WO2012113850A2 - (PYRIDIN-4-YL)BENZYLAMIDES AS ALLOSTERIC MODULATORS OF ALPHA 7 nAChR - Google Patents
(PYRIDIN-4-YL)BENZYLAMIDES AS ALLOSTERIC MODULATORS OF ALPHA 7 nAChR Download PDFInfo
- Publication number
- WO2012113850A2 WO2012113850A2 PCT/EP2012/053047 EP2012053047W WO2012113850A2 WO 2012113850 A2 WO2012113850 A2 WO 2012113850A2 EP 2012053047 W EP2012053047 W EP 2012053047W WO 2012113850 A2 WO2012113850 A2 WO 2012113850A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- dimethyl
- pyridinyl
- trifluoromethyl
- morpholinyl
- Prior art date
Links
- -1 PYRIDIN-4-YL Chemical class 0.000 title claims description 68
- 230000003281 allosteric effect Effects 0.000 title abstract description 11
- 102000015296 acetylcholine-gated cation-selective channel activity proteins Human genes 0.000 title 1
- 108040006409 acetylcholine-gated cation-selective channel activity proteins Proteins 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 54
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- 230000008569 process Effects 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 170
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 63
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 27
- 230000006735 deficit Effects 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 22
- 201000010099 disease Diseases 0.000 claims description 21
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 15
- 208000035475 disorder Diseases 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 201000000980 schizophrenia Diseases 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- 229960002715 nicotine Drugs 0.000 claims description 11
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims description 10
- 208000024827 Alzheimer disease Diseases 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 208000018737 Parkinson disease Diseases 0.000 claims description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 8
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 8
- RPYWXZCFYPVCNQ-RVDMUPIBSA-N DMXB-A Chemical compound COC1=CC(OC)=CC=C1\C=C/1C(C=2C=NC=CC=2)=NCCC\1 RPYWXZCFYPVCNQ-RVDMUPIBSA-N 0.000 claims description 8
- 208000028017 Psychotic disease Diseases 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 8
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 208000019901 Anxiety disease Diseases 0.000 claims description 6
- 208000020925 Bipolar disease Diseases 0.000 claims description 6
- 208000019888 Circadian rhythm sleep disease Diseases 0.000 claims description 6
- 208000023105 Huntington disease Diseases 0.000 claims description 6
- 208000001456 Jet Lag Syndrome Diseases 0.000 claims description 6
- 208000009829 Lewy Body Disease Diseases 0.000 claims description 6
- 201000002832 Lewy body dementia Diseases 0.000 claims description 6
- 206010026749 Mania Diseases 0.000 claims description 6
- 206010057852 Nicotine dependence Diseases 0.000 claims description 6
- 208000002193 Pain Diseases 0.000 claims description 6
- 208000025569 Tobacco Use disease Diseases 0.000 claims description 6
- 208000000323 Tourette Syndrome Diseases 0.000 claims description 6
- 208000016620 Tourette disease Diseases 0.000 claims description 6
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 6
- 230000036506 anxiety Effects 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 208000033915 jet lag type circadian rhythm sleep disease Diseases 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- 208000028683 bipolar I disease Diseases 0.000 claims description 5
- 230000019771 cognition Effects 0.000 claims description 5
- 208000027866 inflammatory disease Diseases 0.000 claims description 5
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- WECKJONDRAUFDD-ZDUSSCGKSA-N N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-4-chlorobenzamide Chemical compound C1=CC(Cl)=CC=C1C(=O)N[C@@H]1C(CC2)CCN2C1 WECKJONDRAUFDD-ZDUSSCGKSA-N 0.000 claims description 4
- 206010033645 Pancreatitis Diseases 0.000 claims description 4
- 206010054048 Postoperative ileus Diseases 0.000 claims description 4
- 206010040047 Sepsis Diseases 0.000 claims description 4
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 4
- 206010069351 acute lung injury Diseases 0.000 claims description 4
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 230000002757 inflammatory effect Effects 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- 125000002971 oxazolyl group Chemical group 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
- 229960004751 varenicline Drugs 0.000 claims description 4
- OCKIPDMKGPYYJS-ZDUSSCGKSA-N (3r)-spiro[1-azabicyclo[2.2.2]octane-3,2'-3h-furo[2,3-b]pyridine] Chemical compound C1N(CC2)CCC2[C@]21OC1=NC=CC=C1C2 OCKIPDMKGPYYJS-ZDUSSCGKSA-N 0.000 claims description 3
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 claims description 3
- 229950003210 bradanicline Drugs 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 3
- CMRLNEYJEPELSM-BTQNPOSSSA-N n-[(3s)-1-azabicyclo[2.2.2]octan-3-yl]-1h-indazole-3-carboxamide;hydrochloride Chemical compound Cl.C1=CC=C2C(C(N[C@H]3C4CCN(CC4)C3)=O)=NNC2=C1 CMRLNEYJEPELSM-BTQNPOSSSA-N 0.000 claims description 3
- SMLPPRNAOTXZTL-KDURUIRLSA-N n-[[5-[(2s,6r)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)phenyl]methyl]-2-methylpropanamide Chemical compound CC(C)C(=O)NCC1=CC(N2C[C@@H](C)O[C@@H](C)C2)=CC=C1C1=CC(C)=NC(C)=C1 SMLPPRNAOTXZTL-KDURUIRLSA-N 0.000 claims description 3
- 239000000181 nicotinic agonist Substances 0.000 claims description 3
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 229960003688 tropisetron Drugs 0.000 claims description 3
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 claims description 3
- TYAGAVRSOFABFO-VIFPVBQESA-N (5s)-spiro[1,3-oxazolidine-5,3'-1-azabicyclo[2.2.2]octane]-2-one Chemical compound O1C(=O)NC[C@]11C(CC2)CCN2C1 TYAGAVRSOFABFO-VIFPVBQESA-N 0.000 claims description 2
- CUJPFPXNDSIBPG-UHFFFAOYSA-N 1,3-propanediyl Chemical group [CH2]C[CH2] CUJPFPXNDSIBPG-UHFFFAOYSA-N 0.000 claims description 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- 208000011231 Crohn disease Diseases 0.000 claims description 2
- 208000037487 Endotoxemia Diseases 0.000 claims description 2
- 206010014824 Endotoxic shock Diseases 0.000 claims description 2
- 206010019280 Heart failures Diseases 0.000 claims description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 2
- 229940123925 Nicotinic receptor agonist Drugs 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 206010040070 Septic Shock Diseases 0.000 claims description 2
- 206010052779 Transplant rejections Diseases 0.000 claims description 2
- 208000024780 Urticaria Diseases 0.000 claims description 2
- 206010003246 arthritis Diseases 0.000 claims description 2
- 208000006673 asthma Diseases 0.000 claims description 2
- 210000000941 bile Anatomy 0.000 claims description 2
- OXKRFEWMSWPKKV-RXVVDRJESA-N bradanicline Chemical compound C([C@@H]1N2CCC(CC2)[C@@H]1NC(=O)C=1OC2=CC=CC=C2C=1)C1=CC=CN=C1 OXKRFEWMSWPKKV-RXVVDRJESA-N 0.000 claims description 2
- 208000010877 cognitive disease Diseases 0.000 claims description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 208000027061 mild cognitive impairment Diseases 0.000 claims description 2
- 201000006417 multiple sclerosis Diseases 0.000 claims description 2
- JRLDZDJDIKSMTP-UHFFFAOYSA-N n-(1-azabicyclo[2.2.2]octan-3-yl)-1-benzofuran-2-carboxamide Chemical compound C1=CC=C2OC(C(NC3C4CCN(CC4)C3)=O)=CC2=C1 JRLDZDJDIKSMTP-UHFFFAOYSA-N 0.000 claims description 2
- SSRDSYXGYPJKRR-ZDUSSCGKSA-N n-[(3r)-1-azabicyclo[2.2.2]octan-3-yl]-7-chloro-1-benzothiophene-2-carboxamide Chemical compound C1N(CC2)CCC2[C@H]1NC(=O)C1=CC(C=CC=C2Cl)=C2S1 SSRDSYXGYPJKRR-ZDUSSCGKSA-N 0.000 claims description 2
- PTGWFYYEAUFEAS-ZYHUDNBSSA-N n-[(3r,5r)-1-azabicyclo[3.2.1]octan-3-yl]furo[2,3-c]pyridine-5-carboxamide Chemical compound N([C@H]1CN2CC[C@@](C2)(C1)[H])C(=O)C(N=C1)=CC2=C1OC=C2 PTGWFYYEAUFEAS-ZYHUDNBSSA-N 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
- UIVFDCIXTSJXBB-ITGUQSILSA-N tropisetron Chemical compound C1=CC=C[C]2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CN=C21 UIVFDCIXTSJXBB-ITGUQSILSA-N 0.000 claims description 2
- XCHIZTUBUXZESJ-UHFFFAOYSA-N way-317,538 Chemical compound C=1C=C(C=2C=NC=CC=2)C=CC=1NC(=O)CCCCN1CCOCC1 XCHIZTUBUXZESJ-UHFFFAOYSA-N 0.000 claims description 2
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 abstract description 67
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 abstract description 67
- 229940044601 receptor agonist Drugs 0.000 abstract description 6
- 239000000018 receptor agonist Substances 0.000 abstract description 6
- 238000002560 therapeutic procedure Methods 0.000 abstract description 5
- LCUREJHJUJCKQS-UHFFFAOYSA-N n-benzylpyridin-4-amine Chemical class C=1C=CC=CC=1CNC1=CC=NC=C1 LCUREJHJUJCKQS-UHFFFAOYSA-N 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 description 231
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 130
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 84
- 239000000203 mixture Substances 0.000 description 67
- 239000011541 reaction mixture Substances 0.000 description 46
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 41
- 239000002904 solvent Substances 0.000 description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 41
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 38
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 37
- 239000000556 agonist Substances 0.000 description 33
- 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 32
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [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 30
- 230000000694 effects Effects 0.000 description 29
- 229940126027 positive allosteric modulator Drugs 0.000 description 29
- 239000003480 eluent Substances 0.000 description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 239000012299 nitrogen atmosphere Substances 0.000 description 27
- 238000004440 column chromatography Methods 0.000 description 26
- 239000012044 organic layer Substances 0.000 description 26
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 26
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 25
- 239000000741 silica gel Substances 0.000 description 25
- 229910002027 silica gel Inorganic materials 0.000 description 25
- 102000005962 receptors Human genes 0.000 description 24
- 108020003175 receptors Proteins 0.000 description 24
- 239000000243 solution Substances 0.000 description 24
- 239000003054 catalyst Substances 0.000 description 23
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 23
- 229960001231 choline Drugs 0.000 description 23
- 238000011282 treatment Methods 0.000 description 23
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 22
- 239000002585 base Chemical class 0.000 description 22
- 239000012298 atmosphere Substances 0.000 description 19
- 238000001035 drying Methods 0.000 description 19
- 229910052757 nitrogen Inorganic materials 0.000 description 19
- 239000007787 solid Substances 0.000 description 19
- XYNDKPYVNTVDAH-UHFFFAOYSA-N 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound CC1=NC(C)=CC(B2OC(C)(C)C(C)(C)O2)=C1 XYNDKPYVNTVDAH-UHFFFAOYSA-N 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 17
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 16
- 239000010410 layer Substances 0.000 description 16
- 230000004044 response Effects 0.000 description 16
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 14
- 229960004373 acetylcholine Drugs 0.000 description 14
- 230000009286 beneficial effect Effects 0.000 description 14
- 238000000586 desensitisation Methods 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 229910052799 carbon Inorganic materials 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 241000282414 Homo sapiens Species 0.000 description 9
- 239000003446 ligand Substances 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 229940122656 Alpha-7 nicotinic receptor agonist Drugs 0.000 description 8
- 230000004913 activation Effects 0.000 description 8
- 229910052796 boron Inorganic materials 0.000 description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- HNVIQLPOGUDBSU-OLQVQODUSA-N (2s,6r)-2,6-dimethylmorpholine Chemical compound C[C@H]1CNC[C@@H](C)O1 HNVIQLPOGUDBSU-OLQVQODUSA-N 0.000 description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 7
- 229910052794 bromium Inorganic materials 0.000 description 7
- 238000011321 prophylaxis Methods 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 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 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000005909 Kieselgur Substances 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000011575 calcium Substances 0.000 description 6
- 229910052791 calcium Inorganic materials 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 230000007278 cognition impairment Effects 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 230000001965 increasing effect Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 5
- 208000000044 Amnesia Diseases 0.000 description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
- 208000026139 Memory disease Diseases 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 230000003935 attention Effects 0.000 description 5
- 230000005540 biological transmission Effects 0.000 description 5
