN201980054903.9A patent/CN112585143B/zh active Active
- 2019-06-24 US US16/450,261 patent/US10787447B2/en active Active
- 2019-06-24 CA CA3104222A patent/CA3104222A1/en active Pending
- 2019-06-24 ES ES19734492T patent/ES2984420T3/es active Active
- 2019-06-24 WO PCT/GB2019/051780 patent/WO2019243851A1/en not_active Ceased
-
2020
- 2020-09-17 US US17/024,085 patent/US11773090B2/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| US10787447B2 (en) | 2020-09-29 |
| AU2019289217A1 (en) | 2021-01-14 |
| TW202019922A (zh) | 2020-06-01 |
| JP7317054B2 (ja) | 2023-07-28 |
| TWI822803B (zh) | 2023-11-21 |
| US20210002271A1 (en) | 2021-01-07 |
| EP3810614A1 (en) | 2021-04-28 |
| JP2021528446A (ja) | 2021-10-21 |
| AU2019289217B2 (en) | 2023-08-17 |
| CN112585143B (zh) | 2024-11-12 |
| EP3810614C0 (en) | 2024-03-27 |
| CA3104222A1 (en) | 2019-12-26 |
| CN112585143A (zh) | 2021-03-30 |
| US20200002328A1 (en) | 2020-01-02 |
| US11773090B2 (en) | 2023-10-03 |
| EP3810614B1 (en) | 2024-03-27 |
| WO2019243851A1 (en) | 2019-12-26 |
| GB201810239D0 (en) | 2018-08-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2852753T3 (es) | Compuestos espirocíclicos como agonistas del receptor muscarínico M1 y/o M4 | |
| ES2980578T3 (es) | Agonistas muscarínicos | |
| CN112585143B (zh) | 作为毒蕈碱m1和/或m4受体的激动剂的桥接化合物 | |
| ES2986327T3 (es) | Compuestos aza bicíclicos como agonistas del receptor muscarínico | |
| ES2872378T3 (es) | Agonistas de receptores muscarínicos | |
| ES2894855T3 (es) | Agonistas muscarínicos | |
| ES2894637T3 (es) | Agonistas muscarínicos | |
| ES2804774T3 (es) | Compuestos de oxima como agonistas del receptor muscarínico M1 y/o M4 | |
| CN112585135B (zh) | 作为毒蕈碱m1和/或m4受体的激动剂的噁二唑 | |
| ES3050708T3 (en) | Pharmaceutical compounds | |
| ES2898206T3 (es) | Compuestos heterocíclicos que tienen actividad como moduladores de los receptores muscarínicos M1 y/o M4 en el tratamiento de enfermedades y dolores del SNC | |
| ES2976504T3 (es) | Derivados de quinolinona y benzoxazina como agonistas de los receptores muscarínicos M1 y/o M4 | |
| BR112014012056B1 (pt) | Compostos agonistas do receptor m1 muscarínico, composição farmacêutica compreendendo os ditos compostos e uso dos mesmos para tratar um distúrbio cognitivo ou psicótico ou para tratamento ou diminuição da severidade da dor aguda, crônica, neuropática ou inflamatória | |
| WO2020115505A1 (en) | Bicyclic aza compounds as muscarinic m1 and/or m4 receptor agonists | |
| HK40044466A (en) | Bridged compounds as agonists of the muscarinic m1 and/or m4 receptor | |
| HK40044466B (en) | Bridged compounds as agonists of the muscarinic m1 and/or m4 receptor | |
| HK40020504B (en) | Pharmaceutical compounds | |
| HK40020504A (en) | Pharmaceutical compounds |