WO2008018639A2 - Inhibiteur de transporteurs de glycine - Google Patents
Inhibiteur de transporteurs de glycine Download PDFInfo
- Publication number
- WO2008018639A2 WO2008018639A2 PCT/JP2007/065988 JP2007065988W WO2008018639A2 WO 2008018639 A2 WO2008018639 A2 WO 2008018639A2 JP 2007065988 W JP2007065988 W JP 2007065988W WO 2008018639 A2 WO2008018639 A2 WO 2008018639A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- phenyl
- methyl
- chloro
- hydrate
- trifluoromethyl
- Prior art date
Links
- 229940088352 Glycine transporter inhibitor Drugs 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 231
- 150000003839 salts Chemical class 0.000 claims abstract description 76
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 6
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 6
- 206010010904 Convulsion Diseases 0.000 claims abstract description 6
- 206010012289 Dementia Diseases 0.000 claims abstract description 6
- 206010013654 Drug abuse Diseases 0.000 claims abstract description 6
- 206010044565 Tremor Diseases 0.000 claims abstract description 6
- 208000010877 cognitive disease Diseases 0.000 claims abstract description 6
- 230000036461 convulsion Effects 0.000 claims abstract description 6
- 201000010099 disease Diseases 0.000 claims abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 6
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 6
- 208000019116 sleep disease Diseases 0.000 claims abstract description 6
- 208000011117 substance-related disease Diseases 0.000 claims abstract description 6
- 230000002265 prevention Effects 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 106
- -1 nitro, amino, aminosulfonyl Chemical group 0.000 claims description 97
- 125000000217 alkyl group Chemical group 0.000 claims description 65
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 64
- 125000004076 pyridyl group Chemical group 0.000 claims description 60
- 229910052736 halogen Inorganic materials 0.000 claims description 47
- 150000002367 halogens Chemical class 0.000 claims description 36
- 125000001424 substituent group Chemical group 0.000 claims description 35
- 125000001188 haloalkyl group Chemical group 0.000 claims description 33
- 239000001257 hydrogen Substances 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 125000003545 alkoxy group Chemical group 0.000 claims description 26
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 26
- 238000006467 substitution reaction Methods 0.000 claims description 26
- 125000003118 aryl group Chemical group 0.000 claims description 24
- 125000004429 atom Chemical group 0.000 claims description 24
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- 125000004254 isoquinolin-1-yl group Chemical group [H]C1=C([H])C2=C([H])C([H])=C([H])C([H])=C2C(*)=N1 0.000 claims description 23
- 125000002950 monocyclic group Chemical group 0.000 claims description 22
- 125000002619 bicyclic group Chemical group 0.000 claims description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 19
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 19
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 18
- 229910052717 sulfur Chemical group 0.000 claims description 18
- 239000011593 sulfur Chemical group 0.000 claims description 18
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 17
- 125000005842 heteroatom Chemical group 0.000 claims description 16
- 125000002252 acyl group Chemical group 0.000 claims description 15
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 14
- 239000001301 oxygen Chemical group 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 14
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 13
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
- 125000001624 naphthyl group Chemical group 0.000 claims description 12
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 11
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000005252 haloacyl group Chemical group 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- GRTMIGGEHNDFHY-FPOVZHCZSA-N 3-chloro-n-[(s)-[3-(1-ethylpyrazol-4-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]-4-(trifluoromethyl)pyridine-2-carboxamide Chemical compound C1=NN(CC)C=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(C=CN=2)C(F)(F)F)Cl)[C@H]2NCCCC2)=C1 GRTMIGGEHNDFHY-FPOVZHCZSA-N 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000002883 imidazolyl group Chemical group 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 6
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 6
- 125000001041 indolyl group Chemical group 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000005493 quinolyl group Chemical group 0.000 claims description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- BNOMEZFNDRXUTD-HKUYNNGSSA-N 3-chloro-n-[(s)-[(2s)-piperidin-2-yl]-[3-(1h-pyrazol-4-yl)phenyl]methyl]-4-(trifluoromethyl)pyridine-2-carboxamide Chemical compound FC(F)(F)C1=CC=NC(C(=O)N[C@H]([C@H]2NCCCC2)C=2C=C(C=CC=2)C2=CNN=C2)=C1Cl BNOMEZFNDRXUTD-HKUYNNGSSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 2
- 150000002688 maleic acid derivatives Chemical class 0.000 claims description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 abstract description 30
- 239000004471 Glycine Substances 0.000 abstract description 15
- 230000002401 inhibitory effect Effects 0.000 abstract description 7
- 208000011688 Generalised anxiety disease Diseases 0.000 abstract description 4
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 abstract description 4
- 206010041250 Social phobia Diseases 0.000 abstract description 4
- 208000031674 Traumatic Acute Stress disease Diseases 0.000 abstract description 4
- 208000026345 acute stress disease Diseases 0.000 abstract description 4
- 208000029364 generalized anxiety disease Diseases 0.000 abstract description 4
- 208000019906 panic disease Diseases 0.000 abstract description 4
- 208000019899 phobic disease Diseases 0.000 abstract description 4
- 208000028173 post-traumatic stress disease Diseases 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 327
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 128
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 118
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 108
- 239000000243 solution Substances 0.000 description 95
- 230000002829 reductive effect Effects 0.000 description 73
- 239000012044 organic layer Substances 0.000 description 68
- 239000000741 silica gel Substances 0.000 description 62
- 229910002027 silica gel Inorganic materials 0.000 description 62
- 238000004519 manufacturing process Methods 0.000 description 61
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 60
- 239000000203 mixture Substances 0.000 description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 52
- 239000000706 filtrate Substances 0.000 description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 46
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 46
- 238000004440 column chromatography Methods 0.000 description 44
- 239000002274 desiccant Substances 0.000 description 44
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 43
- 238000000034 method Methods 0.000 description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- 239000007864 aqueous solution Substances 0.000 description 33
- 229920006395 saturated elastomer Polymers 0.000 description 33
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 32
- 238000003786 synthesis reaction Methods 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 31
- 235000017557 sodium bicarbonate Nutrition 0.000 description 30
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 30