- 230000015556 catabolic process Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000001713 cholinergic effect Effects 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 230000006984 memory degeneration Effects 0.000 description 5
- 208000023060 memory loss Diseases 0.000 description 5
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 5
- 239000005695 Ammonium acetate Substances 0.000 description 4
- 238000011765 DBA/2 mouse Methods 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- 239000007868 Raney catalyst Substances 0.000 description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 4
- 229910000564 Raney nickel Inorganic materials 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 235000019257 ammonium acetate Nutrition 0.000 description 4
- 229940043376 ammonium acetate Drugs 0.000 description 4
- 239000012131 assay buffer Substances 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 230000009151 sensory gating Effects 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- 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 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- CTSHRMBLMKPDAG-UHFFFAOYSA-N 2-bromo-5-chlorobenzonitrile Chemical compound ClC1=CC=C(Br)C(C#N)=C1 CTSHRMBLMKPDAG-UHFFFAOYSA-N 0.000 description 3
- RMKVVKONOMXMAB-KDURUIRLSA-N 2-cyclopropyl-n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)phenyl]methyl]acetamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC=C(C=2C=C(C)N=C(C)C=2)C(CNC(=O)CC2CC2)=C1 RMKVVKONOMXMAB-KDURUIRLSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 102000004086 Ligand-Gated Ion Channels Human genes 0.000 description 3
- 108090000543 Ligand-Gated Ion Channels Proteins 0.000 description 3
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 3
- 150000001266 acyl halides Chemical class 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 230000010405 clearance mechanism Effects 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 230000009849 deactivation Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 210000001320 hippocampus Anatomy 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- UEXQBEVWFZKHNB-UHFFFAOYSA-N intermediate 29 Natural products C1=CC(N)=CC=C1NC1=NC=CC=N1 UEXQBEVWFZKHNB-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 230000000926 neurological effect Effects 0.000 description 3
- LUYQYZLEHLTPBH-UHFFFAOYSA-N perfluorobutanesulfonyl fluoride Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)S(F)(=O)=O LUYQYZLEHLTPBH-UHFFFAOYSA-N 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 208000020016 psychiatric disease Diseases 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 230000000698 schizophrenic effect Effects 0.000 description 3
- 230000031893 sensory processing Effects 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000007910 systemic administration Methods 0.000 description 3
- 238000011200 topical administration Methods 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 238000001851 vibrational circular dichroism spectroscopy Methods 0.000 description 3
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 3
- UFYBTLOLWSABAU-UHFFFAOYSA-N (2-methylpyridin-4-yl)boronic acid Chemical compound CC1=CC(B(O)O)=CC=N1 UFYBTLOLWSABAU-UHFFFAOYSA-N 0.000 description 2
- FZXBJPDVINOGBR-OLQVQODUSA-N (2s,6r)-2,6-dimethyloxan-4-one Chemical compound C[C@H]1CC(=O)C[C@@H](C)O1 FZXBJPDVINOGBR-OLQVQODUSA-N 0.000 description 2
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 2
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 2
- RQEOYYWUVYZZLL-UHFFFAOYSA-N 3,5-bis(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CN=CC(C(F)(F)F)=C1 RQEOYYWUVYZZLL-UHFFFAOYSA-N 0.000 description 2
- IADLVSLZPQYXIF-UHFFFAOYSA-N 3-bromo-5-fluorobenzonitrile Chemical compound FC1=CC(Br)=CC(C#N)=C1 IADLVSLZPQYXIF-UHFFFAOYSA-N 0.000 description 2
- VZJNDMNPPCXLQC-JTQLQIEISA-N 3-fluoro-2-iodo-5-[(2s)-2-(trifluoromethyl)morpholin-4-yl]benzonitrile Chemical compound N#CC1=C(I)C(F)=CC(N2C[C@H](OCC2)C(F)(F)F)=C1 VZJNDMNPPCXLQC-JTQLQIEISA-N 0.000 description 2
- IBXCHLAUBNJQHQ-UHFFFAOYSA-N 5-bromo-3-chloro-2-iodobenzonitrile Chemical compound ClC1=CC(Br)=CC(C#N)=C1I IBXCHLAUBNJQHQ-UHFFFAOYSA-N 0.000 description 2
- KBOSIRPMGVGOEP-UHFFFAOYSA-N 5-methyl-1,2-oxazole-3-carboxamide Chemical compound CC1=CC(C(N)=O)=NO1 KBOSIRPMGVGOEP-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- 108091006146 Channels Proteins 0.000 description 2
- 102000009660 Cholinergic Receptors Human genes 0.000 description 2
- 108010009685 Cholinergic Receptors Proteins 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 229910002666 PdCl2 Inorganic materials 0.000 description 2
- QOMNQGZXFYNBNG-UHFFFAOYSA-N acetyloxymethyl 2-[2-[2-[5-[3-(acetyloxymethoxy)-2,7-difluoro-6-oxoxanthen-9-yl]-2-[bis[2-(acetyloxymethoxy)-2-oxoethyl]amino]phenoxy]ethoxy]-n-[2-(acetyloxymethoxy)-2-oxoethyl]-4-methylanilino]acetate Chemical compound CC(=O)OCOC(=O)CN(CC(=O)OCOC(C)=O)C1=CC=C(C)C=C1OCCOC1=CC(C2=C3C=C(F)C(=O)C=C3OC3=CC(OCOC(C)=O)=C(F)C=C32)=CC=C1N(CC(=O)OCOC(C)=O)CC(=O)OCOC(C)=O QOMNQGZXFYNBNG-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000001270 agonistic effect Effects 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 2
- 230000003185 calcium uptake Effects 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 230000003412 degenerative effect Effects 0.000 description 2
- 230000002939 deleterious effect Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000007831 electrophysiology Effects 0.000 description 2
- 238000002001 electrophysiology Methods 0.000 description 2
- 238000000132 electrospray ionisation Methods 0.000 description 2
- XWRLQRLQUKZEEU-UHFFFAOYSA-N ethyl(hydroxy)silicon Chemical class CC[Si]O XWRLQRLQUKZEEU-UHFFFAOYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000006277 exogenous ligand Substances 0.000 description 2
- 239000003889 eye drop Substances 0.000 description 2
- 229940012356 eye drops Drugs 0.000 description 2
- 230000004907 flux Effects 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000003068 molecular probe Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000006199 nebulizer Substances 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 230000002085 persistent effect Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229920002401 polyacrylamide Polymers 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000004043 responsiveness Effects 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 239000002453 shampoo Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 210000000225 synapse Anatomy 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- INIKTCFEWCCJMM-PGMHMLKASA-N (2r)-2-(trifluoromethyl)morpholine;hydrochloride Chemical compound Cl.FC(F)(F)[C@H]1CNCCO1 INIKTCFEWCCJMM-PGMHMLKASA-N 0.000 description 1
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- INIKTCFEWCCJMM-WCCKRBBISA-N (2s)-2-(trifluoromethyl)morpholine;hydrochloride Chemical compound Cl.FC(F)(F)[C@@H]1CNCCO1 INIKTCFEWCCJMM-WCCKRBBISA-N 0.000 description 1
- YNBXNVUZXFMNSJ-UHFFFAOYSA-N (4-bromophenyl) 1,4-diazabicyclo[3.2.2]nonane-4-carboxylate;hydrochloride Chemical compound Cl.C1=CC(Br)=CC=C1OC(=O)N1C(CC2)CCN2CC1 YNBXNVUZXFMNSJ-UHFFFAOYSA-N 0.000 description 1
- STPKWKPURVSAJF-LJEWAXOPSA-N (4r,5r)-5-[4-[[4-(1-aza-4-azoniabicyclo[2.2.2]octan-4-ylmethyl)phenyl]methoxy]phenyl]-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound O[C@H]1C(CCCC)(CCCC)CS(=O)(=O)C2=CC=C(N(C)C)C=C2[C@H]1C(C=C1)=CC=C1OCC(C=C1)=CC=C1C[N+]1(CC2)CCN2CC1 STPKWKPURVSAJF-LJEWAXOPSA-N 0.000 description 1
- 229930182840 (S)-nicotine Natural products 0.000 description 1
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- WPWVHZJFKOAMKD-KRWDZBQOSA-N 2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-[(2s)-2-(trifluoromethyl)morpholin-4-yl]benzonitrile Chemical compound CC1=NC(C)=CC(C=2C(=CC(=CC=2F)N2C[C@H](OCC2)C(F)(F)F)C#N)=C1 WPWVHZJFKOAMKD-KRWDZBQOSA-N 0.000 description 1
- NBCFPNRKOSHXGH-UHFFFAOYSA-N 2-(2-methylpyridin-4-yl)-5-morpholin-4-ylbenzonitrile Chemical compound C1=NC(C)=CC(C=2C(=CC(=CC=2)N2CCOCC2)C#N)=C1 NBCFPNRKOSHXGH-UHFFFAOYSA-N 0.000 description 1
- AAXUQXCUGYHRJV-IYBDPMFKSA-N 2-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-5-(2,6-dimethylpyridin-4-yl)benzonitrile Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC=C(C=2C=C(C)N=C(C)C=2)C=C1C#N AAXUQXCUGYHRJV-IYBDPMFKSA-N 0.000 description 1
- HUHGPYXAVBJSJV-UHFFFAOYSA-N 2-[3,5-bis(2-hydroxyethyl)-1,3,5-triazinan-1-yl]ethanol Chemical compound OCCN1CN(CCO)CN(CCO)C1 HUHGPYXAVBJSJV-UHFFFAOYSA-N 0.000 description 1
- MDHNVHCZDCSTMS-UHFFFAOYSA-N 2-bromo-5-fluorobenzonitrile Chemical compound FC1=CC=C(Br)C(C#N)=C1 MDHNVHCZDCSTMS-UHFFFAOYSA-N 0.000 description 1
- BWQNTPZCJFCZRC-UHFFFAOYSA-N 2-bromo-5-morpholin-4-ylbenzonitrile Chemical compound C1=C(C#N)C(Br)=CC=C1N1CCOCC1 BWQNTPZCJFCZRC-UHFFFAOYSA-N 0.000 description 1
- SYZRZLUNWVNNNV-UHFFFAOYSA-N 2-bromoacetyl chloride Chemical compound ClC(=O)CBr SYZRZLUNWVNNNV-UHFFFAOYSA-N 0.000 description 1
- JRKHSVRVYYIIMP-JOCHJYFZSA-N 2-cyclobutyl-n-[[6-(2,6-dimethylpyridin-4-yl)-2-fluoro-3-[(2r)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]acetamide Chemical compound CC1=NC(C)=CC(C=2C(=C(F)C(N3C[C@@H](OCC3)C(F)(F)F)=CC=2)CNC(=O)CC2CCC2)=C1 JRKHSVRVYYIIMP-JOCHJYFZSA-N 0.000 description 1
- JRKHSVRVYYIIMP-QFIPXVFZSA-N 2-cyclobutyl-n-[[6-(2,6-dimethylpyridin-4-yl)-2-fluoro-3-[(2s)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]acetamide Chemical compound CC1=NC(C)=CC(C=2C(=C(F)C(N3C[C@H](OCC3)C(F)(F)F)=CC=2)CNC(=O)CC2CCC2)=C1 JRKHSVRVYYIIMP-QFIPXVFZSA-N 0.000 description 1
- QCCQUKAWJOMYEW-UHFFFAOYSA-N 2-cyclopropyl-N-[[2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-[3-(trifluoromethyl)piperidin-1-yl]phenyl]methyl]acetamide Chemical compound Cc1cc(cc(C)n1)-c1c(F)cc(cc1CNC(=O)CC1CC1)N1CCCC(C1)C(F)(F)F QCCQUKAWJOMYEW-UHFFFAOYSA-N 0.000 description 1
- XDGNXVLWEUAKPR-UHFFFAOYSA-N 2-cyclopropyl-n-[[2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-(2-methylmorpholin-4-yl)phenyl]methyl]acetamide Chemical compound C1COC(C)CN1C1=CC(F)=C(C=2C=C(C)N=C(C)C=2)C(CNC(=O)CC2CC2)=C1 XDGNXVLWEUAKPR-UHFFFAOYSA-N 0.000 description 1
- CXNZLPUTIBYZCX-OAQYLSRUSA-N 2-cyclopropyl-n-[[2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-[(2r)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]acetamide Chemical compound CC1=NC(C)=CC(C=2C(=CC(=CC=2F)N2C[C@@H](OCC2)C(F)(F)F)CNC(=O)CC2CC2)=C1 CXNZLPUTIBYZCX-OAQYLSRUSA-N 0.000 description 1
- CXNZLPUTIBYZCX-NRFANRHFSA-N 2-cyclopropyl-n-[[2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-[(2s)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]acetamide Chemical compound CC1=NC(C)=CC(C=2C(=CC(=CC=2F)N2C[C@H](OCC2)C(F)(F)F)CNC(=O)CC2CC2)=C1 CXNZLPUTIBYZCX-NRFANRHFSA-N 0.000 description 1
- HPKKWSYZYHRXJW-UHFFFAOYSA-N 2-cyclopropyl-n-[[2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-[3-(trifluoromethyl)piperidin-1-yl]phenyl]methyl]propanamide Chemical compound C=1C(N2CC(CCC2)C(F)(F)F)=CC(F)=C(C=2C=C(C)N=C(C)C=2)C=1CNC(=O)C(C)C1CC1 HPKKWSYZYHRXJW-UHFFFAOYSA-N 0.000 description 1
- CIGUDZCLUMOKHX-UHFFFAOYSA-N 2-cyclopropyl-n-[[2-(2,6-dimethylpyridin-4-yl)-5-[3-(trifluoromethyl)piperidin-1-yl]phenyl]methyl]acetamide Chemical compound CC1=NC(C)=CC(C=2C(=CC(=CC=2)N2CC(CCC2)C(F)(F)F)CNC(=O)CC2CC2)=C1 CIGUDZCLUMOKHX-UHFFFAOYSA-N 0.000 description 1
- ZBZZJBGECPASSH-UHFFFAOYSA-N 2-cyclopropyl-n-[[2-(2,6-dimethylpyridin-4-yl)-5-morpholin-4-ylphenyl]methyl]acetamide Chemical compound CC1=NC(C)=CC(C=2C(=CC(=CC=2)N2CCOCC2)CNC(=O)CC2CC2)=C1 ZBZZJBGECPASSH-UHFFFAOYSA-N 0.000 description 1
- NTVBPAOALDVFQA-UHFFFAOYSA-N 2-cyclopropyl-n-[[2-(2-methylpyridin-4-yl)-5-morpholin-4-ylphenyl]methyl]acetamide Chemical compound C1=NC(C)=CC(C=2C(=CC(=CC=2)N2CCOCC2)CNC(=O)CC2CC2)=C1 NTVBPAOALDVFQA-UHFFFAOYSA-N 0.000 description 1
- OQCVFIHEUDIMTA-KDURUIRLSA-N 2-cyclopropyl-n-[[2-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-5-(2,6-dimethylpyridin-4-yl)phenyl]methyl]acetamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC=C(C=2C=C(C)N=C(C)C=2)C=C1CNC(=O)CC1CC1 OQCVFIHEUDIMTA-KDURUIRLSA-N 0.000 description 1
- RJALQXYPTVEJIU-DFNIBXOVSA-N 2-cyclopropyl-n-[[3-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-6-(2,6-dimethylpyridin-4-yl)-2-fluorophenyl]methyl]propanamide Chemical compound FC=1C(N2C[C@@H](C)O[C@@H](C)C2)=CC=C(C=2C=C(C)N=C(C)C=2)C=1CNC(=O)C(C)C1CC1 RJALQXYPTVEJIU-DFNIBXOVSA-N 0.000 description 1
- JPKGJVYSFYZUMY-HTZLVSCSSA-N 2-cyclopropyl-n-[[3-[(2r,6s)-2,6-dimethyloxan-4-yl]-6-(2,6-dimethylpyridin-4-yl)-2-fluorophenyl]methyl]acetamide Chemical compound C1[C@@H](C)O[C@@H](C)CC1C1=CC=C(C=2C=C(C)N=C(C)C=2)C(CNC(=O)CC2CC2)=C1F JPKGJVYSFYZUMY-HTZLVSCSSA-N 0.000 description 1
- YKIJPQPZWSPONP-DFNIBXOVSA-N 2-cyclopropyl-n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)-3-fluorophenyl]methyl]propanamide Chemical compound C=1C(N2C[C@@H](C)O[C@@H](C)C2)=CC(F)=C(C=2C=C(C)N=C(C)C=2)C=1CNC(=O)C(C)C1CC1 YKIJPQPZWSPONP-DFNIBXOVSA-N 0.000 description 1
- UAPRUIZWVMYAMC-HDICACEKSA-N 2-cyclopropyl-n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2-methylpyridin-4-yl)phenyl]methyl]acetamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC=C(C=2C=C(C)N=CC=2)C(CNC(=O)CC2CC2)=C1 UAPRUIZWVMYAMC-HDICACEKSA-N 0.000 description 1
- VDBOOHFMTNVFDJ-CALCHBBNSA-N 2-cyclopropyl-n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-pyridin-4-ylphenyl]methyl]acetamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC=C(C=2C=CN=CC=2)C(CNC(=O)CC2CC2)=C1 VDBOOHFMTNVFDJ-CALCHBBNSA-N 0.000 description 1
- VBKPAEIHSMQMEC-CALCHBBNSA-N 2-cyclopropyl-n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-3-fluoro-2-(2-methylpyridin-4-yl)phenyl]methyl]acetamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC(F)=C(C=2C=C(C)N=CC=2)C(CNC(=O)CC2CC2)=C1 VBKPAEIHSMQMEC-CALCHBBNSA-N 0.000 description 1
- DDGVIEHNNFWELI-OAQYLSRUSA-N 2-cyclopropyl-n-[[6-(2,6-dimethylpyridin-4-yl)-2-fluoro-3-[(2r)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]acetamide Chemical compound CC1=NC(C)=CC(C=2C(=C(F)C(N3C[C@@H](OCC3)C(F)(F)F)=CC=2)CNC(=O)CC2CC2)=C1 DDGVIEHNNFWELI-OAQYLSRUSA-N 0.000 description 1
- DDGVIEHNNFWELI-NRFANRHFSA-N 2-cyclopropyl-n-[[6-(2,6-dimethylpyridin-4-yl)-2-fluoro-3-[(2s)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]acetamide Chemical compound CC1=NC(C)=CC(C=2C(=C(F)C(N3C[C@H](OCC3)C(F)(F)F)=CC=2)CNC(=O)CC2CC2)=C1 DDGVIEHNNFWELI-NRFANRHFSA-N 0.000 description 1
- KVVDRQDTODKIJD-UHFFFAOYSA-N 2-cyclopropylacetic acid Chemical compound OC(=O)CC1CC1 KVVDRQDTODKIJD-UHFFFAOYSA-N 0.000 description 1
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 description 1
- WNSWTDWANMVMDB-UHFFFAOYSA-N 3,5-bis(trifluoromethyl)piperidine Chemical compound FC(F)(F)C1CNCC(C(F)(F)F)C1 WNSWTDWANMVMDB-UHFFFAOYSA-N 0.000 description 1
- CQXZSEXZQVKCHW-UHFFFAOYSA-N 3,5-difluorobenzonitrile Chemical compound FC1=CC(F)=CC(C#N)=C1 CQXZSEXZQVKCHW-UHFFFAOYSA-N 0.000 description 1
- JOHFJTBDUSVGQB-UHFFFAOYSA-N 3-(trifluoromethyl)piperidine Chemical compound FC(F)(F)C1CCCNC1 JOHFJTBDUSVGQB-UHFFFAOYSA-N 0.000 description 1
- OOHLQQGLXWPMBY-LSDHHAIUSA-N 3-[(2r,6s)-2,6-dimethyl-3,6-dihydro-2h-pyran-4-yl]-6-(2,6-dimethylpyridin-4-yl)-2-fluorobenzonitrile Chemical compound C[C@@H]1O[C@H](C)CC(C=2C(=C(C#N)C(C=3C=C(C)N=C(C)C=3)=CC=2)F)=C1 OOHLQQGLXWPMBY-LSDHHAIUSA-N 0.000 description 1
- KVYSUJHHJDHMGT-GASCZTMLSA-N 3-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-6-(2,6-dimethylpyridin-4-yl)-2-fluorobenzonitrile Chemical compound C1[C@@H](C)O[C@@H](C)CN1C(C(=C1C#N)F)=CC=C1C1=CC(C)=NC(C)=C1 KVYSUJHHJDHMGT-GASCZTMLSA-N 0.000 description 1
- JWDXMVYPSDQJRP-AOOOYVTPSA-N 3-[(2s,6r)-2,6-dimethylmorpholin-4-yl]-5-fluorobenzonitrile Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC(F)=CC(C#N)=C1 JWDXMVYPSDQJRP-AOOOYVTPSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- VCRQPVFNRGOPIK-UHFFFAOYSA-N 3-bromo-2-fluoro-6-iodobenzonitrile Chemical compound FC1=C(Br)C=CC(I)=C1C#N VCRQPVFNRGOPIK-UHFFFAOYSA-N 0.000 description 1
- JZUXQRPTJMXKBH-UHFFFAOYSA-N 3-bromo-6-(2,6-dimethylpyridin-4-yl)-2-fluorobenzonitrile Chemical compound CC1=NC(C)=CC(C=2C(=C(F)C(Br)=CC=2)C#N)=C1 JZUXQRPTJMXKBH-UHFFFAOYSA-N 0.000 description 1
- IKPKIDKJUVFLBN-GASCZTMLSA-N 3-chloro-5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)benzonitrile Chemical compound C1[C@@H](C)O[C@@H](C)CN1C(C=C1C#N)=CC(Cl)=C1C1=CC(C)=NC(C)=C1 IKPKIDKJUVFLBN-GASCZTMLSA-N 0.000 description 1
- MAMBJKDSVVITCR-NSHDSACASA-N 3-fluoro-5-[(2s)-2-(trifluoromethyl)morpholin-4-yl]benzonitrile Chemical compound FC1=CC(C#N)=CC(N2C[C@H](OCC2)C(F)(F)F)=C1 MAMBJKDSVVITCR-NSHDSACASA-N 0.000 description 1
- ZUAJRTMAVYBJTL-UHFFFAOYSA-N 3-fluoro-5-[3-(trifluoromethyl)piperidin-1-yl]benzonitrile Chemical compound FC1=CC(C#N)=CC(N2CC(CCC2)C(F)(F)F)=C1 ZUAJRTMAVYBJTL-UHFFFAOYSA-N 0.000 description 1
- AVSLCGYMISJJBT-UHFFFAOYSA-N 3-methyl-1,2-oxazole-4-carboxamide Chemical compound CC1=NOC=C1C(N)=O AVSLCGYMISJJBT-UHFFFAOYSA-N 0.000 description 1
- FNVHKGWZLGSUPH-UHFFFAOYSA-N 4-(2,4-dibromo-3,6-difluorophenyl)-2,6-dimethylpyridine Chemical compound CC1=NC(C)=CC(C=2C(=C(F)C(Br)=CC=2F)Br)=C1 FNVHKGWZLGSUPH-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
- QNUKZLCBQCJVLU-UHFFFAOYSA-N 4-(4-bromo-2-chloro-5-fluorophenyl)-2,6-dimethylpyridine Chemical compound CC1=NC(C)=CC(C=2C(=CC(Br)=C(F)C=2)Cl)=C1 QNUKZLCBQCJVLU-UHFFFAOYSA-N 0.000 description 1
- FJVUITXBTLYTRY-UHFFFAOYSA-N 4-benzyl-6-(trifluoromethyl)morpholin-3-one Chemical compound O=C1COC(C(F)(F)F)CN1CC1=CC=CC=C1 FJVUITXBTLYTRY-UHFFFAOYSA-N 0.000 description 1
- WUXPGBIHEZFZIC-UHFFFAOYSA-N 4-fluoro-2-methylbenzamide Chemical compound CC1=CC(F)=CC=C1C(N)=O WUXPGBIHEZFZIC-UHFFFAOYSA-N 0.000 description 1
- 102000035037 5-HT3 receptors Human genes 0.000 description 1
- 108091005477 5-HT3 receptors Proteins 0.000 description 1
- SKMIEMCXFOZMOD-GASCZTMLSA-N 5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)-3-fluorobenzonitrile Chemical compound C1[C@@H](C)O[C@@H](C)CN1C(C=C1C#N)=CC(F)=C1C1=CC(C)=NC(C)=C1 SKMIEMCXFOZMOD-GASCZTMLSA-N 0.000 description 1
- PPWRBMSHZSIENC-GASCZTMLSA-N 5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)-4-fluorobenzonitrile Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC(C#N)=C(C=2C=C(C)N=C(C)C=2)C=C1F PPWRBMSHZSIENC-GASCZTMLSA-N 0.000 description 1
- YYDIQIWQCMEWAK-IYBDPMFKSA-N 5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)benzonitrile Chemical compound C1[C@@H](C)O[C@@H](C)CN1C(C=C1C#N)=CC=C1C1=CC(C)=NC(C)=C1 YYDIQIWQCMEWAK-IYBDPMFKSA-N 0.000 description 1
- YAZLQVIVVNGGGC-OKILXGFUSA-N 5-[(2s,6r)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)-3,6-difluorobenzonitrile Chemical compound C1[C@@H](C)O[C@@H](C)CN1C(C(=C1C#N)F)=CC(F)=C1C1=CC(C)=NC(C)=C1 YAZLQVIVVNGGGC-OKILXGFUSA-N 0.000 description 1
- KIPSTJVUGUVXHI-DTORHVGOSA-N 5-[(2s,6r)-2,6-dimethylmorpholin-4-yl]-3-fluoro-2-iodobenzonitrile Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC(F)=C(I)C(C#N)=C1 KIPSTJVUGUVXHI-DTORHVGOSA-N 0.000 description 1
- NFEUVJHVQWAYPT-UHFFFAOYSA-N 5-bromo-3-chloro-2-(2,6-dimethylpyridin-4-yl)benzonitrile Chemical compound CC1=NC(C)=CC(C=2C(=CC(Br)=CC=2Cl)C#N)=C1 NFEUVJHVQWAYPT-UHFFFAOYSA-N 0.000 description 1
- ISSPZXXKZFKMIU-UHFFFAOYSA-N 5-chloro-2-(2,6-dimethylpyridin-4-yl)benzonitrile Chemical compound CC1=NC(C)=CC(C=2C(=CC(Cl)=CC=2)C#N)=C1 ISSPZXXKZFKMIU-UHFFFAOYSA-N 0.000 description 1
- KLYIMCYTNRJMBX-AOOOYVTPSA-N 5-chloro-2-[(2s,6r)-2,6-dimethylmorpholin-4-yl]benzonitrile Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC=C(Cl)C=C1C#N KLYIMCYTNRJMBX-AOOOYVTPSA-N 0.000 description 1
- LMSFBJQUGBFKMX-KRWDZBQOSA-N 6-(2,6-dimethylpyridin-4-yl)-2-fluoro-3-[(2s)-2-(trifluoromethyl)morpholin-4-yl]benzonitrile Chemical compound CC1=NC(C)=CC(C=2C(=C(F)C(N3C[C@H](OCC3)C(F)(F)F)=CC=2)C#N)=C1 LMSFBJQUGBFKMX-KRWDZBQOSA-N 0.000 description 1
- 101150101112 7 gene Proteins 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 102000012440 Acetylcholinesterase Human genes 0.000 description 1
- 108010022752 Acetylcholinesterase Proteins 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- PFEJOAFRJVXNEZ-OKILXGFUSA-N C[C@H](C1)O[C@@H](C)CN1c(c(F)c1)cc(Cl)c1-c1cc(C)nc(C)c1 Chemical compound C[C@H](C1)O[C@@H](C)CN1c(c(F)c1)cc(Cl)c1-c1cc(C)nc(C)c1 PFEJOAFRJVXNEZ-OKILXGFUSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- JDGDEZDXSLSULS-UHFFFAOYSA-N Cc1cc(-c(cc(c(Br)c2)[F]C)c2Cl)cc(C)n1 Chemical compound Cc1cc(-c(cc(c(Br)c2)[F]C)c2Cl)cc(C)n1 JDGDEZDXSLSULS-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- OVAZCYUQNNFOKS-BYPYZUCNSA-N FC([C@H]1OCCNC1)(F)F Chemical compound FC([C@H]1OCCNC1)(F)F OVAZCYUQNNFOKS-BYPYZUCNSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 102000027484 GABAA receptors Human genes 0.000 description 1
- 108091008681 GABAA receptors Proteins 0.000 description 1
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 1
- 102000011714 Glycine Receptors Human genes 0.000 description 1
- 108010076533 Glycine Receptors Proteins 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- UQOFGTXDASPNLL-XHNCKOQMSA-N Muscarine Chemical compound C[C@@H]1O[C@H](C[N+](C)(C)C)C[C@H]1O UQOFGTXDASPNLL-XHNCKOQMSA-N 0.000 description 1
- IPPZVQZSLQORQY-CALCHBBNSA-N N-[[3-[(2S,6R)-2,6-dimethylmorpholin-4-yl]-6-(2,6-dimethylpyridin-4-yl)-2-fluorophenyl]methyl]-3-methyl-1,2-oxazole-4-carboxamide Chemical compound C[C@H]1CN(C[C@@H](C)O1)c1ccc(-c2cc(C)nc(C)c2)c(CNC(=O)c2conc2C)c1F IPPZVQZSLQORQY-CALCHBBNSA-N 0.000 description 1
- LXUZFYPECGBGDK-FQEVSTJZSA-N N-[[6-(2,6-dimethylpyridin-4-yl)-2-fluoro-3-[(2S)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]-2-methylpropanamide Chemical compound CC(C)C(=O)NCc1c(F)c(ccc1-c1cc(C)nc(C)c1)N1CCO[C@@H](C1)C(F)(F)F LXUZFYPECGBGDK-FQEVSTJZSA-N 0.000 description 1
- GCSACLVTTVHPMT-NRFANRHFSA-N N-[[6-(2,6-dimethylpyridin-4-yl)-2-fluoro-3-[(2S)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]-5-methyl-1,2-oxazole-3-carboxamide Chemical compound Cc1cc(no1)C(=O)NCc1c(F)c(ccc1-c1cc(C)nc(C)c1)N1CCO[C@@H](C1)C(F)(F)F GCSACLVTTVHPMT-NRFANRHFSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 241000208125 Nicotiana Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 108091006275 SLC5A7 Proteins 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
- ICCUUPHUNKTOOR-UHFFFAOYSA-N [2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-(2-methylmorpholin-4-yl)phenyl]methanamine Chemical compound C1COC(C)CN1C1=CC(F)=C(C=2C=C(C)N=C(C)C=2)C(CN)=C1 ICCUUPHUNKTOOR-UHFFFAOYSA-N 0.000 description 1
- AYLLUPJAWQQXHE-QGZVFWFLSA-N [2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-[(2r)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methanamine Chemical compound CC1=NC(C)=CC(C=2C(=CC(=CC=2F)N2C[C@@H](OCC2)C(F)(F)F)CN)=C1 AYLLUPJAWQQXHE-QGZVFWFLSA-N 0.000 description 1
- AYLLUPJAWQQXHE-KRWDZBQOSA-N [2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-[(2s)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methanamine Chemical compound CC1=NC(C)=CC(C=2C(=CC(=CC=2F)N2C[C@H](OCC2)C(F)(F)F)CN)=C1 AYLLUPJAWQQXHE-KRWDZBQOSA-N 0.000 description 1
- KYZXBHMPSGHBDC-UHFFFAOYSA-N [2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-[3-(trifluoromethyl)piperidin-1-yl]phenyl]methanamine Chemical compound CC1=NC(C)=CC(C=2C(=CC(=CC=2F)N2CC(CCC2)C(F)(F)F)CN)=C1 KYZXBHMPSGHBDC-UHFFFAOYSA-N 0.000 description 1
- BCBGDZKLDWYSJZ-UHFFFAOYSA-N [2-(2-methylpyridin-4-yl)-5-morpholin-4-ylphenyl]methanamine Chemical compound C1=NC(C)=CC(C=2C(=CC(=CC=2)N2CCOCC2)CN)=C1 BCBGDZKLDWYSJZ-UHFFFAOYSA-N 0.000 description 1
- YEEMDBBZESCIQU-IYBDPMFKSA-N [2-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-5-(2,6-dimethylpyridin-4-yl)phenyl]methanamine Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC=C(C=2C=C(C)N=C(C)C=2)C=C1CN YEEMDBBZESCIQU-IYBDPMFKSA-N 0.000 description 1
- RJVSBHFFMWBNCS-LSDHHAIUSA-N [3-[(2r,6s)-2,6-dimethyl-3,6-dihydro-2h-pyran-4-yl]-6-(2,6-dimethylpyridin-4-yl)-2-fluorophenyl]methanamine Chemical compound C[C@@H]1O[C@H](C)CC(C=2C(=C(CN)C(C=3C=C(C)N=C(C)C=3)=CC=2)F)=C1 RJVSBHFFMWBNCS-LSDHHAIUSA-N 0.000 description 1
- GHRQNQIHINMRCC-GASCZTMLSA-N [3-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-6-(2,6-dimethylpyridin-4-yl)-2-fluorophenyl]methanamine Chemical compound C1[C@@H](C)O[C@@H](C)CN1C(C(=C1CN)F)=CC=C1C1=CC(C)=NC(C)=C1 GHRQNQIHINMRCC-GASCZTMLSA-N 0.000 description 1
- YUQQSCHZVDDKMO-FKEKPDDDSA-N [3-[(2r,6s)-2,6-dimethyloxan-4-yl]-6-(2,6-dimethylpyridin-4-yl)-2-fluorophenyl]methanamine Chemical compound C1[C@@H](C)O[C@@H](C)CC1C(C(=C1CN)F)=CC=C1C1=CC(C)=NC(C)=C1 YUQQSCHZVDDKMO-FKEKPDDDSA-N 0.000 description 1
- RMRJYIIMVDABKW-GASCZTMLSA-N [3-chloro-5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)phenyl]methanamine Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC(Cl)=C(C=2C=C(C)N=C(C)C=2)C(CN)=C1 RMRJYIIMVDABKW-GASCZTMLSA-N 0.000 description 1
- NZTVCPNWMSEHNQ-GASCZTMLSA-N [5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)-3-fluorophenyl]methanamine Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC(F)=C(C=2C=C(C)N=C(C)C=2)C(CN)=C1 NZTVCPNWMSEHNQ-GASCZTMLSA-N 0.000 description 1
- VVOSSOTXZPHOMM-GASCZTMLSA-N [5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)-4-fluorophenyl]methanamine Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC(CN)=C(C=2C=C(C)N=C(C)C=2)C=C1F VVOSSOTXZPHOMM-GASCZTMLSA-N 0.000 description 1
- ITWOZTLUFXLLLD-IYBDPMFKSA-N [5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)phenyl]methanamine Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC=C(C=2C=C(C)N=C(C)C=2)C(CN)=C1 ITWOZTLUFXLLLD-IYBDPMFKSA-N 0.000 description 1
- FDQDXMKUMRXYMU-OKILXGFUSA-N [5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-3-fluoro-2-(2-methylpyridin-4-yl)phenyl]methanamine Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC(F)=C(C=2C=C(C)N=CC=2)C(CN)=C1 FDQDXMKUMRXYMU-OKILXGFUSA-N 0.000 description 1
- QYBKCUPQTNUWES-OKILXGFUSA-N [5-[(2s,6r)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)-3,6-difluorophenyl]methanamine Chemical compound C1[C@@H](C)O[C@@H](C)CN1C(C(=C1CN)F)=CC(F)=C1C1=CC(C)=NC(C)=C1 QYBKCUPQTNUWES-OKILXGFUSA-N 0.000 description 1
- ZJIOZOSQGKNZCP-QGZVFWFLSA-N [6-(2,6-dimethylpyridin-4-yl)-2-fluoro-3-[(2r)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methanamine Chemical compound CC1=NC(C)=CC(C=2C(=C(F)C(N3C[C@@H](OCC3)C(F)(F)F)=CC=2)CN)=C1 ZJIOZOSQGKNZCP-QGZVFWFLSA-N 0.000 description 1
- ZJIOZOSQGKNZCP-KRWDZBQOSA-N [6-(2,6-dimethylpyridin-4-yl)-2-fluoro-3-[(2s)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methanamine Chemical compound CC1=NC(C)=CC(C=2C(=C(F)C(N3C[C@H](OCC3)C(F)(F)F)=CC=2)CN)=C1 ZJIOZOSQGKNZCP-KRWDZBQOSA-N 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 102000047725 alpha7 Nicotinic Acetylcholine Receptor Human genes 0.000 description 1