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 27
- 239000002904 solvent Substances 0.000 description 27
- 101150041968 CDC13 gene Proteins 0.000 description 26
- 238000005481 NMR spectroscopy Methods 0.000 description 26
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 26
- 230000015572 biosynthetic process Effects 0.000 description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 238000000605 extraction Methods 0.000 description 22
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
- 239000007787 solid Substances 0.000 description 22
- 238000001816 cooling Methods 0.000 description 21
- 239000003054 catalyst Substances 0.000 description 20
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 20
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 19
- 239000010410 layer Substances 0.000 description 19
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 18
- 125000006239 protecting group Chemical group 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 239000012299 nitrogen atmosphere Substances 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000003153 chemical reaction reagent Substances 0.000 description 15
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 229910052763 palladium Inorganic materials 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000001914 filtration Methods 0.000 description 10
- 239000012046 mixed solvent Substances 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 229910052751 metal Inorganic materials 0.000 description 9
- 239000002184 metal Substances 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- 229910021529 ammonia Inorganic materials 0.000 description 8
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 8
- 238000010511 deprotection reaction Methods 0.000 description 8
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 8
- 239000012264 purified product Substances 0.000 description 8
- 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 7
- VVSASNKOFCZVES-UHFFFAOYSA-N 1,3-dimethyl-1,3-diazinane-2,4,6-trione Chemical compound CN1C(=O)CC(=O)N(C)C1=O VVSASNKOFCZVES-UHFFFAOYSA-N 0.000 description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 7
- OFBDNIZZBBTVHK-SBKRINIZSA-N Cl.Cl.CN1CCCC[C@H]1[C@@H](NC(=O)c1cccc(c1Cl)C(F)(F)F)c1cccc(c1)-c1cccnc1 Chemical compound Cl.Cl.CN1CCCC[C@H]1[C@@H](NC(=O)c1cccc(c1Cl)C(F)(F)F)c1cccc(c1)-c1cccnc1 OFBDNIZZBBTVHK-SBKRINIZSA-N 0.000 description 7
- 238000007112 amidation reaction Methods 0.000 description 7
- 239000003638 chemical reducing agent Substances 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 235000011181 potassium carbonates Nutrition 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- BNPFZMGSIZSKMW-FPOVZHCZSA-N 3-chloro-n-[(s)-[(2s)-piperidin-2-yl]-(3-pyridin-3-ylphenyl)methyl]-4-(trifluoromethyl)pyridine-2-carboxamide Chemical compound FC(F)(F)C1=CC=NC(C(=O)N[C@H]([C@H]2NCCCC2)C=2C=C(C=CC=2)C=2C=NC=CC=2)=C1Cl BNPFZMGSIZSKMW-FPOVZHCZSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 6
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 229910001873 dinitrogen Inorganic materials 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 239000012280 lithium aluminium hydride Substances 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 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 6
- ZYTOMCCSXAUNKM-UNMCSNQZSA-N 2-chloro-n-[(s)-[3-(1-methylpyrazol-4-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]-3-(trifluoromethyl)benzamide Chemical compound C1=NN(C)C=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(C=CC=2)C(F)(F)F)Cl)[C@H]2NCCCC2)=C1 ZYTOMCCSXAUNKM-UNMCSNQZSA-N 0.000 description 5
- KJDIGQWBDQJIFR-UHFFFAOYSA-N 3-(trifluoromethyl)pyridine-2-carboxamide Chemical compound NC(=O)C1=NC=CC=C1C(F)(F)F KJDIGQWBDQJIFR-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 102000010726 Glycine Plasma Membrane Transport Proteins Human genes 0.000 description 5
- 108010063380 Glycine Plasma Membrane Transport Proteins Proteins 0.000 description 5
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 5
- 229910052697 platinum Inorganic materials 0.000 description 5
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 4
- RKWKLQQTRRFPQA-UGKGYDQZSA-N 2-chloro-n-[(s)-[3-(3-methylimidazol-4-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]-3-(trifluoromethyl)benzamide Chemical compound CN1C=NC=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(C=CC=2)C(F)(F)F)Cl)[C@H]2NCCCC2)=C1 RKWKLQQTRRFPQA-UGKGYDQZSA-N 0.000 description 4
- WDORPWNWWOLVPN-UHFFFAOYSA-N 3-chloro-4-(trifluoromethyl)pyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC(C(F)(F)F)=C1Cl WDORPWNWWOLVPN-UHFFFAOYSA-N 0.000 description 4
- JGNMKFLMVZNBID-GMAHTHKFSA-N 3-chloro-n-[(s)-[(2s)-1-(cyanomethyl)piperidin-2-yl]-(3-pyridin-3-ylphenyl)methyl]-4-(trifluoromethyl)pyridine-2-carboxamide Chemical compound FC(F)(F)C1=CC=NC(C(=O)N[C@H]([C@H]2N(CCCC2)CC#N)C=2C=C(C=CC=2)C=2C=NC=CC=2)=C1Cl JGNMKFLMVZNBID-GMAHTHKFSA-N 0.000 description 4
- ZFJOTNGEJIOWTJ-PXNSSMCTSA-N 3-chloro-n-[(s)-[(2s)-piperidin-2-yl]-(3-thiophen-2-ylphenyl)methyl]-4-(trifluoromethyl)pyridine-2-carboxamide Chemical compound FC(F)(F)C1=CC=NC(C(=O)N[C@H]([C@H]2NCCCC2)C=2C=C(C=CC=2)C=2SC=CC=2)=C1Cl ZFJOTNGEJIOWTJ-PXNSSMCTSA-N 0.000 description 4
- ULOBXVISOZLPRC-ICSRJNTNSA-N 3-chloro-n-[(s)-[3-(1-methylpyrazol-4-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]-4-(trifluoromethyl)pyridine-2-carboxamide Chemical compound C1=NN(C)C=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(C=CN=2)C(F)(F)F)Cl)[C@H]2NCCCC2)=C1 ULOBXVISOZLPRC-ICSRJNTNSA-N 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000009435 amidation Effects 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- GRJHONXDTNBDTC-UHFFFAOYSA-N phenyl trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OC1=CC=CC=C1 GRJHONXDTNBDTC-UHFFFAOYSA-N 0.000 description 4
- 125000004574 piperidin-2-yl group Chemical group N1C(CCCC1)* 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- ZHIJCVCCKVZBHE-UHFFFAOYSA-N (4-pyridin-3-ylphenyl)methanol Chemical compound C1=CC(CO)=CC=C1C1=CC=CN=C1 ZHIJCVCCKVZBHE-UHFFFAOYSA-N 0.000 description 3
- 108700002662 (R)-(N-(3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl))sarcosine Proteins 0.000 description 3
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-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
- FDORQEIHOKEJNX-UHFFFAOYSA-N 2-[[3-(4-fluorophenyl)-3-(4-phenylphenoxy)propyl]-methylamino]acetic acid Chemical compound C=1C=C(F)C=CC=1C(CCN(C)CC(O)=O)OC(C=C1)=CC=C1C1=CC=CC=C1 FDORQEIHOKEJNX-UHFFFAOYSA-N 0.000 description 3
- AXOAWWUSRZCGKS-UHFFFAOYSA-N 2-chloro-3-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC(C(F)(F)F)=C1Cl AXOAWWUSRZCGKS-UHFFFAOYSA-N 0.000 description 3
- PARVVALCOVPOBF-GMAHTHKFSA-N 2-chloro-n-[(s)-[(2s)-1-methylpiperidin-2-yl]-(3-pyrazin-2-ylphenyl)methyl]-3-(trifluoromethyl)benzamide Chemical compound CN1CCCC[C@H]1[C@H](C=1C=C(C=CC=1)C=1N=CC=NC=1)NC(=O)C1=CC=CC(C(F)(F)F)=C1Cl PARVVALCOVPOBF-GMAHTHKFSA-N 0.000 description 3
- DYASNFVFEIQLLP-UPVQGACJSA-N 2-chloro-n-[(s)-[(2s)-1-methylpiperidin-2-yl]-(3-pyridin-3-ylphenyl)methyl]-3-(trifluoromethyl)benzamide Chemical compound CN1CCCC[C@H]1[C@H](C=1C=C(C=CC=1)C=1C=NC=CC=1)NC(=O)C1=CC=CC(C(F)(F)F)=C1Cl DYASNFVFEIQLLP-UPVQGACJSA-N 0.000 description 3
- SCFJJZAUARSCCN-UGKGYDQZSA-N 2-chloro-n-[(s)-[(2s)-piperidin-2-yl]-(3-pyrazin-2-ylphenyl)methyl]-3-(trifluoromethyl)benzamide Chemical compound FC(F)(F)C1=CC=CC(C(=O)N[C@H]([C@H]2NCCCC2)C=2C=C(C=CC=2)C=2N=CC=NC=2)=C1Cl SCFJJZAUARSCCN-UGKGYDQZSA-N 0.000 description 3
- NUJBHCVTKBLMBP-UPVQGACJSA-N 2-chloro-n-[(s)-[(2s)-piperidin-2-yl]-[3-(1-propylpyrazol-4-yl)phenyl]methyl]-3-(trifluoromethyl)benzamide Chemical compound C1=NN(CCC)C=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(C=CC=2)C(F)(F)F)Cl)[C@H]2NCCCC2)=C1 NUJBHCVTKBLMBP-UPVQGACJSA-N 0.000 description 3
- PCWBBTMGPCZBSC-FPOVZHCZSA-N 2-chloro-n-[(s)-[(2s)-piperidin-2-yl]-[3-(1h-pyrazol-4-yl)phenyl]methyl]-3-(trifluoromethyl)benzamide Chemical compound FC(F)(F)C1=CC=CC(C(=O)N[C@H]([C@H]2NCCCC2)C=2C=C(C=CC=2)C2=CNN=C2)=C1Cl PCWBBTMGPCZBSC-FPOVZHCZSA-N 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- LTCHVAFYGVXKHH-UHFFFAOYSA-N 3-chloro-2-iodopyridine Chemical compound ClC1=CC=CN=C1I LTCHVAFYGVXKHH-UHFFFAOYSA-N 0.000 description 3
- VJMOXUVSDQEEBV-PXNSSMCTSA-N 3-chloro-n-[(s)-[(2s)-piperidin-2-yl]-(3-pyrazin-2-ylphenyl)methyl]-4-(trifluoromethyl)pyridine-2-carboxamide Chemical compound FC(F)(F)C1=CC=NC(C(=O)N[C@H]([C@H]2NCCCC2)C=2C=C(C=CC=2)C=2N=CC=NC=2)=C1Cl VJMOXUVSDQEEBV-PXNSSMCTSA-N 0.000 description 3
- MCQMZYYNBJIIFV-ICSRJNTNSA-N 3-chloro-n-[(s)-[(2s)-piperidin-2-yl]-(3-pyrimidin-5-ylphenyl)methyl]-4-(trifluoromethyl)pyridine-2-carboxamide Chemical compound FC(F)(F)C1=CC=NC(C(=O)N[C@H]([C@H]2NCCCC2)C=2C=C(C=CC=2)C=2C=NC=NC=2)=C1Cl MCQMZYYNBJIIFV-ICSRJNTNSA-N 0.000 description 3
- CBSVFGJOXYOPPT-ZCYQVOJMSA-N 3-chloro-n-[(s)-[(2s)-piperidin-2-yl]-(3-quinolin-3-ylphenyl)methyl]-4-(trifluoromethyl)pyridine-2-carboxamide Chemical compound FC(F)(F)C1=CC=NC(C(=O)N[C@H]([C@H]2NCCCC2)C=2C=C(C=CC=2)C=2C=C3C=CC=CC3=NC=2)=C1Cl CBSVFGJOXYOPPT-ZCYQVOJMSA-N 0.000 description 3
- XSAGYIVUNIQOGH-UNMCSNQZSA-N 3-chloro-n-[(s)-[(2s)-piperidin-2-yl]-[3-(1-propan-2-ylpyrazol-4-yl)phenyl]methyl]-4-(trifluoromethyl)pyridine-2-carboxamide Chemical compound C1=NN(C(C)C)C=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(C=CN=2)C(F)(F)F)Cl)[C@H]2NCCCC2)=C1 XSAGYIVUNIQOGH-UNMCSNQZSA-N 0.000 description 3
- RSEJBLUUZZDKHP-UPVQGACJSA-N 3-chloro-n-[(s)-[3-(1h-indol-5-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]-4-(trifluoromethyl)pyridine-2-carboxamide Chemical compound FC(F)(F)C1=CC=NC(C(=O)N[C@H]([C@H]2NCCCC2)C=2C=C(C=CC=2)C=2C=C3C=CNC3=CC=2)=C1Cl RSEJBLUUZZDKHP-UPVQGACJSA-N 0.000 description 3
- DYZOOVQEPYHDSS-RXVVDRJESA-N 3-chloro-n-[(s)-[3-(6-fluoropyridin-3-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]-4-(trifluoromethyl)pyridine-2-carboxamide Chemical compound C1=NC(F)=CC=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(C=CN=2)C(F)(F)F)Cl)[C@H]2NCCCC2)=C1 DYZOOVQEPYHDSS-RXVVDRJESA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000002440 hepatic effect Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 229910052740 iodine Chemical group 0.000 description 3
- 125000005956 isoquinolyl group Chemical group 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- TXSHSVJCCGEYON-DQEYMECFSA-N n-[(s)-[3-(1-ethylpyrazol-4-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]isoquinoline-1-carboxamide Chemical compound C1=NN(CC)C=C1C1=CC=CC([C@H](NC(=O)C=2C3=CC=CC=C3C=CN=2)[C@H]2NCCCC2)=C1 TXSHSVJCCGEYON-DQEYMECFSA-N 0.000 description 3
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 3
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 3
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 3
- 229910003446 platinum oxide Inorganic materials 0.000 description 3
- 235000011118 potassium hydroxide Nutrition 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 125000000168 pyrrolyl group Chemical group 0.000 description 3
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical class FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- SYSFTTYJTWPOOR-UHFFFAOYSA-N (2-diphenylphosphanyl-1-naphthalen-1-yl-3h-naphthalen-2-yl)-diphenylphosphane Chemical group C1C=C2C=CC=CC2=C(C=2C3=CC=CC=C3C=CC=2)C1(P(C=1C=CC=CC=1)C=1C=CC=CC=1)P(C=1C=CC=CC=1)C1=CC=CC=C1 SYSFTTYJTWPOOR-UHFFFAOYSA-N 0.000 description 2
- 0 *N(CCCC1)[C@@]1[C@](c1cc(Br)ccc1)NC(c(nccc1C(F)(F)F)c1Cl)=O Chemical compound *N(CCCC1)[C@@]1[C@](c1cc(Br)ccc1)NC(c(nccc1C(F)(F)F)c1Cl)=O 0.000 description 2
- DIOHEXPTUTVCNX-UHFFFAOYSA-N 1,1,1-trifluoro-n-phenyl-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=CC=C1 DIOHEXPTUTVCNX-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- MAKFMOSBBNKPMS-UHFFFAOYSA-N 2,3-dichloropyridine Chemical compound ClC1=CC=CN=C1Cl MAKFMOSBBNKPMS-UHFFFAOYSA-N 0.000 description 2
- RJCGWFXUWLHJRP-UGKGYDQZSA-N 2,6-dichloro-n-[(s)-[3-(1-methylpyrazol-4-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]-3-(trifluoromethyl)benzamide Chemical compound C1=NN(C)C=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(C=CC=2Cl)C(F)(F)F)Cl)[C@H]2NCCCC2)=C1 RJCGWFXUWLHJRP-UGKGYDQZSA-N 0.000 description 2
- FIRQBOHLAJRCSN-HKUYNNGSSA-N 2-chloro-n-[(s)-(3-hydroxyphenyl)-[(2s)-1-methylpiperidin-2-yl]methyl]-3-(trifluoromethyl)benzamide Chemical compound CN1CCCC[C@H]1[C@H](C=1C=C(O)C=CC=1)NC(=O)C1=CC=CC(C(F)(F)F)=C1Cl FIRQBOHLAJRCSN-HKUYNNGSSA-N 0.000 description 2
- XDJGVUGEQJOZCE-FPOVZHCZSA-N 2-chloro-n-[(s)-(3-pyrimidin-5-ylphenyl)-[(2s)-pyrrolidin-2-yl]methyl]-3-(trifluoromethyl)benzamide Chemical compound FC(F)(F)C1=CC=CC(C(=O)N[C@H]([C@H]2NCCC2)C=2C=C(C=CC=2)C=2C=NC=NC=2)=C1Cl XDJGVUGEQJOZCE-FPOVZHCZSA-N 0.000 description 2
- NTMRHLBJSQVIRW-GMAHTHKFSA-N 2-chloro-n-[(s)-[(2s)-1-methylpiperidin-2-yl]-(3-pyrimidin-5-ylphenyl)methyl]-3-(trifluoromethyl)benzamide Chemical compound CN1CCCC[C@H]1[C@H](C=1C=C(C=CC=1)C=1C=NC=NC=1)NC(=O)C1=CC=CC(C(F)(F)F)=C1Cl NTMRHLBJSQVIRW-GMAHTHKFSA-N 0.000 description 2
- SIZBMBLWJGIQPZ-GMAHTHKFSA-N 2-chloro-n-[(s)-[(2s)-1-methylpiperidin-2-yl]-[3-(1-methylpyrazol-4-yl)phenyl]methyl]-3-(trifluoromethyl)benzamide Chemical compound CN1CCCC[C@H]1[C@H](C=1C=C(C=CC=1)C1=CN(C)N=C1)NC(=O)C1=CC=CC(C(F)(F)F)=C1Cl SIZBMBLWJGIQPZ-GMAHTHKFSA-N 0.000 description 2
- GEVHJIWHJNINRV-GMAHTHKFSA-N 2-chloro-n-[(s)-[(2s)-1-methylpiperidin-2-yl]-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-3-(trifluoromethyl)benzamide Chemical compound CN1CCCC[C@H]1[C@H](C=1C=C(C=CC=1)B1OC(C)(C)C(C)(C)O1)NC(=O)C1=CC=CC(C(F)(F)F)=C1Cl GEVHJIWHJNINRV-GMAHTHKFSA-N 0.000 description 2
- MIKUWXSLWCTBPE-UNMCSNQZSA-N 2-chloro-n-[(s)-[(2s)-piperidin-2-yl]-(3-pyrimidin-5-ylphenyl)methyl]-3-(trifluoromethyl)benzamide Chemical compound FC(F)(F)C1=CC=CC(C(=O)N[C@H]([C@H]2NCCCC2)C=2C=C(C=CC=2)C=2C=NC=NC=2)=C1Cl MIKUWXSLWCTBPE-UNMCSNQZSA-N 0.000 description 2
- HXMAQUIZEFCDPP-UPVQGACJSA-N 2-chloro-n-[(s)-[(2s)-piperidin-2-yl]-[3-(1-propan-2-ylpyrazol-4-yl)phenyl]methyl]-3-(trifluoromethyl)benzamide Chemical compound C1=NN(C(C)C)C=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(C=CC=2)C(F)(F)F)Cl)[C@H]2NCCCC2)=C1 HXMAQUIZEFCDPP-UPVQGACJSA-N 0.000 description 2
- RNBMGJHSSZONDJ-GMAHTHKFSA-N 2-chloro-n-[(s)-[3-(1-ethylpyrazol-4-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]-3-(trifluoromethyl)benzamide Chemical compound C1=NN(CC)C=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(C=CC=2)C(F)(F)F)Cl)[C@H]2NCCCC2)=C1 RNBMGJHSSZONDJ-GMAHTHKFSA-N 0.000 description 2
- RZFWMIIYMAFHQQ-ZCYQVOJMSA-N 2-chloro-n-[(s)-[3-(1-methylpyrazol-4-yl)phenyl]-[(2s)-1-propan-2-ylpiperidin-2-yl]methyl]-3-(trifluoromethyl)benzamide Chemical compound CC(C)N1CCCC[C@H]1[C@H](C=1C=C(C=CC=1)C1=CN(C)N=C1)NC(=O)C1=CC=CC(C(F)(F)F)=C1Cl RZFWMIIYMAFHQQ-ZCYQVOJMSA-N 0.000 description 2
- MBMZBGMNUXYINL-FPOVZHCZSA-N 2-chloro-n-[(s)-[3-(1-methylpyrazol-4-yl)phenyl]-[(2s)-pyrrolidin-2-yl]methyl]-3-(trifluoromethyl)benzamide Chemical compound C1=NN(C)C=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(C=CC=2)C(F)(F)F)Cl)[C@H]2NCCC2)=C1 MBMZBGMNUXYINL-FPOVZHCZSA-N 0.000 description 2
- GELVZYOEQVJIRR-UHFFFAOYSA-N 2-chloropyrazine Chemical compound ClC1=CN=CC=N1 GELVZYOEQVJIRR-UHFFFAOYSA-N 0.000 description 2