- 108700006085 alpha7 Nicotinic Acetylcholine Receptor Proteins 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 150000001638 boron Chemical class 0.000 description 1
- 239000005388 borosilicate glass Substances 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012822 chemical development Methods 0.000 description 1
- 230000006949 cholinergic function Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940125900 compound 59 Drugs 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 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
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 239000006274 endogenous ligand Substances 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 230000000763 evoking effect Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 210000005153 frontal cortex Anatomy 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 210000004326 gyrus cinguli Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000003585 interneuronal effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 230000001057 ionotropic effect Effects 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- ANYSGBYRTLOUPO-UHFFFAOYSA-N lithium tetramethylpiperidide Chemical compound [Li]N1C(C)(C)CCCC1(C)C ANYSGBYRTLOUPO-UHFFFAOYSA-N 0.000 description 1
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000003551 muscarinic effect Effects 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- NIENXOORHGJQSI-UHFFFAOYSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-(2-methylmorpholin-4-yl)phenyl]methyl]-2-methylpropanamide Chemical compound CC(C)C(=O)NCC1=CC(N2CC(C)OCC2)=CC(F)=C1C1=CC(C)=NC(C)=C1 NIENXOORHGJQSI-UHFFFAOYSA-N 0.000 description 1
- DSXSDBGWZMPFGI-UHFFFAOYSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-(2-methylmorpholin-4-yl)phenyl]methyl]-3-methyl-1,2-oxazole-4-carboxamide Chemical compound C1COC(C)CN1C1=CC(F)=C(C=2C=C(C)N=C(C)C=2)C(CNC(=O)C=2C(=NOC=2)C)=C1 DSXSDBGWZMPFGI-UHFFFAOYSA-N 0.000 description 1
- UAQKORVJVKGBGI-UHFFFAOYSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-(2-methylmorpholin-4-yl)phenyl]methyl]-3-methylbutanamide Chemical compound CC(C)CC(=O)NCC1=CC(N2CC(C)OCC2)=CC(F)=C1C1=CC(C)=NC(C)=C1 UAQKORVJVKGBGI-UHFFFAOYSA-N 0.000 description 1
- LBCGJXSUDHLZTF-UHFFFAOYSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-(2-methylmorpholin-4-yl)phenyl]methyl]cyclopropanecarboxamide Chemical compound C1COC(C)CN1C1=CC(F)=C(C=2C=C(C)N=C(C)C=2)C(CNC(=O)C2CC2)=C1 LBCGJXSUDHLZTF-UHFFFAOYSA-N 0.000 description 1
- TZVYFWRLWCJULE-HXUWFJFHSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-[(2r)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]-2-methylpropanamide Chemical compound CC(C)C(=O)NCC1=CC(N2C[C@@H](OCC2)C(F)(F)F)=CC(F)=C1C1=CC(C)=NC(C)=C1 TZVYFWRLWCJULE-HXUWFJFHSA-N 0.000 description 1
- SRJKHWWPINVIAY-OAQYLSRUSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-[(2r)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]-3-methyl-1,2-oxazole-4-carboxamide Chemical compound CC1=NOC=C1C(=O)NCC1=CC(N2C[C@@H](OCC2)C(F)(F)F)=CC(F)=C1C1=CC(C)=NC(C)=C1 SRJKHWWPINVIAY-OAQYLSRUSA-N 0.000 description 1
- KLZSTGPSEJAVRW-OAQYLSRUSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-[(2r)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]-3-methylbutanamide Chemical compound CC(C)CC(=O)NCC1=CC(N2C[C@@H](OCC2)C(F)(F)F)=CC(F)=C1C1=CC(C)=NC(C)=C1 KLZSTGPSEJAVRW-OAQYLSRUSA-N 0.000 description 1
- GRGGHBYNBCYUOK-OAQYLSRUSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-[(2r)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]-5-methyl-1,2-oxazole-3-carboxamide Chemical compound O1C(C)=CC(C(=O)NCC=2C(=C(F)C=C(C=2)N2C[C@@H](OCC2)C(F)(F)F)C=2C=C(C)N=C(C)C=2)=N1 GRGGHBYNBCYUOK-OAQYLSRUSA-N 0.000 description 1
- BYKWZEOEWWSIGZ-HXUWFJFHSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-[(2r)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]cyclopropanecarboxamide Chemical compound CC1=NC(C)=CC(C=2C(=CC(=CC=2F)N2C[C@@H](OCC2)C(F)(F)F)CNC(=O)C2CC2)=C1 BYKWZEOEWWSIGZ-HXUWFJFHSA-N 0.000 description 1
- TZVYFWRLWCJULE-FQEVSTJZSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-[(2s)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]-2-methylpropanamide Chemical compound CC(C)C(=O)NCC1=CC(N2C[C@H](OCC2)C(F)(F)F)=CC(F)=C1C1=CC(C)=NC(C)=C1 TZVYFWRLWCJULE-FQEVSTJZSA-N 0.000 description 1
- SRJKHWWPINVIAY-NRFANRHFSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-[(2s)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]-3-methyl-1,2-oxazole-4-carboxamide Chemical compound CC1=NOC=C1C(=O)NCC1=CC(N2C[C@H](OCC2)C(F)(F)F)=CC(F)=C1C1=CC(C)=NC(C)=C1 SRJKHWWPINVIAY-NRFANRHFSA-N 0.000 description 1
- KLZSTGPSEJAVRW-NRFANRHFSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-[(2s)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]-3-methylbutanamide Chemical compound CC(C)CC(=O)NCC1=CC(N2C[C@H](OCC2)C(F)(F)F)=CC(F)=C1C1=CC(C)=NC(C)=C1 KLZSTGPSEJAVRW-NRFANRHFSA-N 0.000 description 1
- GRGGHBYNBCYUOK-NRFANRHFSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-[(2s)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]-5-methyl-1,2-oxazole-3-carboxamide Chemical compound O1C(C)=CC(C(=O)NCC=2C(=C(F)C=C(C=2)N2C[C@H](OCC2)C(F)(F)F)C=2C=C(C)N=C(C)C=2)=N1 GRGGHBYNBCYUOK-NRFANRHFSA-N 0.000 description 1
- BYKWZEOEWWSIGZ-FQEVSTJZSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-[(2s)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]cyclopropanecarboxamide Chemical compound CC1=NC(C)=CC(C=2C(=CC(=CC=2F)N2C[C@H](OCC2)C(F)(F)F)CNC(=O)C2CC2)=C1 BYKWZEOEWWSIGZ-FQEVSTJZSA-N 0.000 description 1
- AHEWUPLMMYPEJB-UHFFFAOYSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-[3-(trifluoromethyl)piperidin-1-yl]phenyl]methyl]-2-methylpropanamide Chemical compound CC(C)C(=O)NCC1=CC(N2CC(CCC2)C(F)(F)F)=CC(F)=C1C1=CC(C)=NC(C)=C1 AHEWUPLMMYPEJB-UHFFFAOYSA-N 0.000 description 1
- WIJFCCNASYZMAA-UHFFFAOYSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-[3-(trifluoromethyl)piperidin-1-yl]phenyl]methyl]-3-methyl-1,2-oxazole-4-carboxamide Chemical compound CC1=NOC=C1C(=O)NCC1=CC(N2CC(CCC2)C(F)(F)F)=CC(F)=C1C1=CC(C)=NC(C)=C1 WIJFCCNASYZMAA-UHFFFAOYSA-N 0.000 description 1
- KRDUZDIHPKGRGO-UHFFFAOYSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-[3-(trifluoromethyl)piperidin-1-yl]phenyl]methyl]-5-methyl-1,2-oxazole-3-carboxamide Chemical compound O1C(C)=CC(C(=O)NCC=2C(=C(F)C=C(C=2)N2CC(CCC2)C(F)(F)F)C=2C=C(C)N=C(C)C=2)=N1 KRDUZDIHPKGRGO-UHFFFAOYSA-N 0.000 description 1
- JRTBLDSGVDKLBR-UHFFFAOYSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-3-fluoro-5-[3-(trifluoromethyl)piperidin-1-yl]phenyl]methyl]cyclopropanecarboxamide Chemical compound CC1=NC(C)=CC(C=2C(=CC(=CC=2F)N2CC(CCC2)C(F)(F)F)CNC(=O)C2CC2)=C1 JRTBLDSGVDKLBR-UHFFFAOYSA-N 0.000 description 1
- WMUJFYAVUORZHT-UHFFFAOYSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl]methyl]-2-methylpropanamide Chemical compound CC(C)C(=O)NCC1=CC(N2CC3CCC(O3)C2)=CC=C1C1=CC(C)=NC(C)=C1 WMUJFYAVUORZHT-UHFFFAOYSA-N 0.000 description 1
- MZRQNJSULMYVLM-UHFFFAOYSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-5-[3-(trifluoromethyl)piperidin-1-yl]phenyl]methyl]-2-methylpropanamide Chemical compound CC(C)C(=O)NCC1=CC(N2CC(CCC2)C(F)(F)F)=CC=C1C1=CC(C)=NC(C)=C1 MZRQNJSULMYVLM-UHFFFAOYSA-N 0.000 description 1
- QWNHUKUALZHIAK-UHFFFAOYSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-5-morpholin-4-ylphenyl]methyl]-2-methylpropanamide Chemical compound CC(C)C(=O)NCC1=CC(N2CCOCC2)=CC=C1C1=CC(C)=NC(C)=C1 QWNHUKUALZHIAK-UHFFFAOYSA-N 0.000 description 1
- RWKYJRNLJRFTOV-UHFFFAOYSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-5-morpholin-4-ylphenyl]methyl]-3,3,3-trifluoropropanamide Chemical compound CC1=NC(C)=CC(C=2C(=CC(=CC=2)N2CCOCC2)CNC(=O)CC(F)(F)F)=C1 RWKYJRNLJRFTOV-UHFFFAOYSA-N 0.000 description 1
- YGRXLSFIJOQMJC-UHFFFAOYSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-5-morpholin-4-ylphenyl]methyl]-3-methyl-1,2-oxazole-4-carboxamide Chemical compound CC1=NOC=C1C(=O)NCC1=CC(N2CCOCC2)=CC=C1C1=CC(C)=NC(C)=C1 YGRXLSFIJOQMJC-UHFFFAOYSA-N 0.000 description 1
- UNIDYTDCAKTUKK-UHFFFAOYSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-5-morpholin-4-ylphenyl]methyl]-4-fluoro-2-methylbenzamide Chemical compound CC1=NC(C)=CC(C=2C(=CC(=CC=2)N2CCOCC2)CNC(=O)C=2C(=CC(F)=CC=2)C)=C1 UNIDYTDCAKTUKK-UHFFFAOYSA-N 0.000 description 1
- CFXYGDDJOBVFPD-UHFFFAOYSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-5-morpholin-4-ylphenyl]methyl]-5-methyl-1,2-oxazole-3-carboxamide Chemical compound O1C(C)=CC(C(=O)NCC=2C(=CC=C(C=2)N2CCOCC2)C=2C=C(C)N=C(C)C=2)=N1 CFXYGDDJOBVFPD-UHFFFAOYSA-N 0.000 description 1
- OREAORROQLPWOK-UHFFFAOYSA-N n-[[2-(2,6-dimethylpyridin-4-yl)-5-morpholin-4-ylphenyl]methyl]cyclopropanecarboxamide Chemical compound CC1=NC(C)=CC(C=2C(=CC(=CC=2)N2CCOCC2)CNC(=O)C2CC2)=C1 OREAORROQLPWOK-UHFFFAOYSA-N 0.000 description 1
- VOASFKVGAFXDBJ-KDURUIRLSA-N n-[[2-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-5-(2,6-dimethylpyridin-4-yl)phenyl]methyl]-2-methylpropanamide Chemical compound CC(C)C(=O)NCC1=CC(C=2C=C(C)N=C(C)C=2)=CC=C1N1C[C@H](C)O[C@H](C)C1 VOASFKVGAFXDBJ-KDURUIRLSA-N 0.000 description 1
- GKFUSNZYKSWSIL-HDICACEKSA-N n-[[2-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-5-(2,6-dimethylpyridin-4-yl)phenyl]methyl]-3-methyl-1,2-oxazole-4-carboxamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC=C(C=2C=C(C)N=C(C)C=2)C=C1CNC(=O)C1=CON=C1C GKFUSNZYKSWSIL-HDICACEKSA-N 0.000 description 1
- CMCPRNBQEUAGRJ-OYRHEFFESA-N n-[[2-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-5-(2,6-dimethylpyridin-4-yl)phenyl]methyl]-4-fluoro-2-methylbenzamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC=C(C=2C=C(C)N=C(C)C=2)C=C1CNC(=O)C1=CC=C(F)C=C1C CMCPRNBQEUAGRJ-OYRHEFFESA-N 0.000 description 1
- FTDMNFPPQWNIAF-KDURUIRLSA-N n-[[2-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-5-(2,6-dimethylpyridin-4-yl)phenyl]methyl]-5-methyl-1,2-oxazole-3-carboxamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC=C(C=2C=C(C)N=C(C)C=2)C=C1CNC(=O)C1=NOC(C)=C1 FTDMNFPPQWNIAF-KDURUIRLSA-N 0.000 description 1
- TXVSUVSHXRZLKU-UHFFFAOYSA-N n-[[3-(2,6-dimethyloxan-4-yl)-6-(2,6-dimethylpyridin-4-yl)-2-fluorophenyl]methyl]-2-methylpropanamide Chemical compound CC(C)C(=O)NCC1=C(F)C(C2CC(C)OC(C)C2)=CC=C1C1=CC(C)=NC(C)=C1 TXVSUVSHXRZLKU-UHFFFAOYSA-N 0.000 description 1
- YMYQRRPNGWFRAA-UHFFFAOYSA-N n-[[3-(2,6-dimethyloxan-4-yl)-6-(2,6-dimethylpyridin-4-yl)-2-fluorophenyl]methyl]-3-methyl-1,2-oxazole-4-carboxamide Chemical compound C1C(C)OC(C)CC1C(C(=C1CNC(=O)C=2C(=NOC=2)C)F)=CC=C1C1=CC(C)=NC(C)=C1 YMYQRRPNGWFRAA-UHFFFAOYSA-N 0.000 description 1
- MVKPAMIZZADSOG-UHFFFAOYSA-N n-[[3-(2,6-dimethyloxan-4-yl)-6-(2,6-dimethylpyridin-4-yl)-2-fluorophenyl]methyl]-5-methyl-1,2-oxazole-3-carboxamide Chemical compound C1C(C)OC(C)CC1C(C(=C1CNC(=O)C2=NOC(C)=C2)F)=CC=C1C1=CC(C)=NC(C)=C1 MVKPAMIZZADSOG-UHFFFAOYSA-N 0.000 description 1
- RHEPMSBNCGBITM-KDURUIRLSA-N n-[[3-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-6-(2,6-dimethylpyridin-4-yl)-2-fluorophenyl]methyl]-3,3-dimethylbutanamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C(C(=C1CNC(=O)CC(C)(C)C)F)=CC=C1C1=CC(C)=NC(C)=C1 RHEPMSBNCGBITM-KDURUIRLSA-N 0.000 description 1
- UWTOKVHYOHNENJ-BGYRXZFFSA-N n-[[3-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-6-(2,6-dimethylpyridin-4-yl)-2-fluorophenyl]methyl]-4-fluoro-2-methylbenzamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C(C(=C1CNC(=O)C=2C(=CC(F)=CC=2)C)F)=CC=C1C1=CC(C)=NC(C)=C1 UWTOKVHYOHNENJ-BGYRXZFFSA-N 0.000 description 1
- UMMUDLGEWBFHLB-HDICACEKSA-N n-[[3-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-6-(2,6-dimethylpyridin-4-yl)-2-fluorophenyl]methyl]-5-methyl-1,2-oxazole-3-carboxamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C(C(=C1CNC(=O)C2=NOC(C)=C2)F)=CC=C1C1=CC(C)=NC(C)=C1 UMMUDLGEWBFHLB-HDICACEKSA-N 0.000 description 1
- HSJZHTCTAZNXAF-PMSBKCLSSA-N n-[[3-[(2r,6s)-2,6-dimethyloxan-4-yl]-6-(2,6-dimethylpyridin-4-yl)-2-fluorophenyl]methyl]-3-methylbutanamide Chemical compound CC(C)CC(=O)NCC1=C(F)C(C2C[C@@H](C)O[C@@H](C)C2)=CC=C1C1=CC(C)=NC(C)=C1 HSJZHTCTAZNXAF-PMSBKCLSSA-N 0.000 description 1
- RCOLSDANURRFLI-XEWABKELSA-N n-[[3-[(2r,6s)-2,6-dimethyloxan-4-yl]-6-(2,6-dimethylpyridin-4-yl)-2-fluorophenyl]methyl]cyclopropanecarboxamide Chemical compound C1[C@@H](C)O[C@@H](C)CC1C1=CC=C(C=2C=C(C)N=C(C)C=2)C(CNC(=O)C2CC2)=C1F RCOLSDANURRFLI-XEWABKELSA-N 0.000 description 1
- HGBPJGUPZOWPFU-HDICACEKSA-N n-[[3-[(2s,6r)-2,6-dimethylmorpholin-4-yl]-6-(2,6-dimethylpyridin-4-yl)-2-fluorophenyl]methyl]-2-methylpropanamide Chemical compound CC(C)C(=O)NCC1=C(F)C(N2C[C@@H](C)O[C@@H](C)C2)=CC=C1C1=CC(C)=NC(C)=C1 HGBPJGUPZOWPFU-HDICACEKSA-N 0.000 description 1
- KNJZNXUGBWUAGT-HDICACEKSA-N n-[[3-[(2s,6r)-2,6-dimethylmorpholin-4-yl]-6-(2,6-dimethylpyridin-4-yl)-2-fluorophenyl]methyl]-3-methoxypropanamide Chemical compound COCCC(=O)NCC1=C(F)C(N2C[C@@H](C)O[C@@H](C)C2)=CC=C1C1=CC(C)=NC(C)=C1 KNJZNXUGBWUAGT-HDICACEKSA-N 0.000 description 1
- ZBYNODRSFDYHNJ-KDURUIRLSA-N n-[[3-[(2s,6r)-2,6-dimethylmorpholin-4-yl]-6-(2,6-dimethylpyridin-4-yl)-2-fluorophenyl]methyl]-3-methylbutanamide Chemical compound CC(C)CC(=O)NCC1=C(F)C(N2C[C@@H](C)O[C@@H](C)C2)=CC=C1C1=CC(C)=NC(C)=C1 ZBYNODRSFDYHNJ-KDURUIRLSA-N 0.000 description 1