- IIGNZLVHOZEOPV-UHFFFAOYSA-N 3-Methoxybenzyl alcohol Chemical compound COC1=CC=CC(CO)=C1 IIGNZLVHOZEOPV-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- UVJBNXZJTBKRQB-UHFFFAOYSA-N 3-chloro-2-(trifluoromethyl)pyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC(C(F)(F)F)=C1Cl UVJBNXZJTBKRQB-UHFFFAOYSA-N 0.000 description 2
- UWFLUNNTITXCJU-UGKGYDQZSA-N 3-chloro-2-fluoro-n-[(s)-[3-(1-methylpyrazol-4-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]-6-(trifluoromethyl)benzamide Chemical compound C1=NN(C)C=C1C1=CC=CC([C@H](NC(=O)C=2C(=CC=C(Cl)C=2F)C(F)(F)F)[C@H]2NCCCC2)=C1 UWFLUNNTITXCJU-UGKGYDQZSA-N 0.000 description 2
- YNYROPYZSZBORI-UHFFFAOYSA-N 3-chloro-4-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC=NC=C1Cl YNYROPYZSZBORI-UHFFFAOYSA-N 0.000 description 2
- QMFJSWJAEARXCU-UNMCSNQZSA-N 3-chloro-n-[(s)-[(2s)-1-methylpiperidin-2-yl]-(4-pyridin-3-ylphenyl)methyl]-4-(trifluoromethyl)pyridine-2-carboxamide Chemical compound CN1CCCC[C@H]1[C@H](C=1C=CC(=CC=1)C=1C=NC=CC=1)NC(=O)C1=NC=CC(C(F)(F)F)=C1Cl QMFJSWJAEARXCU-UNMCSNQZSA-N 0.000 description 2
- TULIVMASKXUMTC-MKSBGGEFSA-N 3-chloro-n-[(s)-[(2s)-piperidin-2-yl]-(3-pyrimidin-5-ylphenyl)methyl]-4-(trifluoromethyl)pyridine-2-carboxamide;hydrochloride Chemical compound Cl.FC(F)(F)C1=CC=NC(C(=O)N[C@H]([C@H]2NCCCC2)C=2C=C(C=CC=2)C=2C=NC=NC=2)=C1Cl TULIVMASKXUMTC-MKSBGGEFSA-N 0.000 description 2
- HXGQUMKWKHWZOT-FPOVZHCZSA-N 3-chloro-n-[(s)-[(2s)-piperidin-2-yl]-(4-pyridin-3-ylphenyl)methyl]-4-(trifluoromethyl)pyridine-2-carboxamide Chemical compound FC(F)(F)C1=CC=NC(C(=O)N[C@H]([C@H]2NCCCC2)C=2C=CC(=CC=2)C=2C=NC=CC=2)=C1Cl HXGQUMKWKHWZOT-FPOVZHCZSA-N 0.000 description 2
- HREOCPUXMWEYBG-UNMCSNQZSA-N 3-chloro-n-[(s)-[(2s)-piperidin-2-yl]-[3-(1-propylpyrazol-4-yl)phenyl]methyl]-4-(trifluoromethyl)pyridine-2-carboxamide Chemical compound C1=NN(CCC)C=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(C=CN=2)C(F)(F)F)Cl)[C@H]2NCCCC2)=C1 HREOCPUXMWEYBG-UNMCSNQZSA-N 0.000 description 2
- OKHVVVAVMITPBH-GMAHTHKFSA-N 3-chloro-n-[(s)-[3-(4-cyanophenyl)phenyl]-[(2s)-piperidin-2-yl]methyl]-4-(trifluoromethyl)pyridine-2-carboxamide Chemical compound FC(F)(F)C1=CC=NC(C(=O)N[C@H]([C@H]2NCCCC2)C=2C=C(C=CC=2)C=2C=CC(=CC=2)C#N)=C1Cl OKHVVVAVMITPBH-GMAHTHKFSA-N 0.000 description 2
- 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 2
- DMABVQFFNAXIHN-ROUUACIJSA-N 4-[(s)-[tert-butyl(dimethyl)silyl]oxy-[(2s)-1-methylpiperidin-2-yl]methyl]phenol Chemical compound CN1CCCC[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C1=CC=C(O)C=C1 DMABVQFFNAXIHN-ROUUACIJSA-N 0.000 description 2
- YOXFQJJRSXVPOI-STQMWFEESA-N 4-[(s)-hydroxy-[(2s)-1-methylpiperidin-2-yl]methyl]phenol Chemical compound CN1CCCC[C@H]1[C@@H](O)C1=CC=C(O)C=C1 YOXFQJJRSXVPOI-STQMWFEESA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 229910015845 BBr3 Inorganic materials 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 235000010724 Wisteria floribunda Nutrition 0.000 description 2
- JNHJVLYSUQYTSM-HKUYNNGSSA-N [3-[(s)-[[2-chloro-3-(trifluoromethyl)benzoyl]amino]-[(2s)-1-methylpiperidin-2-yl]methyl]phenyl] trifluoromethanesulfonate Chemical compound CN1CCCC[C@H]1[C@H](C=1C=C(OS(=O)(=O)C(F)(F)F)C=CC=1)NC(=O)C1=CC=CC(C(F)(F)F)=C1Cl JNHJVLYSUQYTSM-HKUYNNGSSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 2
- PQLAYKMGZDUDLQ-UHFFFAOYSA-K aluminium bromide Chemical compound Br[Al](Br)Br PQLAYKMGZDUDLQ-UHFFFAOYSA-K 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 2
- 125000006268 biphenyl-3-yl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C([H])C(*)=C([H])C([H])=C1[H] 0.000 description 2
- 229910000085 borane Inorganic materials 0.000 description 2
- 229910010277 boron hydride Inorganic materials 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 2
- CNXMDTWQWLGCPE-UHFFFAOYSA-N ditert-butyl-(2-phenylphenyl)phosphane Chemical group CC(C)(C)P(C(C)(C)C)C1=CC=CC=C1C1=CC=CC=C1 CNXMDTWQWLGCPE-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- OWKXPDYTUOIXSG-UPVQGACJSA-N n-[(s)-[3-(4-acetylphenyl)phenyl]-[(2s)-piperidin-2-yl]methyl]-3-chloro-4-(trifluoromethyl)pyridine-2-carboxamide Chemical compound C1=CC(C(=O)C)=CC=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(C=CN=2)C(F)(F)F)Cl)[C@H]2NCCCC2)=C1 OWKXPDYTUOIXSG-UPVQGACJSA-N 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 102200082402 rs751610198 Human genes 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 230000000946 synaptic effect Effects 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- MPFACKVSVGMQME-HNNXBMFYSA-N tert-butyl (2s)-2-(3-methoxybenzoyl)piperidine-1-carboxylate Chemical compound COC1=CC=CC(C(=O)[C@H]2N(CCCC2)C(=O)OC(C)(C)C)=C1 MPFACKVSVGMQME-HNNXBMFYSA-N 0.000 description 2
- YZNOURCSWOFMHR-PMACEKPBSA-N tert-butyl (2s)-2-[(s)-hydroxy-(4-pyridin-3-ylphenyl)methyl]piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC[C@H]1[C@@H](O)C1=CC=C(C=2C=NC=CC=2)C=C1 YZNOURCSWOFMHR-PMACEKPBSA-N 0.000 description 2
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- BZMMRNKDONDVIB-UHFFFAOYSA-N (1-ethoxycyclopropyl)oxy-trimethylsilane Chemical compound CCOC1(O[Si](C)(C)C)CC1 BZMMRNKDONDVIB-UHFFFAOYSA-N 0.000 description 1
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- JQAOHGMPAAWWQO-QMMMGPOBSA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCCC[C@H]1C(O)=O JQAOHGMPAAWWQO-QMMMGPOBSA-N 0.000 description 1
- FSWNRRSWFBXQCL-UHFFFAOYSA-N (3-bromophenyl)methanol Chemical compound OCC1=CC=CC(Br)=C1 FSWNRRSWFBXQCL-UHFFFAOYSA-N 0.000 description 1
- OOKAZRDERJMRCJ-KOUAFAAESA-N (3r)-7-[(1s,2s,4ar,6s,8s)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-3-hydroxy-5-oxoheptanoic acid Chemical compound C1=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(O)=O)C2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C[C@@H]21 OOKAZRDERJMRCJ-KOUAFAAESA-N 0.000 description 1
- PDVFSPNIEOYOQL-UHFFFAOYSA-N (4-methylphenyl)sulfonyl 4-methylbenzenesulfonate Chemical class C1=CC(C)=CC=C1S(=O)(=O)OS(=O)(=O)C1=CC=C(C)C=C1 PDVFSPNIEOYOQL-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- HYUQLOVUWQUTCU-RYUDHWBXSA-N (s)-(3-bromophenyl)-[(2s)-piperidin-2-yl]methanol Chemical compound C([C@H]1[C@@H](O)C=2C=C(Br)C=CC=2)CCCN1 HYUQLOVUWQUTCU-RYUDHWBXSA-N 0.000 description 1
- RBPYDEBRWUNIMW-LWKPJOBUSA-N (s)-(3-methoxy-4-methylphenyl)-(1-prop-2-enylpiperidin-2-yl)methanamine Chemical compound C1=C(C)C(OC)=CC([C@H](N)C2N(CCCC2)CC=C)=C1 RBPYDEBRWUNIMW-LWKPJOBUSA-N 0.000 description 1
- WJGNOUHQQQKUSJ-WMCAAGNKSA-N (s)-(4-chloro-3-methoxyphenyl)-(1-prop-2-enylpiperidin-2-yl)methanamine Chemical compound C1=C(Cl)C(OC)=CC([C@H](N)C2N(CCCC2)CC=C)=C1 WJGNOUHQQQKUSJ-WMCAAGNKSA-N 0.000 description 1
- MFQLJSMCXHLSGV-PMACEKPBSA-N (s)-[(2s)-1-methylpiperidin-2-yl]-(3-phenylmethoxyphenyl)methanamine Chemical compound CN1CCCC[C@H]1[C@@H](N)C1=CC=CC(OCC=2C=CC=CC=2)=C1 MFQLJSMCXHLSGV-PMACEKPBSA-N 0.000 description 1
- QKJPEIJVRZVKTJ-ROUUACIJSA-N (s)-[(2s)-1-methylpiperidin-2-yl]-(3-pyridin-3-ylphenyl)methanamine Chemical compound CN1CCCC[C@H]1[C@@H](N)C1=CC=CC(C=2C=NC=CC=2)=C1 QKJPEIJVRZVKTJ-ROUUACIJSA-N 0.000 description 1
- QNQCQOCWDRSPGT-OALUTQOASA-N (s)-[(2s)-1-methylpiperidin-2-yl]-(4-phenylphenyl)methanol Chemical compound CN1CCCC[C@H]1[C@@H](O)C1=CC=C(C=2C=CC=CC=2)C=C1 QNQCQOCWDRSPGT-OALUTQOASA-N 0.000 description 1
- OCESAVZPZGELGN-ROUUACIJSA-N (s)-[(2s)-1-methylpiperidin-2-yl]-(4-pyridin-3-ylphenyl)methanamine Chemical compound CN1CCCC[C@H]1[C@@H](N)C1=CC=C(C=2C=NC=CC=2)C=C1 OCESAVZPZGELGN-ROUUACIJSA-N 0.000 description 1
- DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 description 1