- IDZJRYHQKWCFGD-HDICACEKSA-N n-[[3-chloro-5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)phenyl]methyl]-5-methyl-1,2-oxazole-3-carboxamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC(Cl)=C(C=2C=C(C)N=C(C)C=2)C(CNC(=O)C2=NOC(C)=C2)=C1 IDZJRYHQKWCFGD-HDICACEKSA-N 0.000 description 1
- WRSMHEYZMQXMTA-HDICACEKSA-N n-[[3-chloro-5-[(2s,6r)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)phenyl]methyl]-2-cyclopropylacetamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC(Cl)=C(C=2C=C(C)N=C(C)C=2)C(CNC(=O)CC2CC2)=C1 WRSMHEYZMQXMTA-HDICACEKSA-N 0.000 description 1
- RLMSKOGXLWPQIN-HDICACEKSA-N n-[[3-chloro-5-[(2s,6r)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)phenyl]methyl]-2-methylpropanamide Chemical compound CC(C)C(=O)NCC1=CC(N2C[C@@H](C)O[C@@H](C)C2)=CC(Cl)=C1C1=CC(C)=NC(C)=C1 RLMSKOGXLWPQIN-HDICACEKSA-N 0.000 description 1
- CDDNUGWHMKFQJR-CALCHBBNSA-N n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)-3-fluorophenyl]methyl]-2-(2,2,2-trifluoroethoxy)acetamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC(F)=C(C=2C=C(C)N=C(C)C=2)C(CNC(=O)COCC(F)(F)F)=C1 CDDNUGWHMKFQJR-CALCHBBNSA-N 0.000 description 1
- GDOVJMJBCDXNTE-IYBDPMFKSA-N n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)-3-fluorophenyl]methyl]-3,3,3-trifluoropropanamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC(F)=C(C=2C=C(C)N=C(C)C=2)C(CNC(=O)CC(F)(F)F)=C1 GDOVJMJBCDXNTE-IYBDPMFKSA-N 0.000 description 1
- UKXSRMRKICVKRU-KDURUIRLSA-N n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)-3-fluorophenyl]methyl]-3,3-dimethylbutanamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC(F)=C(C=2C=C(C)N=C(C)C=2)C(CNC(=O)CC(C)(C)C)=C1 UKXSRMRKICVKRU-KDURUIRLSA-N 0.000 description 1
- VBCQVRZCTDSBGV-CALCHBBNSA-N n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)-3-fluorophenyl]methyl]-3-methyl-1,2-oxazole-4-carboxamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC(F)=C(C=2C=C(C)N=C(C)C=2)C(CNC(=O)C=2C(=NOC=2)C)=C1 VBCQVRZCTDSBGV-CALCHBBNSA-N 0.000 description 1
- DFFDVCULKAENRE-CALCHBBNSA-N n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)-3-fluorophenyl]methyl]-4,4,4-trifluorobutanamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC(F)=C(C=2C=C(C)N=C(C)C=2)C(CNC(=O)CCC(F)(F)F)=C1 DFFDVCULKAENRE-CALCHBBNSA-N 0.000 description 1
- NNZAEPQEXZGHIJ-HDICACEKSA-N n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)-3-fluorophenyl]methyl]-5-methyl-1,2-oxazole-3-carboxamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC(F)=C(C=2C=C(C)N=C(C)C=2)C(CNC(=O)C2=NOC(C)=C2)=C1 NNZAEPQEXZGHIJ-HDICACEKSA-N 0.000 description 1
- GVMZSZYOTCLDNW-HDICACEKSA-N n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)-4-fluorophenyl]methyl]-2-methylpropanamide Chemical compound FC=1C=C(C=2C=C(C)N=C(C)C=2)C(CNC(=O)C(C)C)=CC=1N1C[C@H](C)O[C@H](C)C1 GVMZSZYOTCLDNW-HDICACEKSA-N 0.000 description 1
- AOIHCLPJDROAJN-HDICACEKSA-N n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)-4-fluorophenyl]methyl]-5-methyl-1,2-oxazole-3-carboxamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC(CNC(=O)C2=NOC(C)=C2)=C(C=2C=C(C)N=C(C)C=2)C=C1F AOIHCLPJDROAJN-HDICACEKSA-N 0.000 description 1
- FKGOWSCJSGEWDH-CALCHBBNSA-N n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)phenyl]methyl]-3,3,3-trifluoropropanamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC=C(C=2C=C(C)N=C(C)C=2)C(CNC(=O)CC(F)(F)F)=C1 FKGOWSCJSGEWDH-CALCHBBNSA-N 0.000 description 1
- GWFSGONPEMHNMX-HDICACEKSA-N n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)phenyl]methyl]-3-methyl-1,2-oxazole-4-carboxamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC=C(C=2C=C(C)N=C(C)C=2)C(CNC(=O)C=2C(=NOC=2)C)=C1 GWFSGONPEMHNMX-HDICACEKSA-N 0.000 description 1
- PHZYHKMTYAYZCH-OYRHEFFESA-N n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)phenyl]methyl]-4-fluoro-2-methylbenzamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC=C(C=2C=C(C)N=C(C)C=2)C(CNC(=O)C=2C(=CC(F)=CC=2)C)=C1 PHZYHKMTYAYZCH-OYRHEFFESA-N 0.000 description 1
- NMBSNMVZQZBJCX-KDURUIRLSA-N n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)phenyl]methyl]-5-methyl-1,2-oxazole-3-carboxamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC=C(C=2C=C(C)N=C(C)C=2)C(CNC(=O)C2=NOC(C)=C2)=C1 NMBSNMVZQZBJCX-KDURUIRLSA-N 0.000 description 1
- IBNXDMFNUDBLPF-HDICACEKSA-N n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)phenyl]methyl]cyclopropanecarboxamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC=C(C=2C=C(C)N=C(C)C=2)C(CNC(=O)C2CC2)=C1 IBNXDMFNUDBLPF-HDICACEKSA-N 0.000 description 1
- LIKIVRDAQIHTKS-HDICACEKSA-N n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2-methylpyridin-4-yl)phenyl]methyl]-2-methylpropanamide Chemical compound CC(C)C(=O)NCC1=CC(N2C[C@@H](C)O[C@@H](C)C2)=CC=C1C1=CC=NC(C)=C1 LIKIVRDAQIHTKS-HDICACEKSA-N 0.000 description 1
- UVGBMWQPLKQBTB-CALCHBBNSA-N n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2-methylpyridin-4-yl)phenyl]methyl]-3-methyl-1,2-oxazole-4-carboxamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC=C(C=2C=C(C)N=CC=2)C(CNC(=O)C=2C(=NOC=2)C)=C1 UVGBMWQPLKQBTB-CALCHBBNSA-N 0.000 description 1
- OMEVPTWGGCHHDM-BGYRXZFFSA-N n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2-methylpyridin-4-yl)phenyl]methyl]-4-fluoro-2-methylbenzamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC=C(C=2C=C(C)N=CC=2)C(CNC(=O)C=2C(=CC(F)=CC=2)C)=C1 OMEVPTWGGCHHDM-BGYRXZFFSA-N 0.000 description 1
- QNKHGSWVLLSPHB-HDICACEKSA-N n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2-methylpyridin-4-yl)phenyl]methyl]-5-methyl-1,2-oxazole-3-carboxamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC=C(C=2C=C(C)N=CC=2)C(CNC(=O)C2=NOC(C)=C2)=C1 QNKHGSWVLLSPHB-HDICACEKSA-N 0.000 description 1
- YCBDPDFQZOXKBB-CALCHBBNSA-N n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-2-(2-methylpyridin-4-yl)phenyl]methyl]cyclopropanecarboxamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC=C(C=2C=C(C)N=CC=2)C(CNC(=O)C2CC2)=C1 YCBDPDFQZOXKBB-CALCHBBNSA-N 0.000 description 1
- RUMHDQDYSKLFTE-CALCHBBNSA-N n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-3-fluoro-2-(2-methylpyridin-4-yl)phenyl]methyl]-2-methylpropanamide Chemical compound CC(C)C(=O)NCC1=CC(N2C[C@@H](C)O[C@@H](C)C2)=CC(F)=C1C1=CC=NC(C)=C1 RUMHDQDYSKLFTE-CALCHBBNSA-N 0.000 description 1
- KROXOHIBNDKFBR-IYBDPMFKSA-N n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-3-fluoro-2-(2-methylpyridin-4-yl)phenyl]methyl]-3-methyl-1,2-oxazole-4-carboxamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC(F)=C(C=2C=C(C)N=CC=2)C(CNC(=O)C=2C(=NOC=2)C)=C1 KROXOHIBNDKFBR-IYBDPMFKSA-N 0.000 description 1
- LFENPEZTLYEUJZ-HDICACEKSA-N n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-3-fluoro-2-(2-methylpyridin-4-yl)phenyl]methyl]-3-methylbutanamide Chemical compound CC(C)CC(=O)NCC1=CC(N2C[C@@H](C)O[C@@H](C)C2)=CC(F)=C1C1=CC=NC(C)=C1 LFENPEZTLYEUJZ-HDICACEKSA-N 0.000 description 1
- AAYNSLZWSOUXES-CALCHBBNSA-N n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-3-fluoro-2-(2-methylpyridin-4-yl)phenyl]methyl]-5-methyl-1,2-oxazole-3-carboxamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC(F)=C(C=2C=C(C)N=CC=2)C(CNC(=O)C2=NOC(C)=C2)=C1 AAYNSLZWSOUXES-CALCHBBNSA-N 0.000 description 1
- WKSVHSWSBGFPOO-IYBDPMFKSA-N n-[[5-[(2r,6s)-2,6-dimethylmorpholin-4-yl]-3-fluoro-2-(2-methylpyridin-4-yl)phenyl]methyl]cyclopropanecarboxamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC(F)=C(C=2C=C(C)N=CC=2)C(CNC(=O)C2CC2)=C1 WKSVHSWSBGFPOO-IYBDPMFKSA-N 0.000 description 1
- GOUGJEVRGCQIOV-CALCHBBNSA-N n-[[5-[(2s,6r)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)-3,6-difluorophenyl]methyl]-5-methyl-1,2-oxazole-3-carboxamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C(C(=C1CNC(=O)C2=NOC(C)=C2)F)=CC(F)=C1C1=CC(C)=NC(C)=C1 GOUGJEVRGCQIOV-CALCHBBNSA-N 0.000 description 1
- PBBXJVWYUWWVIJ-HDICACEKSA-N n-[[5-[(2s,6r)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)-3-fluorophenyl]methyl]-2-methylpropanamide Chemical compound CC(C)C(=O)NCC1=CC(N2C[C@@H](C)O[C@@H](C)C2)=CC(F)=C1C1=CC(C)=NC(C)=C1 PBBXJVWYUWWVIJ-HDICACEKSA-N 0.000 description 1
- JHBVXZSKZMIXPA-KDURUIRLSA-N n-[[5-[(2s,6r)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)-3-fluorophenyl]methyl]-3-methylbutanamide Chemical compound CC(C)CC(=O)NCC1=CC(N2C[C@@H](C)O[C@@H](C)C2)=CC(F)=C1C1=CC(C)=NC(C)=C1 JHBVXZSKZMIXPA-KDURUIRLSA-N 0.000 description 1
- BPEKSPOJHTUKAU-HDICACEKSA-N n-[[5-[(2s,6r)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)-3-fluorophenyl]methyl]cyclobutanecarboxamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC(F)=C(C=2C=C(C)N=C(C)C=2)C(CNC(=O)C2CCC2)=C1 BPEKSPOJHTUKAU-HDICACEKSA-N 0.000 description 1
- GWUCVVGYXGIGIK-KDURUIRLSA-N n-[[5-[(2s,6r)-2,6-dimethylmorpholin-4-yl]-2-(2,6-dimethylpyridin-4-yl)-3-fluorophenyl]methyl]oxane-4-carboxamide Chemical compound C1[C@@H](C)O[C@@H](C)CN1C1=CC(F)=C(C=2C=C(C)N=C(C)C=2)C(CNC(=O)C2CCOCC2)=C1 GWUCVVGYXGIGIK-KDURUIRLSA-N 0.000 description 1
- WBDOTDFUIUFUND-CALCHBBNSA-N n-[[5-[(3s,5r)-3,5-dimethylpiperidin-1-yl]-2-(2,6-dimethylpyridin-4-yl)phenyl]methyl]-5-methyl-1,2-oxazole-3-carboxamide Chemical compound C1[C@@H](C)C[C@@H](C)CN1C1=CC=C(C=2C=C(C)N=C(C)C=2)C(CNC(=O)C2=NOC(C)=C2)=C1 WBDOTDFUIUFUND-CALCHBBNSA-N 0.000 description 1
- LXUZFYPECGBGDK-HXUWFJFHSA-N n-[[6-(2,6-dimethylpyridin-4-yl)-2-fluoro-3-[(2r)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]-2-methylpropanamide Chemical compound CC(C)C(=O)NCC1=C(F)C(N2C[C@@H](OCC2)C(F)(F)F)=CC=C1C1=CC(C)=NC(C)=C1 LXUZFYPECGBGDK-HXUWFJFHSA-N 0.000 description 1
- IJKRTEYPGJEZMH-OAQYLSRUSA-N n-[[6-(2,6-dimethylpyridin-4-yl)-2-fluoro-3-[(2r)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]-3-methyl-1,2-oxazole-4-carboxamide Chemical compound CC1=NOC=C1C(=O)NCC1=C(F)C(N2C[C@@H](OCC2)C(F)(F)F)=CC=C1C1=CC(C)=NC(C)=C1 IJKRTEYPGJEZMH-OAQYLSRUSA-N 0.000 description 1
- JTJWSCLFRZZTKR-OAQYLSRUSA-N n-[[6-(2,6-dimethylpyridin-4-yl)-2-fluoro-3-[(2r)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]-3-methylbutanamide Chemical compound CC(C)CC(=O)NCC1=C(F)C(N2C[C@@H](OCC2)C(F)(F)F)=CC=C1C1=CC(C)=NC(C)=C1 JTJWSCLFRZZTKR-OAQYLSRUSA-N 0.000 description 1
- GCSACLVTTVHPMT-OAQYLSRUSA-N n-[[6-(2,6-dimethylpyridin-4-yl)-2-fluoro-3-[(2r)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]-5-methyl-1,2-oxazole-3-carboxamide Chemical compound O1C(C)=CC(C(=O)NCC=2C(=CC=C(C=2F)N2C[C@@H](OCC2)C(F)(F)F)C=2C=C(C)N=C(C)C=2)=N1 GCSACLVTTVHPMT-OAQYLSRUSA-N 0.000 description 1
- GAJFBVVWJTWQHR-HXUWFJFHSA-N n-[[6-(2,6-dimethylpyridin-4-yl)-2-fluoro-3-[(2r)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]cyclopropanecarboxamide Chemical compound CC1=NC(C)=CC(C=2C(=C(F)C(N3C[C@@H](OCC3)C(F)(F)F)=CC=2)CNC(=O)C2CC2)=C1 GAJFBVVWJTWQHR-HXUWFJFHSA-N 0.000 description 1
- IJKRTEYPGJEZMH-NRFANRHFSA-N n-[[6-(2,6-dimethylpyridin-4-yl)-2-fluoro-3-[(2s)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]-3-methyl-1,2-oxazole-4-carboxamide Chemical compound CC1=NOC=C1C(=O)NCC1=C(F)C(N2C[C@H](OCC2)C(F)(F)F)=CC=C1C1=CC(C)=NC(C)=C1 IJKRTEYPGJEZMH-NRFANRHFSA-N 0.000 description 1
- JTJWSCLFRZZTKR-NRFANRHFSA-N n-[[6-(2,6-dimethylpyridin-4-yl)-2-fluoro-3-[(2s)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]-3-methylbutanamide Chemical compound CC(C)CC(=O)NCC1=C(F)C(N2C[C@H](OCC2)C(F)(F)F)=CC=C1C1=CC(C)=NC(C)=C1 JTJWSCLFRZZTKR-NRFANRHFSA-N 0.000 description 1
- GAJFBVVWJTWQHR-FQEVSTJZSA-N n-[[6-(2,6-dimethylpyridin-4-yl)-2-fluoro-3-[(2s)-2-(trifluoromethyl)morpholin-4-yl]phenyl]methyl]cyclopropanecarboxamide Chemical compound CC1=NC(C)=CC(C=2C(=C(F)C(N3C[C@H](OCC3)C(F)(F)F)=CC=2)CNC(=O)C2CC2)=C1 GAJFBVVWJTWQHR-FQEVSTJZSA-N 0.000 description 1
- TXGACLFWUPIXRC-UHFFFAOYSA-N n-benzyl-2-bromo-n-(3,3,3-trifluoro-2-hydroxypropyl)acetamide Chemical compound FC(F)(F)C(O)CN(C(=O)CBr)CC1=CC=CC=C1 TXGACLFWUPIXRC-UHFFFAOYSA-N 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000000422 nocturnal effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000001208 nuclear magnetic resonance pulse sequence Methods 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 210000002963 paraventricular hypothalamic nucleus Anatomy 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 102000054765 polymorphisms of proteins Human genes 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- HIGSLXSBYYMVKI-UHFFFAOYSA-N pralidoxime chloride Chemical compound [Cl-].C[N+]1=CC=CC=C1\C=N\O HIGSLXSBYYMVKI-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 210000002442 prefrontal cortex Anatomy 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000006977 prepulse inhibition Effects 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 210000004129 prosencephalon Anatomy 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000004544 spot-on Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000009495 transient activation Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000036967 uncompetitive effect Effects 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/22—Anxiolytics
-
- 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
- A61P25/24—Antidepressants
-
- 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
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/34—Tobacco-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- Allosteric modulators of nicotinic acetylcholine alpha 7 receptors have been disclosed in WO-2007/031440, WO-2007/118903, WO-2009/050186, WO-2009/050185, WO-2009/115547 and WO-2009/135944.
- nicotinic receptors The effects of nicotine from tobacco are also mediated by nicotinic receptors and since the effect of nicotine is to stabilize receptors in a desensitized state, an increased activity of nicotinic receptors may reduce the desire to smoke.
- positive allosteric modulators are not expected to produce long-term inactivation of receptors as may occur with prolonged application of agonists.
- Positive nAChR modulators of the present invention are useful for treatment and prophylaxis of psychotic disorders, intellectual impairment disorders and diseases, inflammatory diseases and conditions in which modulation of the alpha 7 nicotinic receptor is beneficial.
- the present invention relates to a compound having the formula (I)
- Y is N or CH
- Z is O or CH 2 ;
- tetrahydrofuryl tetrahydropyranyl
- phenyl phenyl substituted with 1, 2 or 3 substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, Ci- 6 alkyl, and Ci- 4 alkyloxy
- a monocyclic aromatic heterocyclic radical containing at least one heteroatom selected from N, O and S optionally substituted with 1, 2 or where possible with 3 substituents selected from halogen, Ci- 4 alkyl, Ci- 4 alkyloxy, C 3 - 6 cycloalkyl, and trifluoromethyl;
- R 2 and R 3 are independently H, Ci- 4 alkyl or trifluoromethyl; or R 2 and R 3 are taken together to form 1,2-ethanediyl or 1,3-propanediyl;
- R 1 is furanyl, oxazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrazinyl, thienyl, 1,2,3-thiadiazolyl, thiazolyl or benzisoxazolyl, each unsubstituted or substituted with 1, 2 or where possible 3 substituents selected from methyl, isopropyl, tert-butyl, cyclopropyl, methoxy and trifluoromethyl.
- R 2 is hydrogen, methyl or trifluoromethyl.
- R 5 is hydrogen or methyl.
- halo or halogen as a group or part of a group is generic for fluoro, chloro, bromo, iodo unless otherwise is indicated or is clear from the context.
- Alkyl groups may be linear or branched and may be substituted as indicated herein.
- the subscript refers to the number of carbon atoms that the named group may contain.
- Ci-salkyl includes all linear, or branched alkyl groups with between
- Ci- 4 alkyl as a group or part of a group refers to a hydrocarbyl radical of
- Ci- 4 alkyl groups comprise from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms, more preferably 1 to 2 carbon atoms.
- Ci- 4 alkyl includes all linear, or branched alkyl groups with between 1 and 4 carbon atoms, and thus includes such as for example methyl, ethyl, n-propyl, isopropyl, butyl and its isomers e.g. n-butyl, isobutyl, sec-butyl and tert-butyl.
- Ci- 6 alkyloxy refers to a radical having the Formula -OR a wherein R a is Ci- 6 alkyl.
- suitable alkyloxy include methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, pentyloxy, and hexyloxy.
- Ci- 4 alkyloxy include methyloxy (also methoxy), ethyloxy (also ethoxy), propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy and tert-butyloxy.
- haloCi- 4 alkyloxy as a group or part of a group refers to a Ci- 4 alkyloxy radical wherein said Ci- 4 alkyloxy radical is further substituted with 1, 2 or 3 halo atoms.
- suitable haloCi- 4 alkyloxy radicals include
- C 3 - 6 cycloalkyl alone or in combination, refers to a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms.
- suitable cycloC3-6alkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- the invention includes all stereoisomers of the compound of Formula (I) either as a pure stereoisomer or as a mixture of two or more stereoisomers.
- Enantiomers are stereoisomers that are non-superimposable mirror images of each other.
- a 1 : 1 mixture of a pair of enantiomers is a racemate or racemic mixture.
- stereoisomer When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other isomers.
- a compound of formula (I) is for instance specified as (R), this means that the compound is
- the pharmaceutically acceptable acid and base addition salts as mentioned hereinabove or hereinafter are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds according to formula (I) are able to form.
- the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
- Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.
- solvates refers to hydrates and alcoholates which the compounds according to formula (I) as well as the salts thereof, may form.
- R 2 , R 3 , R 4 , R 5 , Z, and X are as defined in Formula (I), with a compound of Formula (III) where R 1 is as defined in Formula (I), in the presence of a suitable amide coupling reagent, such as HBTU, a suitable base, such as DIPEA, in a suitable solvent, such as DCM and at a suitable temperature, such as room temperature.
- a suitable amide coupling reagent such as HBTU
- a suitable base such as DIPEA
- a suitable solvent such as DCM
- the acylation reaction of (II) may be conducted with a symmetric or asymmetric anhydride, or an acyl halide of carboxylic acid (III).
- R 2 , R 3 , Z, and X n are as defined in Formula (I), and Hal 1 is a halogen atom such as iodine, bromine or chlorine with a compound of Formula (VI)
- R 4 and R 5 are as defined in Formula (I), in the presence of a suitable catalyst, such as Pd(PPh 3 ) 4 , with a suitable base, such as sodium carbonate, in a suitable solvent, such as 1,4-dioxane and ethanol/water (1 : 1) and at a suitable temperature, such as 120°C in a sealed tube, under a suitable inert atmosphere, such as a nitrogen
- Hal 1 and X n are as defined as in Formula (V) and Hal 2 is a halogen atom such as fluorine, with a compound of Formula (VIII)
- compounds of Formula (V) can be prepared by reacting a compound of Formula (IX)
- R 2 , R 3 , Z, and X n are as defined in Formula (V) with a suitable base such as lithium tetramethylpiperidide and a halogen (Hal 1 )!, such as iodine, in a suitable solvent, such as THF, at a suitable temperature, such as -78°C and under a suitable inert atmosphere, such as a nitrogen atmosphere.
- a suitable base such as lithium tetramethylpiperidide and a halogen (Hal 1 )!, such as iodine
- a suitable solvent such as THF
- Hal 3 is a halogen atom, such as bromine, with a compound of Formula (VIII), in the presence of a suitable catalyst, such as Pd 2 (dba) 3 or the Nolan catalyst [478980-01-7], a suitable ligand, such as Xantphos, and a suitable base, such as sodium tert-butanolate, in a suitable solvent, such as toluene or monoglyme, at a suitable temperature, such as 120 °C, in a sealed tube, and under a suitable inert atmosphere, such as a nitrogen atmosphere.
- a suitable catalyst such as Pd 2 (dba) 3 or the Nolan catalyst [478980-01-7
- a suitable ligand such as Xantphos
- a suitable base such as sodium tert-butanolate
- compounds of Formula (IV) can be prepared by reacting a compound of Formula (XI)
- R 4 , R 5 , and X n are as defined in Fo Drrmmuulla (I), and Hal 4 is a halogen atom such as chlorine or bromine, with a compound of Formula (VIII), in the presence of a suitable catalyst such as Pd 2 (dba)3 or the Nolan catalyst [478980-01-7], a suitable ligand, such as Xantphos, and a suitable base, such as sodium tert-butanolate, in a suitable solvent, such as toluene or monoglyme, at a suitable temperature, such as 120 °C, in a sealed tube, and under a suitable inert atmosphere, such as a nitrogen atmosphere.
- a suitable catalyst such as Pd 2 (dba)3 or the Nolan catalyst [478980-01-7]
- a suitable ligand such as Xantphos
- a suitable base such as sodium tert-butanolate
- a suitable solvent such as toluene or monoglyme
- a suitable catalyst such as Pd(PPh 3 ) 4
- a suitable base such as sodium carbonate or potassium carbonate
- a suitable solvent such as 1,4-dioxane or dimethoxy ethane and water
- a suitable temperature such as 100°C
- a suitable inert atmosphere such as a nitrogen atmosphere.
- compounds of Formula (IV) can be prepared by reacting a compound of Formula (XIII)
- Hal 6 is a halogen atom such as, bromine, with a suitable cyanide salt, such as zinc cyanide, in the presence of a suitable catalyst, such as Pd(PPh 3 ) 4 , and in the presence of a suitable ligand, such as triphenylphosphine, in a suitable solvent, such as acetonitrile, and at a suitable temperature, such as 150°C, in a sealed tube, and under a suitable inert atmosphere, such as a nitrogen atmosphere.
- a suitable cyanide salt such as zinc cyanide
- a suitable catalyst such as Pd(PPh 3 ) 4
- a suitable ligand such as triphenylphosphine
- Compounds of Formula (XIII) can be prepared by reacting a compound of Formula (XIV) where R 4 , R 5 , X n and Hal 6 are as defined in Formula (XIII), and Hal 7 is a halogen atom such as bromine, with a compound of Formula (VIII), in the presence of a suitable catalyst, such as Pd 2 (dba) 3 , a suitable ligand, such as Xantphos, and a suitable base, such as sodium tert-butanolate, in a suitable solvent, such as toluene, at a suitable temperature, such as 120 °C, in a sealed tube, and under a suitable inert atmosphere, such as a nitrogen atmosphere.
- a suitable catalyst such as Pd 2 (dba) 3
- a suitable ligand such as Xantphos
- a suitable base such as sodium tert-butanolate
- R 2 , R 3 , R 4 , R 5 , Z, and X lake are as defined in Formula (lb), with a compound of Formula (III), in the presence of a suitable amide coupling reagent, such as HBTU, a suitable base, such as DIPEA, in a suitable solvent, such as DCM and at a suitable temperature, such as room temperature.
- a suitable amide coupling reagent such as HBTU
- a suitable base such as DIPEA
- a suitable solvent such as DCM
- a suitable temperature such as room temperature.
- the acylation reaction of (XVI) may be conducted with a symmetric or asymmetric anhydride, or an acyl halide of carboxylic acid (III).
- R 2 , R 3 , R 4 , R 5 , Z, and X bin are as defined in Formula (lb), with a suitable reducing agent, such as hydrogen, in the presence of a suitable catalyst, such as Raney Nickel, in a suitable solvent, such as 7M ammonia in methanol, at a suitable temperature, such as room temperature.
- a suitable reducing agent such as hydrogen
- a suitable catalyst such as Raney Nickel
- a suitable solvent such as 7M ammonia in methanol
- R 2 , R 3 , Z, and X n are as defined in Formula (lb), and Hal 9 is a halogen atom such as chlorine, with a compound of Formula (VI), in the presence of a suitable catalyst, such as Pd(PPh 3 ) 4 or PdCl 2 (dppf), with a suitable base, such as sodium carbonate, in a suitable solvent, such as a mixture of dioxane, ethanol and water, or acetonitrile, at a suitable temperature, such as 130°C, in a sealed tube, and under a suitable inert atmosphere, such as a nitrogen atmosphere.
- a suitable catalyst such as Pd(PPh 3 ) 4 or PdCl 2 (dppf)
- a suitable base such as sodium carbonate
- a suitable solvent such as a mixture of dioxane, ethanol and water, or acetonitrile
- Hal 9 and X n are as defined in Formula (XVIII) and Hal 10 is a halogen atom such as, bromine, with a compound of Formula (VIII), in the presence of a suitable catalyst, such as Pd 2 (dba) 3 , in the presence of a suitable ligand, such as Xantphos, with a suitable base, such as cesium carbonate, in a suitable solvent, such as dioxane, at a suitable temperature, such as 145 °C, in a sealed tube, and under a suitable inert atmosphere, such as a nitrogen atmosphere.
- a suitable catalyst such as Pd 2 (dba) 3
- a suitable ligand such as Xantphos
- a suitable base such as cesium carbonate
- a suitable solvent such as dioxane
- R 1 is as defined in Formula (I)
- a suitable amide coupling reagent such as HBTU
- a suitable base such as DIPEA
- a suitable solvent such as DCM
- a suitable temperature such as room temperature.
- the acylation reaction of (XX) may be conducted with a symmetric or asymmetric anhydride, or an acyl halide of carboxylic acid (III).
- R 2 , R 3 , R 4 , R 5 , Z, and X bin are as defined in Formula (I), with a suitable reducing agent, such as hydrogen, in the presence of a suitable catalyst, such as platinum on charcoal, in a suitable solvent, such as THF, at a suitable temperature, such as 50 °C.
- a suitable reducing agent such as hydrogen
- a suitable catalyst such as platinum on charcoal
- a suitable solvent such as THF
- R 2 , R 3 , R 4 , R 5 , Z, and X lake are as defined in Formula (I), with a suitable reducing agent, such as hydrogen, in the presence of a suitable catalyst, such as Raney Nickel, in a suitable solvent, such as 7M ammonia in methanol, at a suitable temperature, such as room temperature.
- a suitable reducing agent such as hydrogen
- a suitable catalyst such as Raney Nickel
- a suitable solvent such as 7M ammonia in methanol
- R 2 , R 3 , and Z are as defined in Formula (I), and R 6 is Ci- 6 alkyl or both R 6 together form C 2 -8alkanediyl, with a compound of Formula (XI), in the presence of a suitable catalyst such as Pd(PPh 3 ) 4 , with a suitable base, such as potassium carbonate, in a suitable solvent, such as dimethoxyethane, at a suitable temperature, such as 100°C, under a suitable inert atmosphere, such as nitrogen atmosphere.
- a suitable catalyst such as Pd(PPh 3 ) 4
- a suitable base such as potassium carbonate
- a suitable solvent such as dimethoxyethane
- R 2 , R 3 , and Z are as defined in Formula (I), with a suitable boron derivative, such as bis(pinacolato)diboron, in the presence of a suitable catalyst, such as
- the compounds of the present invention were found to be positive allosteric modulators of the alpha 7 nicotinic receptor.
- the alpha 7 nicotinic receptor (alpha 7 nAChR) belongs to the superfamily of cys-loop, ionotropic ligand-gated ion channels which includes the 5-HT 3 , GABAA and glycine receptor families. It is activated by acetylcholine and its breakdown product choline and a major feature of the alpha 7 nAChR is its rapid desensitisation in the persistent presence of agonist. It is the second most abundant nicotinic receptor subtype in the brain and is an important regulator of release of many neurotransmitters. It has a discrete distribution in several brain structures with relevance to attentional and cognitive processes, such as the
- hippocampus and pre-frontal cortex have been implicated in a variety of psychiatric and neurological disorders in humans. It is also implicated in the cholinergic inflammatory pathway.
- Pathological evidence points to a loss of alpha 7 immunoreactivity and a-bungarotoxin (Btx)-binding in the hippocampus, frontal and cingulate cortex of schizophrenic brains, in Parkinson's and Alzheimer's disease, and in the paraventricular nucleus and nucleus reuniens in autism.
- Btx a-bungarotoxin
- the alpha 7 nAChR rapidly desensitizes in the persistent presence of the natural transmitter acetylcholine as well as exogenous ligands such as nicotine. In the desensitized state the receptor remains ligand-bound but functionally inactive. This is not so much a problem for natural transmitters such as acetylcholine and choline since these are substrates for very powerful breakdown (acetylcholinesterase) and clearance (choline transporter) mechanisms. These transmitter breakdown/clearance mechanisms are likely to maintain the balance between activatible and desensitized alpha 7 nAChRs in a physiologically useful range.
- a PAM is defined as an agent which binds to a site distinct from the agonist binding site, and therefore is not expected to have agonist or desensitization properties, but enhances the responsiveness of the alpha 7 nAChR to the natural transmitter.