- JSRLURSZEMLAFO-UHFFFAOYSA-N 1,3-dibromobenzene Chemical compound BrC1=CC=CC(Br)=C1 JSRLURSZEMLAFO-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UGCRHVPUHAXAAE-UHFFFAOYSA-N 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound C1=NN(CC)C=C1B1OC(C)(C)C(C)(C)O1 UGCRHVPUHAXAAE-UHFFFAOYSA-N 0.000 description 1
- PKJCXHILXIEALN-UHFFFAOYSA-N 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound CCN1N=CC=C1B1OC(C)(C)C(C)(C)O1 PKJCXHILXIEALN-UHFFFAOYSA-N 0.000 description 1
- UCNGGGYMLHAMJG-UHFFFAOYSA-N 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound C1=NN(C)C=C1B1OC(C)(C)C(C)(C)O1 UCNGGGYMLHAMJG-UHFFFAOYSA-N 0.000 description 1
- OGYYMVGDKVJYSU-UHFFFAOYSA-N 1-propan-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound C1=NN(C(C)C)C=C1B1OC(C)(C)C(C)(C)O1 OGYYMVGDKVJYSU-UHFFFAOYSA-N 0.000 description 1
- BKLGYJWLZWMIDO-UHFFFAOYSA-N 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound C1=NN(CCC)C=C1B1OC(C)(C)C(C)(C)O1 BKLGYJWLZWMIDO-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 description 1
- OTTXCOAOKOEENK-UHFFFAOYSA-N 2,2-difluoroethenone Chemical group FC(F)=C=O OTTXCOAOKOEENK-UHFFFAOYSA-N 0.000 description 1
- WBUSGFGQZQCLOD-UNMCSNQZSA-N 2,3-dichloro-n-[(s)-[3-(1-methylpyrazol-4-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]benzamide Chemical compound C1=NN(C)C=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(Cl)C=CC=2)Cl)[C@H]2NCCCC2)=C1 WBUSGFGQZQCLOD-UNMCSNQZSA-N 0.000 description 1
- ZHJCQPQEMDIYPQ-UNMCSNQZSA-N 2,4,6-trichloro-n-[(s)-[3-(1-methylpyrazol-4-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]benzamide Chemical compound C1=NN(C)C=C1C1=CC=CC([C@H](NC(=O)C=2C(=CC(Cl)=CC=2Cl)Cl)[C@H]2NCCCC2)=C1 ZHJCQPQEMDIYPQ-UNMCSNQZSA-N 0.000 description 1
- IWOYLHWDJMDPRJ-UGKGYDQZSA-N 2,6-dichloro-n-[(s)-[4-(1-methylpyrazol-4-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]-3-(trifluoromethyl)benzamide Chemical compound C1=NN(C)C=C1C1=CC=C([C@H](NC(=O)C=2C(=C(C=CC=2Cl)C(F)(F)F)Cl)[C@H]2NCCCC2)C=C1 IWOYLHWDJMDPRJ-UGKGYDQZSA-N 0.000 description 1
- QBAYIBZITZBSFO-UHFFFAOYSA-N 2-(trifluoromethyl)benzamide Chemical compound NC(=O)C1=CC=CC=C1C(F)(F)F QBAYIBZITZBSFO-UHFFFAOYSA-N 0.000 description 1
- AMQMPEWAPNBLDS-UHFFFAOYSA-N 2-[C-[3-(1-ethylpyrazol-4-yl)phenyl]-N-hydroxycarbonimidoyl]piperidine-1-carboxylic acid Chemical compound C1=NN(CC)C=C1C1=CC=CC(C(=NO)C2N(CCCC2)C(O)=O)=C1 AMQMPEWAPNBLDS-UHFFFAOYSA-N 0.000 description 1
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- OKZNPLXOJIQDMY-GMAHTHKFSA-N 2-chloro-6-methyl-n-[(s)-[3-(1-methylpyrazol-4-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]benzamide Chemical compound CC1=CC=CC(Cl)=C1C(=O)N[C@@H](C=1C=C(C=CC=1)C1=CN(C)N=C1)[C@H]1NCCCC1 OKZNPLXOJIQDMY-GMAHTHKFSA-N 0.000 description 1
- OLKUVMQVORACCM-UNMCSNQZSA-N 2-chloro-n-[(s)-(3-pyridin-3-ylphenyl)-[(2s)-pyrrolidin-2-yl]methyl]-3-(trifluoromethyl)benzamide Chemical compound FC(F)(F)C1=CC=CC(C(=O)N[C@H]([C@H]2NCCC2)C=2C=C(C=CC=2)C=2C=NC=CC=2)=C1Cl OLKUVMQVORACCM-UNMCSNQZSA-N 0.000 description 1
- AKRLJQJXLNYZJG-ZCYQVOJMSA-N 2-chloro-n-[(s)-[(2s)-1-cyclopropylpiperidin-2-yl]-[3-(1-methylpyrazol-4-yl)phenyl]methyl]-3-(trifluoromethyl)benzamide Chemical compound C1=NN(C)C=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(C=CC=2)C(F)(F)F)Cl)[C@H]2N(CCCC2)C2CC2)=C1 AKRLJQJXLNYZJG-ZCYQVOJMSA-N 0.000 description 1
- SBYCJPBDTOOQBB-AHWVRZQESA-N 2-chloro-n-[(s)-[(2s)-1-methylpiperidin-2-yl]-(3-phenylmethoxyphenyl)methyl]-3-(trifluoromethyl)benzamide Chemical compound CN1CCCC[C@H]1[C@H](C=1C=C(OCC=2C=CC=CC=2)C=CC=1)NC(=O)C1=CC=CC(C(F)(F)F)=C1Cl SBYCJPBDTOOQBB-AHWVRZQESA-N 0.000 description 1
- MPWGDVAYPVJIKU-UPVQGACJSA-N 2-chloro-n-[(s)-[(2s)-1-methylpiperidin-2-yl]-(3-pyridin-2-ylphenyl)methyl]-3-(trifluoromethyl)benzamide Chemical compound CN1CCCC[C@H]1[C@H](C=1C=C(C=CC=1)C=1N=CC=CC=1)NC(=O)C1=CC=CC(C(F)(F)F)=C1Cl MPWGDVAYPVJIKU-UPVQGACJSA-N 0.000 description 1
- VNYHTZUCRMCVOF-UPVQGACJSA-N 2-chloro-n-[(s)-[(2s)-1-methylpiperidin-2-yl]-(3-pyridin-4-ylphenyl)methyl]-3-(trifluoromethyl)benzamide Chemical compound CN1CCCC[C@H]1[C@H](C=1C=C(C=CC=1)C=1C=CN=CC=1)NC(=O)C1=CC=CC(C(F)(F)F)=C1Cl VNYHTZUCRMCVOF-UPVQGACJSA-N 0.000 description 1
- WKJVNIJLYCTPKX-UPVQGACJSA-N 2-chloro-n-[(s)-[(2s)-1-methylpiperidin-2-yl]-(4-pyridin-2-ylphenyl)methyl]-3-(trifluoromethyl)benzamide Chemical compound CN1CCCC[C@H]1[C@H](C=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)C1=CC=CC(C(F)(F)F)=C1Cl WKJVNIJLYCTPKX-UPVQGACJSA-N 0.000 description 1
- YDEWZEDLURGZOH-UPVQGACJSA-N 2-chloro-n-[(s)-[(2s)-1-methylpiperidin-2-yl]-(4-pyridin-3-ylphenyl)methyl]-3-(trifluoromethyl)benzamide Chemical compound CN1CCCC[C@H]1[C@H](C=1C=CC(=CC=1)C=1C=NC=CC=1)NC(=O)C1=CC=CC(C(F)(F)F)=C1Cl YDEWZEDLURGZOH-UPVQGACJSA-N 0.000 description 1
- GATAJJWIECRXTR-IUQUCOCYSA-N 2-chloro-n-[(s)-[(2s)-1-methylpiperidin-2-yl]-[3-(1-methylpyrazol-4-yl)phenyl]methyl]-3-(trifluoromethyl)benzamide;hydrochloride Chemical compound Cl.CN1CCCC[C@H]1[C@H](C=1C=C(C=CC=1)C1=CN(C)N=C1)NC(=O)C1=CC=CC(C(F)(F)F)=C1Cl GATAJJWIECRXTR-IUQUCOCYSA-N 0.000 description 1
- XSIFABYCELKFDT-CQERKEQDSA-N 2-chloro-n-[(s)-[(2s)-piperidin-2-yl]-(3-pyrazin-2-ylphenyl)methyl]-3-(trifluoromethyl)benzamide;hydrochloride Chemical compound Cl.FC(F)(F)C1=CC=CC(C(=O)N[C@H]([C@H]2NCCCC2)C=2C=C(C=CC=2)C=2N=CC=NC=2)=C1Cl XSIFABYCELKFDT-CQERKEQDSA-N 0.000 description 1
- ZDRKMNWVCXKMET-GMAHTHKFSA-N 2-chloro-n-[(s)-[(2s)-piperidin-2-yl]-(3-pyridin-3-ylphenyl)methyl]-3-(trifluoromethyl)benzamide Chemical compound FC(F)(F)C1=CC=CC(C(=O)N[C@H]([C@H]2NCCCC2)C=2C=C(C=CC=2)C=2C=NC=CC=2)=C1Cl ZDRKMNWVCXKMET-GMAHTHKFSA-N 0.000 description 1
- XJMVWVTUKXUWBB-DTRWSJPISA-N 2-chloro-n-[(s)-[3-(1-methylpyrazol-4-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]-3-(trifluoromethyl)benzamide;hydrochloride Chemical compound Cl.C1=NN(C)C=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(C=CC=2)C(F)(F)F)Cl)[C@H]2NCCCC2)=C1 XJMVWVTUKXUWBB-DTRWSJPISA-N 0.000 description 1
- DHKYRYQIWVBPNL-VXKWHMMOSA-N 2-chloro-n-[(s)-[3-(1-methylpyrazol-4-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]-5-(trifluoromethyl)benzamide Chemical compound C1=NN(C)C=C1C1=CC=CC([C@H](NC(=O)C=2C(=CC=C(C=2)C(F)(F)F)Cl)[C@H]2NCCCC2)=C1 DHKYRYQIWVBPNL-VXKWHMMOSA-N 0.000 description 1
- VIRUNVBKDXDYCY-GMAHTHKFSA-N 2-chloro-n-[(s)-[3-(1-propan-2-ylpyrazol-4-yl)phenyl]-[(2s)-pyrrolidin-2-yl]methyl]-3-(trifluoromethyl)benzamide Chemical compound C1=NN(C(C)C)C=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(C=CC=2)C(F)(F)F)Cl)[C@H]2NCCC2)=C1 VIRUNVBKDXDYCY-GMAHTHKFSA-N 0.000 description 1
- KWTTVZSAFOCXOQ-REWPJTCUSA-N 2-chloro-n-[(s)-[3-(3,5-dimethyl-1,2-oxazol-4-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]-3-(trifluoromethyl)benzamide Chemical compound CC1=NOC(C)=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(C=CC=2)C(F)(F)F)Cl)[C@H]2NCCCC2)=C1 KWTTVZSAFOCXOQ-REWPJTCUSA-N 0.000 description 1
- VRCHAXOXIQNJHR-VVJLZRNGSA-N 2-chloro-n-[(s)-[3-(3-methylimidazol-4-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]-3-(trifluoromethyl)benzamide;dihydrochloride Chemical compound Cl.Cl.CN1C=NC=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(C=CC=2)C(F)(F)F)Cl)[C@H]2NCCCC2)=C1 VRCHAXOXIQNJHR-VVJLZRNGSA-N 0.000 description 1
- UWZLBIFJOYDSNS-REWPJTCUSA-N 2-chloro-n-[(s)-[3-(furan-2-yl)phenyl]-[(2s)-1-methylpiperidin-2-yl]methyl]-3-(trifluoromethyl)benzamide Chemical compound CN1CCCC[C@H]1[C@H](C=1C=C(C=CC=1)C=1OC=CC=1)NC(=O)C1=CC=CC(C(F)(F)F)=C1Cl UWZLBIFJOYDSNS-REWPJTCUSA-N 0.000 description 1