- the value of this strategy is that for a given amount of transmitter the magnitude of the alpha 7 nAChR response is increased in the presence of the PAM relative to the level of transmission possible in its absence.
- PAMs can also increase the potency of the natural transmitter. So for disorders in which there is a deficit in alpha 7 nAChR protein, the PAM-induced increase in alpha 7 nicotinergic transmission can be beneficial. As a PAM relies on the presence of the natural transmitter the potential for over-stimulation is limited by the breakdown/clearance mechanisms for the natural transmitter.
- Type 1 compounds enhance the effect size of the current elicited by 1 mM choline but minimally alter the kinetics of the receptor. In particular, the rate and the extent of desensitization and of deactivation of the receptor elicited by the agonist is not affected.
- the compound-modulated response to 1 mM choline therefore, is close to a linear scaling of the 1 mM choline response in absence of the alpha 7 PAM compound.
- Type 2 compounds enhance the effect size of the current elicited by 1 mM choline while reducing the rate and/or the extent of desensitization. Deactivation of the receptor is generally unaffected.
- Type 3 compounds enhance the effect size of the current elicited by 1 mM choline.
- Type 4 compounds allow for an initial desensitization of the receptor followed by a re-opening of the receptor during agonist application.
- the agonist-induced activation which is followed by desensitization, can still be separated from the compound-induced re-opening as an initial inward current-maximum.
- the re-opening occurs faster than the closure due to desensitization so that the initial current- maximum disappears.
- the method of treatment comprises treatment with a positive allosteric modulator of the alpha 7 nicotinic receptor as described herein and an alpha 7 nicotinic receptor agonist or partial agonist.
- suitable compounds with alpha 7 nicotinic receptor agonistic activity include
- Suitable compounds with a.7 nicotinic receptor agonistic activity include l,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester, monohydrochloride (SSR18071 1A) ;
- Positive nAChR modulators of the present invention are useful for treatment or prophylaxis of psychotic disorders, intellectual impairment disorders or diseases or conditions in which modulation of alpha 7 nicotinic receptor activity is beneficial.
- a particular aspect of the method of the invention is a method of treatment for learning deficit, cognition deficit, attention deficit or memory loss, modulation of alpha 7 nicotinic receptor activity is expected to be beneficial in a number of diseases including Alzheimer's disease, Lewy Body Dementia, Attention Deficit Hyperactivity Disorder, anxiety, schizophrenia, mania, manic depression, Parkinson's disease, Huntington's disease, Tourette's syndrome, brain trauma or other neurological, degenerative or psychiatric disorders in which there is loss of cholinergic synapses, including jetlag, nicotine addiction, pain.
- the compounds may also find therapeutical use as anti-inflammatory medicines because the nicotinic acetylcholine receptor alpha 7 subunit is essential for inhibiting cytokine synthesis by the cholinergic inflammatory pathway.
- indications which may be treated by the compounds are endotoxaemia, endotoxic shock, sepsis, rheumatoid arthritis, asthma, multiple sclerosis, psoriasis, urticaria, inflammatory bowel disease, inflammatory bile disease, Crohn's disease, ulcerative colitis, post- operative ileus, pancreatitis, heart failure, acute lung injury and allograft rejection.
- the compounds of the invention may find therapeutical use in the following indications as cognition in schizophrenia, cognition in Alzheimer's disease, mild cognitive impairment, Parkinson's disease, attention deficit hyperactivity disorder, ulcerative colitis, pancreatitis, arthritis, sepsis, postoperative ileus and acute lung injury.
- the compounds according to formula (I) or any subgroup thereof, their pharmaceutically acceptable addition salts, solvates and stereochemically isomeric forms may be used as a medicine.
- the present compounds can be used for the manufacture of a medicament for treatment or prophylaxis of psychotic disorders, intellectual impairment disorders or diseases or conditions in which modulation of the alpha 7 nicotinic receptor is beneficial.
- the present invention relates to the compounds according to formula (I) for treating or preventing, in particular treating, said diseases or conditions.
- Said methods comprise the administration, i.e. the systemic or topical administration, preferably oral administration, of an effective amount of a compound according to formula (I), a stereochemically isomeric form thereof, a pharmaceutically acceptable addition salt, or a solvate thereof, to warm-blooded animals, including humans.
- a therapeutically effective amount of the PAM's of the present invention is the amount sufficient to modulate the activity of the alpha 7 nicotinic receptor and that this amount varies inter alia, depending on the type of disease, the concentration of the compound in the therapeutic formulation, and the condition of the patient.
- an amount of PAM to be administered as a therapeutic agent for treating diseases in which modulation of the alpha 7 nicotinic receptor is beneficial such as schizophrenia, mania, and manic depression, anxiety, Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, Lewy Body Dementia, Attention Deficit Hyperactivity Disorder, Parkinson's disease, Huntington's disease, Tourette's syndrome, brain trauma, jetlag, nicotine addiction and pain will be determined on a case by case by an attending physician.
- a suitable dose is one that results in a concentration of the PAM at the treatment site in the range of 0.5 nM to 200 ⁇ , and more usually 5 nM to 50 ⁇ .
- a patient in need of treatment likely will be administered between 0.01 mg/kg to 2.50 mg/kg body weight, in particular from 0.1 mg/kg to 0.50 mg/kg body weight.
- the amount of a compound according to the present invention, also referred to here as the active ingredient, which is required to achieve a therapeutically effect will be, of course vary on case-by-case basis, vary with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated.
- the present invention also provides compositions for preventing or treating diseases in which modulation of the alpha 7 nicotinic receptor is beneficial, such as schizophrenia, mania, and manic depression, anxiety, Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, Lewy Body Dementia, Attention Deficit Hyperactivity Disorder, Parkinson's disease, Huntington's disease, Tourette's syndrome, brain trauma, jetlag, nicotine addiction and pain.
- Said compositions comprising a therapeutically effective amount of a compound according to formula (I) and a pharmaceutically acceptable carrier or diluent.
- a therapeutically effective amount of the particular compound, in base form or addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration.
- a pharmaceutically acceptable carrier which may take a wide variety of forms depending on the form of preparation desired for administration.
- These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for systemic administration such as oral, percutaneous or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like.
- any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid
- the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
- injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
- injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
- the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin.
- Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
- These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment.
- Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
- the exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
- the pharmaceutical composition will comprise from 0.05 to 99 % by weight, preferably from 0.1 to 70 % by weight, more preferably from 0.1 to 50 % by weight of the active ingredient, and, from 1 to 99.95 % by weight, preferably from 30 to 99.9 % by weight, more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
- suitable unit doses for the compounds of the present invention can, for example, preferably contain between 0.1 mg to about 1000 mg of the active compound.
- a preferred unit dose is between 1 mg to about 500 mg.
- a more preferred unit dose is between 1 mg to about 300mg.
- Even more preferred unit dose is between 1 mg to about 100 mg.
- the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs that have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those of skill in the area.
- a typical dosage can be one 1 mg to about 100 mg tablet or 1 mg to about 300 mg taken once a day, or, multiple times per day, or one time-release capsule or tablet taken once a day and containing a proportionally higher content of active ingredient.
- the time-release effect can be obtained by capsule materials that dissolve at different pH values, by capsules that release slowly by osmotic pressure, or by any other known means of controlled release.
- the present compounds can be used for systemic administration such as oral, percutaneous or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like.
- the compounds are preferably orally administered.
- the exact dosage and frequency of administration depends on the particular compound according to formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art.
- said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
- the compounds according to formula (I) may also be used in combination with other conventional a.7 nicotinic receptor agonists, such as for example 1,4-Diazabicyclo- [3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester, monohydrochloride
- PNU-282987 nicotine; varenicline; MEM3454; AZD-0328; MEM63908; (+)-N- (l-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan-2-carboxamide; A-582941 ; AR-R17779;
- the present invention also relates to the combination of a compound according to formula (I) and a alpha 7 nicotinic receptor agonist. Said combination may be used as a medicine.
- the present invention also relates to a product comprising (a) a compound according to formula (I), and (b) an alpha 7 nicotinic receptor agonist, as a combined preparation for simultaneous, separate or sequential use in the treatment of diseases wherein modulation of the alpha 7 nicotinic receptor is beneficial.
- the different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers.
- min means minutes
- MeOH means methanol
- EtOH means ethanol
- Et 2 0 means diethyl ether
- TFA means trifluoroacetic acid
- NH 4 OAc means ammonium acetate
- HBTU means O-(benzotriazol-l-yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluronium hexafluorophosphate
- DIPEA means DIPEA
- Microwave assisted reactions were performed in a single-mode reactor: Initiator Sixty EXP microwave reactor (Biotage AB), or in a multimode reactor: MicroSYNTH Labstation (Milestone, Inc.).
- a pressure tube was charged with a mixture of Intermediate 43 (5.6 g, 17.8 mmol), cis- 2,6-dimethylmorpholine (2.05 g, 17.8 mmol) and sodium tert-butoxide (2.56 g, 26.7 mmol) in toluene (150 mL).
- the mixture was degassed for 5 min before Xantphos [161265-03-8] (618 mg, 1.07 mmol) and Pd 2 (dba) 3 (326 mg, 0.35 mmol) were added.
- the mixture was further degassed for 15 min.
- the tube was sealed and the reaction mixture was stirred at 120 °C for 1 h. The solvent was evaporated. Water was added to the residue and it was extracted twice with DCM.
- a pressure tube was charged with a mixture of Intermediate 48 (280 mg, 0.68 mmol), zinc cyanide (48 mg, 0.41 mmol), triphenylphosphine (18 mg, 0.07 mmol) and tetrakis(triphenylphosphine)palladium (79 mg, 0.07 mmol) in acetonitrile (15 mL).
- the mixture was stirred at 150 °C in a microwave oven for 18 h.
- the solvent was evaporated and the residue taken up in water and DCM.
- the organic layer was separated, dried with MgS0 4 , filtered and evaporated.
- the residue was purified by column chromatography on silica gel (eluent: DCM). The desired fractions were collected and concentrated, yielding Intermediate 49 quantitatively.
- a pressure tube was charged with a mixture of Intermediate 51 (2.2 g, 6.84 mmol), cis- 2,6-dimethylmorpholine (656 mg, 5.70 mmol) and sodium tert-butoxide (822 mg, 8.55 mmol) in toluene (100 mL).
- the mixture was degassed for 5 min before Xantphos [161265-03-8] (198 mg, 0.34 mmol) and Pd 2 (dba) 3 (104 mg, 0.11 mmol) were added.
- the mixture was further degassed for 15 min.
- the tube was sealed and the reaction mixture was stirred at 100 °C for 5 h. The solvent was evaporated. Water was added to the residue and it was extracted with DCM.
- the LC measurement was performed using an Acquity UPLC (Waters) system comprising a binary pump, a sample organizer, a column heater (set at 55 °C), a diode- array detector (DAD) and a column as specified in the respective methods below.
- Flow from the column was split to a MS spectrometer.
- the MS detector was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 0.18 seconds using a dwell time of 0.02 seconds.
- the capillary needle voltage was 3.5 kV and the source temperature was maintained at 140 °C. Nitrogen was used as the nebulizer gas.
- Data acquisition was performed with a Waters-Mi cromass
- the HPLC measurement was performed using an Alliance HT 2790 (Waters) system comprising a quaternary pump with degasser, an autosampler, a column oven (set at 40 °C, unless otherwise indicated), a diode-array detector (DAD) and a column as specified in the respective methods below.
- Flow from the column was split to a MS spectrometer.
- the MS detector was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 1 second using a dwell time of 0.1 second.
- the capillary needle voltage was 3 kV and the source temperature was maintained at 140 °C. Nitrogen was used as the nebulizer gas.
- Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.
- Reversed phase UPLC Ultra Performance Liquid Chromatography
- BEH bridged ethylsiloxane/silica hybrid
- Waters Acquity a flow rate of 0.8 ml/min.
- Two mobile phases (mobile phase A: 0.1 % formic acid in H 2 0/methanol 95/5; mobile phase B: methanol) were used to run a gradient condition from 95 % A and 5 % B to 5 % A and 95 % B in 1.3 minutes and hold for 0.2 minutes.
- An injection volume of 0.5 ⁇ was used.
- Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.
- Cone voltage was 30 V for positive ionization mode and 30 V for negative ionization mode.
- Reversed phase HPLC was carried out on an Xterra MS C18 column (3.5 ⁇ , 4.6 x 100 mm) with a flow rate of 1.6 ml/min.
- Three mobile phases (mobile phase A: 95% 25 mM ammoniumacetate + 5 % acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100 % A to 1 % A, 49 % B and 50 % C in 6.5 minutes, to 1 % A and 99 % B in 1 minute and hold these conditions for 1 minute and reequilibrate with 100 % A for 1.5 minutes.
- An injection volume of 10 ⁇ was used.
- Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.
- Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.
- melting points were determined with a DSC823e from Mettler-Toledo. Melting points were measured with a temperature gradient of 30°C/minute. Values are peak values.
- FDSS Functional drug screening system
- Monolayers of human alpha 7-wt nAChR-expressing cells were grown in black-sided, transparent bottomed 384 well plates coated with PDL for 24 hours prior to loading with a fluorescent calcium indicator, fluo-4AM for up to 120 minutes.
- PAM activity was detected in real time by applying the compounds to be tested to the loaded cells along with an alpha 7 nicotinic receptor agonist during constant monitoring of cellular fluorescence in a FDSS.
- the alpha 7 nicotinic receptor agonist was choline, applied at a sub-maximal concentration of 100 ⁇ .
- the compounds were applied prior to the alpha 7 nicotinic receptor agonist, in a particular 10 minutes prior to the agonist.
- a control response to choline was calculated on each plate from the difference in peak in fluorescence in wells receiving either choline or assay buffer alone.
- Compounds of the present invention were tested at a concentration range from 0.01 ⁇ to 30 ⁇ . Compounds were considered to have an interesting activity when they potentiated the choline signal at least with 200 % when tested at a concentration of 30 ⁇ (the efficacy of 100 ⁇ choline was defined as 100% in the absence of a PAM).
- An EC 50 (or pEC 5 o) was determined as a concentration relating to half the maximal effect, when a clear sigmoidal curve with top plateau was obtained. The EC50 (or pEC 5 o) was defined as lower than maximal concentration in case the compound activity did not reach a top plateau at maximal concentration (indicated in table 7 as " ⁇ 5")
- the compounds also have a potentiating effect on the response to choline when measured by whole-cell patch clamp electrophysiology in GH4C1 cells stably over-expressing the human wild-type alpha 7 receptor.
- the preferential permeability to calcium of this receptor means that calcium flows into the cell upon activation by ACh, choline and other nicotinic ligands giving rise to a calcium current. Since this receptor rapidly desensitizes in the presence of agonist it is important that an application system is used which is capable of very rapid switching of solutions ( ⁇ 100 ms) to prevent partial or full desensitisation of receptor responses coincident with the time of agonist application. Consequently, a second convenient technique to assess the enhancement of nicotinic efficacy is a patch-clamp recording from human alpha 7-wt
- the external recording solution consisted of 152 mM NaCl, 5 mM KC1, 1 mM MgCl 2 , 1 mM Calcium, 10 mM HEPES ; pH 7.3.
- the internal recording solution consisted of 140 mM CsCl, 10 mM HEPES, 10 mM EGTA, 1 mM MgCl 2 , pH 7.3.
- Patch-clamp recording was carried out using a Patch -clamp amplifier (Multiclamp 700 A, Axon Instruments, CA, USA).
- Human alpha 7-wt nAChR-expressing GH4C1 cells were patch-clamped in the whole cell configuration (Hamill et al, 1981) with a borosilicate glass electrode of 1.5-3 ⁇ tip resistance when filled with the internal recording solution. Recordings were made on cells with membrane resistance
- ACh choline, were purchased from Sigma- Aldrich NV, Belgium.
- Human alpha 7-wt nAChR-expressing GH4C1 cells were plated in external recording solution in the Dynaflow perfusion chamber and were allowed to settle for up to 20 minutes. Individual cells were whole-cell patched and gently lifted off the chamber bottom with the patch pipette into a continuously-flowing perfusion stream (12 ⁇ /min) of external recording solution. PAM activity was detected in real time by pre-applying the compounds to the loaded cells followed by an alpha 7 nicotinic receptor agonist during constant monitoring of cellular membrane current. Compounds giving current responses greater than the response due to agonist alone, were considered to be alpha 7 nAChR PAM's.
- the alpha 7 nicotinic receptor was activated by a non-selective nicotinic agonist, choline applied at a sub-maximal concentration of 1 mM.
- the compounds were applied prior to the alpha 7 nicotinic receptor agonist, 30 seconds prior to the agonist or 5 seconds prior to the agonist.
- a control response was calculated from the area under the curve of the current elicited in each cell to the application of submaximal choline for 250 ms. Area under the curve is the integration of net current over time and is a common representation of the total ion flux through the channel.
- the pEC 5 o and % efficacy values are those from the Ca 2+ assay as described in D. l .
- the PAM type is obtained from the patch clamp current recording as described hereinbefore ("-" means no value ).
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- Immunology (AREA)
- Pain & Pain Management (AREA)
- Dermatology (AREA)
- Pulmonology (AREA)
- Psychology (AREA)
- Addiction (AREA)
- Cardiology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Hospice & Palliative Care (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Transplantation (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
Claims
Priority Applications (16)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020137023963A KR101851140B1 (en) | 2011-02-25 | 2012-02-23 | (PYRIDIN-4-YL)BENZYLAMIDES AS ALLOSTERIC MODULATORS OF ALPHA 7 nAChR |
ES12704845.2T ES2563113T3 (en) | 2011-02-25 | 2012-02-23 | (Pyridin-4-yl) benzylamides as allosteric modulators of nAChR alpha 7 |
NZ612688A NZ612688B2 (en) | 2011-02-25 | 2012-02-23 | (PYRIDIN-4-YL)BENZYLAMIDES AS ALLOSTERIC MODULATORS OF ALPHA 7 nAChR |
JP2013554890A JP5841617B2 (en) | 2011-02-25 | 2012-02-23 | (Pyridin-4-yl) benzylamide as an allosteric regulator of alpha 7nAChR |
AU2012219537A AU2012219537B2 (en) | 2011-02-25 | 2012-02-23 | (pyridin-4-yl)benzylamides as allosteric modulators of alpha 7 nAChR |
EP12704845.2A EP2678315B1 (en) | 2011-02-25 | 2012-02-23 | (Pyridin-4-yl)benzylamides as allosteric modulators of alpha 7 nAChR |
UAA201308962A UA109803C2 (en) | 2011-02-25 | 2012-02-23 | (PYRIDIN-4-IL) BENZYLAMIDES AS ALLOSTERICAL ALPHA-7 nAChR MODULATORS |
CN201280010276.7A CN103402983B (en) | 2011-02-25 | 2012-02-23 | As (pyridin-4-yl) benzyl amide of the allosteric modulators of α 7nAChR |
SG2013064225A SG192939A1 (en) | 2011-02-25 | 2012-02-23 | PYRIDIN-4-YL)BENZYLAMIDES AS ALLOSTERIC MODULATORS OF ALPHA 7 nAChR |
EA201391228A EA022164B1 (en) | 2011-02-25 | 2012-02-23 | (PYRIDIN-4-YL)BENZYLAMIDES AS ALLOSTERIC MODULATORS OF ALPHA 7 nAChR |
CA2824350A CA2824350C (en) | 2011-02-25 | 2012-02-23 | (pyridin-4-yl)benzylamides as allosteric modulators of alpha 7 nachr |
MX2013009798A MX345656B (en) | 2011-02-25 | 2012-02-23 | (PYRIDIN-4-YL)BENZYLAMIDES AS ALLOSTERIC MODULATORS OF ALPHA 7 nAChR. |
BR112013021599A BR112013021599A2 (en) | 2011-02-25 | 2012-02-23 | (pyridin-4-yl) benzylamides as nachr alpha 7 allosteric modulators |
IL228054A IL228054A (en) | 2011-02-25 | 2013-08-21 | (pyridin-4-yl)benzylamides as allosteric modulators of alpha7 nachr |
ZA2013/06385A ZA201306385B (en) | 2011-02-25 | 2013-08-23 | (pyridin-4-yl)benzylamides as allosteric modulators of alpha 7 nachr |
HK14102158.8A HK1189222A1 (en) | 2011-02-25 | 2014-03-04 | (pyridin-4-yl) benzylamides as allosteric modulators of alpha 7 nachr 7nachr (-4-) |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11155937 | 2011-02-25 | ||
EP11155937.3 | 2011-02-25 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2012113850A2 true WO2012113850A2 (en) | 2012-08-30 |
WO2012113850A3 WO2012113850A3 (en) | 2012-10-18 |
Family
ID=44259750
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2012/053047 WO2012113850A2 (en) | 2011-02-25 | 2012-02-23 | (PYRIDIN-4-YL)BENZYLAMIDES AS ALLOSTERIC MODULATORS OF ALPHA 7 nAChR |
Country Status (18)
Country | Link |
---|---|
EP (1) | EP2678315B1 (en) |
JP (1) | JP5841617B2 (en) |
KR (1) | KR101851140B1 (en) |
CN (1) | CN103402983B (en) |
AU (1) | AU2012219537B2 (en) |
BR (1) | BR112013021599A2 (en) |
CA (1) | CA2824350C (en) |
CL (1) | CL2013002424A1 (en) |
EA (1) | EA022164B1 (en) |
ES (1) | ES2563113T3 (en) |
HK (1) | HK1189222A1 (en) |
IL (1) | IL228054A (en) |
MX (1) | MX345656B (en) |
MY (1) | MY161236A (en) |
SG (1) | SG192939A1 (en) |
UA (1) | UA109803C2 (en) |
WO (1) | WO2012113850A2 (en) |
ZA (1) | ZA201306385B (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8404851B2 (en) | 2007-10-18 | 2013-03-26 | Janssen Pharmaceutica Nv | 1,3,5-trisubstituted triazole derivative |
US8440701B2 (en) | 2007-10-18 | 2013-05-14 | Janssen Pharmaceutica Nv | Trisubstituted 1,2,4 triazoles |
US8778974B2 (en) | 2008-03-19 | 2014-07-15 | Janssen Pharmaceutica Nv | Trisubstituted 1,2,4 triazoles |
US8779158B2 (en) | 2008-05-09 | 2014-07-15 | Janssen Pharmaceutica Nv | Trisubstituted pyrazoles as acetylcholine receptor modulators |
WO2017049321A1 (en) | 2015-09-17 | 2017-03-23 | Miller Marvin J | Benzyl amine-containing heterocyclic compounds and compositions useful against mycobacterial infection |
US9670219B2 (en) | 2015-08-19 | 2017-06-06 | Astellas Pharma Inc. | Tetrahydrooxepinopyridine compound |
WO2020064655A1 (en) * | 2018-09-24 | 2020-04-02 | Astrazeneca Ab | Azd0328 dosage regime for treating cognitive impairment |
CN113264867A (en) * | 2021-06-08 | 2021-08-17 | 安徽星宇化工有限公司 | Preparation method of cis-2, 6-dimethylpiperidine |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108689957B (en) * | 2018-07-23 | 2020-07-03 | 南京药石科技股份有限公司 | Preparation method and application of 2R/2S-trifluoromethyl morpholine and hydrochloride thereof |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006096358A1 (en) | 2005-03-04 | 2006-09-14 | Eli Lilly And Company | Azabicycloalkane derivatives useful as nicotinic acetylcholine receptor agonists |
WO2007031440A2 (en) | 2005-09-13 | 2007-03-22 | Janssen Pharmaceutica N.V. | 2-aniline-4-aryl substituted thiazole derivatives |
WO2007118903A1 (en) | 2006-04-19 | 2007-10-25 | Janssen Pharmaceutica N.V. | Trisubstituted 1,2,4-triazoles |
WO2009050185A1 (en) | 2007-10-18 | 2009-04-23 | Janssen Pharmaceutica Nv | 1,3,5-trisubstituted triazole derivative |
WO2009050186A1 (en) | 2007-10-18 | 2009-04-23 | Janssen Pharmaceutica Nv | Trisubstituted 1,2,4-triazoles |
WO2009115547A1 (en) | 2008-03-19 | 2009-09-24 | Janssen Pharmaceutica Nv | Trisubstituted 1, 2, 4 -triazoiies as nicotinic acetylcholine receptor modulators |
WO2009135944A1 (en) | 2008-05-09 | 2009-11-12 | Janssen Pharmaceutica Nv | Trisubstituted pyrazoles as acetylcholine receptor modulators |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1913901A (en) * | 2004-02-04 | 2007-02-14 | 神经研究公司 | Diazabicyclic aryl derivatives as cholinergic receptor modulators |
US20090048258A1 (en) * | 2005-02-01 | 2009-02-19 | Masaki Ogino | Amide Compound |
JP5420398B2 (en) * | 2006-05-19 | 2014-02-19 | アッヴィ・バハマズ・リミテッド | CNS active fused bicycloheterocyclic substituted azabicyclic alkane derivatives |
JP5564251B2 (en) * | 2006-06-29 | 2014-07-30 | キネックス ファーマシューティカルズ, エルエルシー | Biaryl compositions and methods for modulating kinase cascades |
NZ575354A (en) * | 2006-10-25 | 2012-05-25 | Neurosearch As | Oxadiazole and thiadiazole compounds and their use as nicotinic acetylcholine receptor modulators |
TW200948788A (en) * | 2008-04-22 | 2009-12-01 | Daiichi Sankyo Co Ltd | 5-hydroxypyrimidine-4-carboxamide compounds |
-
2012
- 2012-02-23 KR KR1020137023963A patent/KR101851140B1/en active IP Right Grant
- 2012-02-23 BR BR112013021599A patent/BR112013021599A2/en not_active Application Discontinuation
- 2012-02-23 UA UAA201308962A patent/UA109803C2/en unknown
- 2012-02-23 EP EP12704845.2A patent/EP2678315B1/en not_active Not-in-force
- 2012-02-23 CN CN201280010276.7A patent/CN103402983B/en not_active Expired - Fee Related
- 2012-02-23 SG SG2013064225A patent/SG192939A1/en unknown
- 2012-02-23 JP JP2013554890A patent/JP5841617B2/en not_active Expired - Fee Related
- 2012-02-23 MX MX2013009798A patent/MX345656B/en active IP Right Grant
- 2012-02-23 CA CA2824350A patent/CA2824350C/en active Active
- 2012-02-23 MY MYPI2013003103A patent/MY161236A/en unknown
- 2012-02-23 ES ES12704845.2T patent/ES2563113T3/en active Active
- 2012-02-23 WO PCT/EP2012/053047 patent/WO2012113850A2/en active Application Filing
- 2012-02-23 AU AU2012219537A patent/AU2012219537B2/en not_active Ceased
- 2012-02-23 EA EA201391228A patent/EA022164B1/en not_active IP Right Cessation
-
2013
- 2013-08-21 IL IL228054A patent/IL228054A/en active IP Right Grant
- 2013-08-22 CL CL2013002424A patent/CL2013002424A1/en unknown
- 2013-08-23 ZA ZA2013/06385A patent/ZA201306385B/en unknown
-
2014
- 2014-03-04 HK HK14102158.8A patent/HK1189222A1/en not_active IP Right Cessation
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006096358A1 (en) | 2005-03-04 | 2006-09-14 | Eli Lilly And Company | Azabicycloalkane derivatives useful as nicotinic acetylcholine receptor agonists |
WO2007031440A2 (en) | 2005-09-13 | 2007-03-22 | Janssen Pharmaceutica N.V. | 2-aniline-4-aryl substituted thiazole derivatives |
WO2007118903A1 (en) | 2006-04-19 | 2007-10-25 | Janssen Pharmaceutica N.V. | Trisubstituted 1,2,4-triazoles |
WO2009050185A1 (en) | 2007-10-18 | 2009-04-23 | Janssen Pharmaceutica Nv | 1,3,5-trisubstituted triazole derivative |
WO2009050186A1 (en) | 2007-10-18 | 2009-04-23 | Janssen Pharmaceutica Nv | Trisubstituted 1,2,4-triazoles |
WO2009115547A1 (en) | 2008-03-19 | 2009-09-24 | Janssen Pharmaceutica Nv | Trisubstituted 1, 2, 4 -triazoiies as nicotinic acetylcholine receptor modulators |
WO2009135944A1 (en) | 2008-05-09 | 2009-11-12 | Janssen Pharmaceutica Nv | Trisubstituted pyrazoles as acetylcholine receptor modulators |
Non-Patent Citations (1)
Title |
---|
GENNARO ET AL.: "Remington's Pharmaceutical Sciences", 1990, MACK PUBLISHING COMPANY, article "Pharmaceutical preparations and their Manufacture" |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8404851B2 (en) | 2007-10-18 | 2013-03-26 | Janssen Pharmaceutica Nv | 1,3,5-trisubstituted triazole derivative |
US8440701B2 (en) | 2007-10-18 | 2013-05-14 | Janssen Pharmaceutica Nv | Trisubstituted 1,2,4 triazoles |
US8778974B2 (en) | 2008-03-19 | 2014-07-15 | Janssen Pharmaceutica Nv | Trisubstituted 1,2,4 triazoles |
US8779158B2 (en) | 2008-05-09 | 2014-07-15 | Janssen Pharmaceutica Nv | Trisubstituted pyrazoles as acetylcholine receptor modulators |
US9670219B2 (en) | 2015-08-19 | 2017-06-06 | Astellas Pharma Inc. | Tetrahydrooxepinopyridine compound |
KR20180037983A (en) | 2015-08-19 | 2018-04-13 | 아스텔라스세이야쿠 가부시키가이샤 | Tetrahydrooxepinopyridine Compound |
WO2017049321A1 (en) | 2015-09-17 | 2017-03-23 | Miller Marvin J | Benzyl amine-containing heterocyclic compounds and compositions useful against mycobacterial infection |
WO2020064655A1 (en) * | 2018-09-24 | 2020-04-02 | Astrazeneca Ab | Azd0328 dosage regime for treating cognitive impairment |
CN113264867A (en) * | 2021-06-08 | 2021-08-17 | 安徽星宇化工有限公司 | Preparation method of cis-2, 6-dimethylpiperidine |
Also Published As
Publication number | Publication date |
---|---|
CN103402983B (en) | 2015-12-23 |
NZ612688A (en) | 2015-08-28 |
JP2014506587A (en) | 2014-03-17 |
KR20140014163A (en) | 2014-02-05 |
BR112013021599A2 (en) | 2016-11-16 |
EP2678315B1 (en) | 2015-12-16 |
AU2012219537A1 (en) | 2013-07-18 |
CL2013002424A1 (en) | 2014-03-28 |
MY161236A (en) | 2017-04-14 |
EA022164B1 (en) | 2015-11-30 |
IL228054A (en) | 2016-06-30 |
KR101851140B1 (en) | 2018-04-23 |
MX345656B (en) | 2017-02-08 |
JP5841617B2 (en) | 2016-01-13 |
IL228054A0 (en) | 2013-09-30 |
CN103402983A (en) | 2013-11-20 |
EA201391228A1 (en) | 2013-12-30 |
UA109803C2 (en) | 2015-10-12 |
EP2678315A2 (en) | 2014-01-01 |
ES2563113T3 (en) | 2016-03-10 |
WO2012113850A3 (en) | 2012-10-18 |
CA2824350A1 (en) | 2012-08-30 |
HK1189222A1 (en) | 2014-05-30 |
ZA201306385B (en) | 2015-03-25 |
SG192939A1 (en) | 2013-09-30 |
CA2824350C (en) | 2019-07-02 |
MX2013009798A (en) | 2013-09-26 |
AU2012219537B2 (en) | 2016-07-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2678315B1 (en) | (Pyridin-4-yl)benzylamides as allosteric modulators of alpha 7 nAChR | |
EP2504333B1 (en) | Morpholinothiazoles as alpha 7 positive allosteric modulators | |
AU2015250610B2 (en) | Isoindoline-1-one derivatives as cholinergic muscarinic M1 receptor positive alloesteric modulator activity for the treatment of Alzheimers disease | |
JP2021529740A (en) | Inhibitor of cyclin-dependent kinase | |
AU2008313775B2 (en) | 1,3,5-trisubstituted triazole derivative | |
EP2491024B1 (en) | Substituted n-phenyl-1-(4-pyridinyl)-1h-pyrazol-3-amines | |
EP3558318B1 (en) | Nmda receptor modulators and uses thereof | |
PT2699547E (en) | 5-(phenyl/pyridinyl-ethinyl)-2-pyridine/2-pyrimidine-carborxamides as mglur5 modulators | |
KR20120101551A (en) | Bicyclic thiazoles as allosteric modulators of mglur5 receptors | |
NZ612688B2 (en) | (PYRIDIN-4-YL)BENZYLAMIDES AS ALLOSTERIC MODULATORS OF ALPHA 7 nAChR | |
JP2022524077A (en) | Azetidinyl O-glycoprotein-2-acetamide-2-deoxy-3-D-glucopyranosidase inhibitor | |
EA038455B1 (en) | Novel naphthyridinone derivatives and their use in the treatment of arrhythmia |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 12704845 Country of ref document: EP Kind code of ref document: A2 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2012704845 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2824350 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2012219537 Country of ref document: AU Date of ref document: 20120223 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2013554890 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2013002424 Country of ref document: CL |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2013/009798 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1301004594 Country of ref document: TH |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 20137023963 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 201391228 Country of ref document: EA |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112013021599 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 112013021599 Country of ref document: BR Kind code of ref document: A2 Effective date: 20130823 |