- FZBGKGFNBDBPFK-ZCYQVOJMSA-N 2-chloro-n-[(s)-[3-[1-(2-methylpropyl)pyrazol-4-yl]phenyl]-[(2s)-piperidin-2-yl]methyl]-3-(trifluoromethyl)benzamide Chemical compound C1=NN(CC(C)C)C=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(C=CC=2)C(F)(F)F)Cl)[C@H]2NCCCC2)=C1 FZBGKGFNBDBPFK-ZCYQVOJMSA-N 0.000 description 1
- UTSMWAKWOZYPFN-UNMCSNQZSA-N 2-chloro-n-[(s)-[4-(1-methylpyrazol-4-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]-3-(trifluoromethyl)benzamide Chemical compound C1=NN(C)C=C1C1=CC=C([C@H](NC(=O)C=2C(=C(C=CC=2)C(F)(F)F)Cl)[C@H]2NCCCC2)C=C1 UTSMWAKWOZYPFN-UNMCSNQZSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- CDJXZHINSSEDFU-GOTSBHOMSA-N 2-methyl-n-[(s)-[3-(1-methylpyrazol-4-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]-3-(trifluoromethyl)benzamide Chemical compound C1=CC=C(C(F)(F)F)C(C)=C1C(=O)N[C@@H](C=1C=C(C=CC=1)C1=CN(C)N=C1)[C@H]1NCCCC1 CDJXZHINSSEDFU-GOTSBHOMSA-N 0.000 description 1
- RPIVAXWHZQCWBE-GOTSBHOMSA-N 2-methyl-n-[(s)-[3-(1-methylpyrazol-4-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]-5-(trifluoromethyl)benzamide Chemical compound CC1=CC=C(C(F)(F)F)C=C1C(=O)N[C@@H](C=1C=C(C=CC=1)C1=CN(C)N=C1)[C@H]1NCCCC1 RPIVAXWHZQCWBE-GOTSBHOMSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- JTNCEQNHURODLX-UHFFFAOYSA-N 2-phenylethanimidamide Chemical compound NC(=N)CC1=CC=CC=C1 JTNCEQNHURODLX-UHFFFAOYSA-N 0.000 description 1
- BEGHWTCZMCELAH-UHFFFAOYSA-N 3,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2-oxazole Chemical compound CC1(NOC(=C1)C)B1OC(C)(C)C(C)(C)O1 BEGHWTCZMCELAH-UHFFFAOYSA-N 0.000 description 1
- PAAQTNCVNKNNNE-UNMCSNQZSA-N 3,6-dichloro-2-methoxy-n-[(s)-[3-(1-methylpyrazol-4-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]benzamide Chemical compound COC1=C(Cl)C=CC(Cl)=C1C(=O)N[C@@H](C=1C=C(C=CC=1)C1=CN(C)N=C1)[C@H]1NCCCC1 PAAQTNCVNKNNNE-UNMCSNQZSA-N 0.000 description 1
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 1
- ZBEXSWCPJRQAKS-UNMCSNQZSA-N 3-chloro-n-[(s)-(3-phenylphenyl)-[(2s)-piperidin-2-yl]methyl]-4-(trifluoromethyl)pyridine-2-carboxamide Chemical compound FC(F)(F)C1=CC=NC(C(=O)N[C@H]([C@H]2NCCCC2)C=2C=C(C=CC=2)C=2C=CC=CC=2)=C1Cl ZBEXSWCPJRQAKS-UNMCSNQZSA-N 0.000 description 1
- SCJCFGQGQFGHGB-ANXDEKAJSA-N 3-chloro-n-[(s)-[(2s)-piperidin-2-yl]-(3-pyridin-3-ylphenyl)methyl]-4-(trifluoromethyl)pyridine-2-carboxamide;dihydrochloride Chemical compound Cl.Cl.FC(F)(F)C1=CC=NC(C(=O)N[C@H]([C@H]2NCCCC2)C=2C=C(C=CC=2)C=2C=NC=CC=2)=C1Cl SCJCFGQGQFGHGB-ANXDEKAJSA-N 0.000 description 1
- OQJSYFFGHBMJGX-ANXDEKAJSA-N 3-chloro-n-[(s)-[(2s)-piperidin-2-yl]-(4-pyridin-3-ylphenyl)methyl]-4-(trifluoromethyl)pyridine-2-carboxamide;dihydrochloride Chemical compound Cl.Cl.FC(F)(F)C1=CC=NC(C(=O)N[C@H]([C@H]2NCCCC2)C=2C=CC(=CC=2)C=2C=NC=CC=2)=C1Cl OQJSYFFGHBMJGX-ANXDEKAJSA-N 0.000 description 1
- DYRRJQZDJQJTGB-UNMCSNQZSA-N 3-chloro-n-[(s)-[(2s)-piperidin-2-yl]-[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]-4-(trifluoromethyl)pyridine-2-carboxamide Chemical compound C1=CC(C(F)(F)F)=CC=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(C=CN=2)C(F)(F)F)Cl)[C@H]2NCCCC2)=C1 DYRRJQZDJQJTGB-UNMCSNQZSA-N 0.000 description 1
- VKTBGTVBHJJCTP-RQBPZYBGSA-N 3-chloro-n-[(s)-[3-(1-ethylpyrazol-4-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]-4-(trifluoromethyl)pyridine-2-carboxamide;hydrochloride Chemical compound Cl.C1=NN(CC)C=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(C=CN=2)C(F)(F)F)Cl)[C@H]2NCCCC2)=C1 VKTBGTVBHJJCTP-RQBPZYBGSA-N 0.000 description 1
- FUNKZKALSMJAOH-UGKGYDQZSA-N 3-chloro-n-[(s)-[3-(6-methoxypyridin-3-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]-4-(trifluoromethyl)pyridine-2-carboxamide Chemical compound C1=NC(OC)=CC=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(C=CN=2)C(F)(F)F)Cl)[C@H]2NCCCC2)=C1 FUNKZKALSMJAOH-UGKGYDQZSA-N 0.000 description 1
- KWLOIDOKWUESNM-UHFFFAOYSA-N 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=NN1 KWLOIDOKWUESNM-UHFFFAOYSA-N 0.000 description 1
- GDUANFXPOZTYKS-UHFFFAOYSA-N 6-bromo-8-[(2,6-difluoro-4-methoxybenzoyl)amino]-4-oxochromene-2-carboxylic acid Chemical compound FC1=CC(OC)=CC(F)=C1C(=O)NC1=CC(Br)=CC2=C1OC(C(O)=O)=CC2=O GDUANFXPOZTYKS-UHFFFAOYSA-N 0.000 description 1
- VDBMZBBCROFHND-CVDCTZTESA-N 6-chloro-n-[(s)-[3-(1-ethylpyrazol-4-yl)phenyl]-[(2s)-piperidin-2-yl]methyl]-2-fluoro-3-hydroxybenzamide Chemical compound C1=NN(CC)C=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(O)C=CC=2Cl)F)[C@H]2NCCCC2)=C1 VDBMZBBCROFHND-CVDCTZTESA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- OSDWBNJEKMUWAV-UHFFFAOYSA-N Allyl chloride Chemical compound ClCC=C OSDWBNJEKMUWAV-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- IYHHRZBKXXKDDY-UHFFFAOYSA-N BI-605906 Chemical compound N=1C=2SC(C(N)=O)=C(N)C=2C(C(F)(F)CC)=CC=1N1CCC(S(C)(=O)=O)CC1 IYHHRZBKXXKDDY-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- QOPUCBVIOGZUOW-AWEZNQCLSA-N BrC=1C=C(C=CC1)C([C@H]1N(CCCC1)C(=O)OC(C)(C)C)=NO Chemical compound BrC=1C=C(C=CC1)C([C@H]1N(CCCC1)C(=O)OC(C)(C)C)=NO QOPUCBVIOGZUOW-AWEZNQCLSA-N 0.000 description 1
- PKUBLPJOWUIRKP-OALUTQOASA-N C=CCN(CCCC1)[C@@H]1[C@H](c1cc(-c2cncnc2)ccc1)N Chemical compound C=CCN(CCCC1)[C@@H]1[C@H](c1cc(-c2cncnc2)ccc1)N PKUBLPJOWUIRKP-OALUTQOASA-N 0.000 description 1
- QLPJTEZFSLAADE-GMAHTHKFSA-N C=CCN(CCCC1)[C@@H]1[C@H](c1cc(-c2cncnc2)ccc1)NC(c(nccc1C(F)(F)F)c1Cl)=O Chemical compound C=CCN(CCCC1)[C@@H]1[C@H](c1cc(-c2cncnc2)ccc1)NC(c(nccc1C(F)(F)F)c1Cl)=O QLPJTEZFSLAADE-GMAHTHKFSA-N 0.000 description 1
- OYZPQFMABUHNOV-GJZGRUSLSA-N C=CCN(CCCC1)[C@@H]1[C@H](c1cccc(Br)c1)N Chemical compound C=CCN(CCCC1)[C@@H]1[C@H](c1cccc(Br)c1)N OYZPQFMABUHNOV-GJZGRUSLSA-N 0.000 description 1
- TZYWZUIYFVLGHB-HKUYNNGSSA-N C=CCN(CCCC1)[C@@H]1[C@H](c1cccc(Br)c1)NC(c(nccc1C(F)(F)F)c1Cl)=O Chemical compound C=CCN(CCCC1)[C@@H]1[C@H](c1cccc(Br)c1)NC(c(nccc1C(F)(F)F)c1Cl)=O TZYWZUIYFVLGHB-HKUYNNGSSA-N 0.000 description 1
- OBFVZILSNVOZFI-OALUTQOASA-N CC(C)(C)OC(=O)N1CCCC[C@H]1[C@@H](O)c1cccc(c1)-c1cnccn1 Chemical compound CC(C)(C)OC(=O)N1CCCC[C@H]1[C@@H](O)c1cccc(c1)-c1cnccn1 OBFVZILSNVOZFI-OALUTQOASA-N 0.000 description 1
- UTQMVMNKDNCESU-WOJBJXKFSA-N CCn1cc(cn1)-c1cccc(c1)[C@@H](N)[C@H]1CCCCN1C(=O)OC(C)(C)C Chemical compound CCn1cc(cn1)-c1cccc(c1)[C@@H](N)[C@H]1CCCCN1C(=O)OC(C)(C)C UTQMVMNKDNCESU-WOJBJXKFSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- YGFJRGUENWFYSX-IUQUCOCYSA-N Cl.CN1CCCC[C@H]1[C@@H](NC(=O)c1cccc(c1Cl)C(F)(F)F)c1cccc(c1)-c1cnccn1 Chemical compound Cl.CN1CCCC[C@H]1[C@@H](NC(=O)c1cccc(c1Cl)C(F)(F)F)c1cccc(c1)-c1cnccn1 YGFJRGUENWFYSX-IUQUCOCYSA-N 0.000 description 1
- LZXUCENCHUXANT-UHFFFAOYSA-N Cl.FC(F)(F)C=1C(=NC=CC1)C(=O)N Chemical compound Cl.FC(F)(F)C=1C(=NC=CC1)C(=O)N LZXUCENCHUXANT-UHFFFAOYSA-N 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- IJOSVNBGIKAARU-UHFFFAOYSA-N FC(c1ncccc1Cl)(F)F Chemical compound FC(c1ncccc1Cl)(F)F IJOSVNBGIKAARU-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 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 1
- 102000018899 Glutamate Receptors Human genes 0.000 description 1
- 108010027915 Glutamate Receptors Proteins 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 101000684936 Homo sapiens Sodium- and chloride-dependent glycine transporter 1 Proteins 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 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
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 229910020889 NaBH3 Inorganic materials 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 102100028886 Sodium- and chloride-dependent glycine transporter 2 Human genes 0.000 description 1
- 101710083167 Sodium- and chloride-dependent glycine transporter 2 Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000036982 action potential Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- QBYJBZPUGVGKQQ-SJJAEHHWSA-N aldrin Chemical compound C1[C@H]2C=C[C@@H]1[C@H]1[C@@](C3(Cl)Cl)(Cl)C(Cl)=C(Cl)[C@@]3(Cl)[C@H]12 QBYJBZPUGVGKQQ-SJJAEHHWSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000003935 attention Effects 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- FLLNLJJKHKZKMB-UHFFFAOYSA-N boron;tetramethylazanium Chemical compound [B].C[N+](C)(C)C FLLNLJJKHKZKMB-UHFFFAOYSA-N 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- VDQQXEISLMTGAB-UHFFFAOYSA-N chloramine T Chemical compound [Na+].CC1=CC=C(S(=O)(=O)[N-]Cl)C=C1 VDQQXEISLMTGAB-UHFFFAOYSA-N 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000006637 cyclobutyl carbonyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 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
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ZWWWLCMDTZFSOO-UHFFFAOYSA-N diethoxyphosphorylformonitrile Chemical compound CCOP(=O)(C#N)OCC ZWWWLCMDTZFSOO-UHFFFAOYSA-N 0.000 description 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000000575 glycinergic effect Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 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
- 210000001320 hippocampus Anatomy 0.000 description 1
- 102000058125 human SLC6A9 Human genes 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- GQNMAZUQZDEAFI-UHFFFAOYSA-N lithium;1h-naphthalen-1-ide Chemical compound [Li+].[C-]1=CC=CC2=CC=CC=C21 GQNMAZUQZDEAFI-UHFFFAOYSA-N 0.000 description 1
- 210000001853 liver microsome Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000015654 memory Effects 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical class CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000003061 neural cell Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000007996 neuronal plasticity Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 210000000063 presynaptic terminal Anatomy 0.000 description 1
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- MVILWLLYYQVYNH-UHFFFAOYSA-N pyridine-2-carboxamide Chemical compound NC(=O)C1=CC=CC=N1.NC(=O)C1=CC=CC=N1 MVILWLLYYQVYNH-UHFFFAOYSA-N 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000001476 sodium potassium tartrate Substances 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- LTKPMKCQRZSOOH-AWEZNQCLSA-N tert-butyl (2s)-2-(3-bromobenzoyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)C1=CC=CC(Br)=C1 LTKPMKCQRZSOOH-AWEZNQCLSA-N 0.000 description 1
- DVTZDOAIOCSMKK-AWEZNQCLSA-N tert-butyl (2s)-2-(4-hydroxybenzoyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)C1=CC=C(O)C=C1 DVTZDOAIOCSMKK-AWEZNQCLSA-N 0.000 description 1
- VWLGMBZDJXUNNT-ROUUACIJSA-N tert-butyl (2s)-2-[(s)-2,2-dimethylpropanoyloxy-(3-methoxyphenyl)methyl]pyrrolidine-1-carboxylate Chemical compound COC1=CC=CC([C@H](OC(=O)C(C)(C)C)[C@H]2N(CCC2)C(=O)OC(C)(C)C)=C1 VWLGMBZDJXUNNT-ROUUACIJSA-N 0.000 description 1
- LEAXRDWSYUABRG-PMACEKPBSA-N tert-butyl (2s)-2-[(s)-[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-hydroxymethyl]piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC[C@H]1[C@@H](O)C1=CC=C(O[Si](C)(C)C(C)(C)C)C=C1 LEAXRDWSYUABRG-PMACEKPBSA-N 0.000 description 1
- GIDNEGJCNIFMDI-UPVQGACJSA-N tert-butyl (2s)-2-[(s)-[[3-chloro-4-(trifluoromethyl)pyridine-2-carbonyl]amino]-[3-(1-ethylpyrazol-4-yl)phenyl]methyl]piperidine-1-carboxylate Chemical compound C1=NN(CC)C=C1C1=CC=CC([C@H](NC(=O)C=2C(=C(C=CN=2)C(F)(F)F)Cl)[C@H]2N(CCCC2)C(=O)OC(C)(C)C)=C1 GIDNEGJCNIFMDI-UPVQGACJSA-N 0.000 description 1
- ZQYIBSBYOJGTGU-GJZGRUSLSA-N tert-butyl (2s)-2-[(s)-hydroxy-[3-(trifluoromethylsulfonyloxy)phenyl]methyl]piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC[C@H]1[C@@H](O)C1=CC=CC(OS(=O)(=O)C(F)(F)F)=C1 ZQYIBSBYOJGTGU-GJZGRUSLSA-N 0.000 description 1
- RRHBKGVONKDESC-AWEZNQCLSA-N tert-butyl (2s)-2-[3-(trifluoromethylsulfonyloxy)benzoyl]piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)C1=CC=CC(OS(=O)(=O)C(F)(F)F)=C1 RRHBKGVONKDESC-AWEZNQCLSA-N 0.000 description 1
- FZIORAZNRSLUNU-AWEZNQCLSA-N tert-butyl (2s)-2-[4-(trifluoromethylsulfonyloxy)benzoyl]piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)C1=CC=C(OS(=O)(=O)C(F)(F)F)C=C1 FZIORAZNRSLUNU-AWEZNQCLSA-N 0.000 description 1
- DXUWFVGNSRDQFM-IBGZPJMESA-N tert-butyl (2s)-2-[c-[3-(1-ethylpyrazol-4-yl)phenyl]-n-hydroxycarbonimidoyl]piperidine-1-carboxylate Chemical compound C1=NN(CC)C=C1C1=CC=CC(C(=NO)[C@H]2N(CCCC2)C(=O)OC(C)(C)C)=C1 DXUWFVGNSRDQFM-IBGZPJMESA-N 0.000 description 1
- BYYHZPIPLAIBOA-JTQLQIEISA-N tert-butyl (2s)-2-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate Chemical compound CON(C)C(=O)[C@@H]1CCCCN1C(=O)OC(C)(C)C BYYHZPIPLAIBOA-JTQLQIEISA-N 0.000 description 1
- KPVRHJIGNMLCHG-VIFPVBQESA-N tert-butyl (2s)-2-[methoxy(methyl)carbamoyl]pyrrolidine-1-carboxylate Chemical compound CON(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C KPVRHJIGNMLCHG-VIFPVBQESA-N 0.000 description 1
- QQWYQAQQADNEIC-UHFFFAOYSA-N tert-butyl [[cyano(phenyl)methylidene]amino] carbonate Chemical compound CC(C)(C)OC(=O)ON=C(C#N)C1=CC=CC=C1 QQWYQAQQADNEIC-UHFFFAOYSA-N 0.000 description 1
- MGAOWZWCPYVDKW-GOTSBHOMSA-N tert-butyl-[4-[(s)-[tert-butyl(dimethyl)silyl]oxy-[(2s)-1-methylpiperidin-2-yl]methyl]phenoxy]-dimethylsilane Chemical compound CN1CCCC[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C1=CC=C(O[Si](C)(C)C(C)(C)C)C=C1 MGAOWZWCPYVDKW-GOTSBHOMSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- 210000001103 thalamus Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- ARYHTUPFQTUBBG-UHFFFAOYSA-N thiophen-2-ylboronic acid Chemical compound OB(O)C1=CC=CS1 ARYHTUPFQTUBBG-UHFFFAOYSA-N 0.000 description 1
- 229960001479 tosylchloramide sodium Drugs 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- ZDHXKXAHOVTTAH-UHFFFAOYSA-N trichlorosilane Chemical compound Cl[SiH](Cl)Cl ZDHXKXAHOVTTAH-UHFFFAOYSA-N 0.000 description 1
- 239000005052 trichlorosilane Substances 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- XQKBFQXWZCFNFF-UHFFFAOYSA-K triiodosamarium Chemical compound I[Sm](I)I XQKBFQXWZCFNFF-UHFFFAOYSA-K 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A47—FURNITURE; DOMESTIC ARTICLES OR APPLIANCES; COFFEE MILLS; SPICE MILLS; SUCTION CLEANERS IN GENERAL
- A47J—KITCHEN EQUIPMENT; COFFEE MILLS; SPICE MILLS; APPARATUS FOR MAKING BEVERAGES
- A47J27/00—Cooking-vessels
- A47J27/002—Construction of cooking-vessels; Methods or processes of manufacturing specially adapted for cooking-vessels
-
- A—HUMAN NECESSITIES
- A47—FURNITURE; DOMESTIC ARTICLES OR APPLIANCES; COFFEE MILLS; SPICE MILLS; SUCTION CLEANERS IN GENERAL
- A47J—KITCHEN EQUIPMENT; COFFEE MILLS; SPICE MILLS; APPARATUS FOR MAKING BEVERAGES
- A47J36/00—Parts, details or accessories of cooking-vessels
- A47J36/02—Selection of specific materials, e.g. heavy bottoms with copper inlay or with insulating inlay
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
-
- 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
-
- 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
- C07D401/10—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 carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- 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
- C07D405/10—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 carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero 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
- C07D413/02—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
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- the present invention relates to a compound having a glycine transporter inhibitory effect .
- An NMDA receptor one of glutamate receptors, exists in neural cell membranes in the brain and participates in various neurophysiological phenomena such as neural plasticity, cognition, attention, and memory.
- the NMDA receptor has several allosteri ⁇ binding sites, one of which is a glycine- binding site (glycine-binding site of an NMDA receptor complex) .
- the glycine-binding site of an NMDA receptor complex has been reported to participate in the activation of the NMDA receptor (Molecular Psychiatry (2004) 9, 984-997).
- An action potential reaches the presynaptic terminal of the glycinergic nerve, starting glycine release into synaptic clefts.
- the released glycine binds to postsynaptic receptors and so on and is then removed from the synaptic clefts by transporters .
- glycine transporters presumably regulate the amount of glycine in extracellular fluids and thereby regulate NMDA receptor function.
- the glycine transporter (GIyT) is a protein that participates in reuptake of extracellular glycine into the cells .
- the presence of two subtypes , GIyTl and GlyT2 has been elucidated so far.
- GIyTl is expressed mainly in the cerebral cortex, hippocampus, and thalamus, and has been reported to be associated with diseases such as schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorders (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post- traumatic stress disorder, particular phobias, acute stress disorder, etc.) * depression, drug abuse, convulsion, tremor, and sleep disorders (Current Medicinal Chemistry, 2006, 13, 1017-1044, Neuropsychopharmacology (2005), 1-23, Expert Opinion on Therapeutic Patents (2004) 14 (2) 201-214).
- diseases such as schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorders (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post- traumatic stress disorder, particular phobias, acute stress disorder, etc.) * depression, drug abuse, convulsion, tremor, and sleep disorders (Current Medicinal Chemistry, 2006, 13, 1017-1044, Neuropsychopharmac
- Piperidine derivatives and pyrrolidine derivatives have been reported as compounds having a GIyTl inhibitory effect (WO 03/089411, WO 2004/013100, WO 2004/013101, WO 2005/037781, WO 2005/037782, WO 2005/037783, WO 2005/037785, WO 2005/037792) .
- GIyTl inhibitory effect WO 03/089411, WO 2004/013100, WO 2004/013101, WO 2005/037781, WO 2005/037782, WO 2005/037783, WO 2005/037785, WO 2005/037792
- An object of the present invention is to provide a novel compound, a salt thereof or a hydrate of the compound or the salt, which is useful for the prevention or treatment of diseases such as schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorders (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post-traumatic stress disorder, particular phobias, acute stress disorder, etc.), depression, drug abuse, convulsion, tremor, or sleep disorders, based on glycine uptake inhibitory effect.
- diseases such as schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorders (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post-traumatic stress disorder, particular phobias, acute stress disorder, etc.), depression, drug abuse, convulsion, tremor, or sleep disorders, based on glycine uptake inhibitory effect.
- the present inventors have conducted diligent studies for a compound with a novel skeleton having an inhibitory effect on GIyTl and have consequently completed the present invention by finding out that compounds represented by the formulas described below are an excellent GIyTl inhibitor.
- An embodiment of the present invention relates to a compound of the following formula [I], or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or the salt:
- ring A is phenyl, naphthyl, or a monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms, wherein the phenyl, the naphthyl, and the monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms are each unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of Ci. 6 alkyl, Ci-e haloalkyl, cyano, Ci_ 6 alkoxy, halogen, Ci.
- Ar 1 is phenyl, naphthyl, or a monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms, wherein the phenyl, the naphthyl, and the monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms are each unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxy, halogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, cyano, Ci- ⁇ alkoxy, Ci_ 6 acyl, Ci. 6 haloacyl, Ci- 6 haloalkoxy, C 3 _ 8 cycloalkyl, nitro, amino, aminosulfonyl and carbamoyl or with methylenedioxy;
- R 1 is hydrogen, Ci_ 6 alkyl, C 3 - 6 alkenyl, or C 3 _ 8 cycloalkyl, wherein the Ci_ 6 alkyl is unsubstituted or substituted with cyano ;
- R 3 is hydrogen, C ⁇ . 6 alkyl, or halogen; and n is 1 or 2.
- ring A is a monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen and sulfur as endocyclic atoms, wherein the aromatic ring is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of Ci_ 6 alkyl, Ci- 6 alkoxy and halogen;
- Ar 1 is phenyl, naphthyl, or a monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms, wherein the phenyl, the naphthyl, and the monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms are each unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxy, halogen, Ci. 6 alkyl, C 3.
- - 6 haloalkyl ⁇ yano, Ci_ 6 alkoxy, Ci- 6 acyl, C 3 ._ 6 haloacyl, Ci_ 6 haloalkoxy, C 3 _ 8 cycloalkyl, nitro, amino, aminosulfonyl and carbamoyl or with methylenedioxy (preferably, phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci.6 alkyl and Ci-6 haloalkyl) ;
- R 1 is hydrogen, C 1 . 6 alkyl, C 3 . 6 alkenyl, or C 3 -B cycloalkyl, wherein the Ci- ⁇ alkyl is unsubstituted or substituted with cyano; and n is 1 or 2.
- R 4 is hydrogen, C ⁇ - 6 haloalkyl, cyano or Ci_ 6 acyl (preferably, cyano or C ⁇ - 6 acyl) ;
- Ar 1 is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, C ⁇ _ 6 alkyl, Ci_ 6 haloalkyl, cyano, Ci_ 6 alkoxy, Ci_ 6 acyl, Ci- 6 haloacyl and Ci_ 6 haloalkoxy or with methylenedioxy;
- R 1 is hydrogen, Ci_ 6 alkyl, C 3 -6 alkenyl, or C 3 _ 8 cycloalkyl, wherein the C ⁇ . 6 alkyl is unsubstituted or substituted with cyano; and n is 1 or 2.
- ring A is a monocyclic or bicyclic aromatic ring (particularly, a five- or six-membered aromatic ring) having 1 or 2 nitrogen atoms as endocyclic atoms, wherein the aromatic ring is unsubstituted or substituted with one substituent selected from the group consisting of C 1 . 6 alkyl, halogen and Ci. 6 alkoxy (particularly, one C ⁇ . 6 alkyl);
- Ar 1 is phenyl, pyridyl, or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 1 to 3 substituents selected from the group consisting of halogen, Ci- ⁇ alkyl, Ci. ⁇ haloalkyl, Ci_ 6 alkoxy and Ci_ 6 haloalkoxy; and n is 1 or 2.
- Ar 1 is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci- 6 alkyl and Ci- 6 haloalkyl;
- R 2 is hydrogen or Ci. 6 alkyl; and n is 1 or 2, wherein the substitution position of the pyrazolyl in the benzene ring is position 3 or 4.
- Ar 1 is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci_6 alkyl and Ci-6 haloalkyl; R 2 is hydrogen or Ci_ ⁇ alkyl; and n is 1 or 2 , wherein the substitution position of the pyrazolyl in the benzene ring is position 3 or 4.
- R 5 is hydrogen, halogen or Ci- 6 alkoxy
- Ar 1 is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci- ⁇ alkyl and Ci- 6 haloalkyl; and n is 1 or 2 , wherein the substitution position of the pyridyl in the benzene ring is position 3 or 4. 11.
- R 5 is hydrogen, halogen or Ci_ 6 alkoxy
- Ar 1 is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci_ 6 alkyl and Ci_ 6 haloalkyl; and n is 1 or 2, wherein the substitution position of the pyridyl in the benzene ring is position 3 or 4.
- Ar 1 is phenyl, pyridyl or isoquinolin-1- ⁇ l, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, C 1 . 6 alkyl and C 1 - S haloalkyl; and n is 1 or 2, wherein the substitution position of the pyrimidinyl in the benzene ring is position 3 or 4.
- Ar 1 is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, Ci- 6 alkyl and Ci- 6 haloalkyl; and n is 1 or 2 , wherein the substitution position of the pyrimidinyl in the benzene ring is position 3 or 4.
- Ar 1 is phenyl, pyridyl or isoquinolin-1-yl, wherein the phenyl or the pyridyl is substituted with 2 or 3 substituents selected from the group consisting of halogen, C x . 6 alkyl and Ci- 6 haloalkyl; and n is 1 or 2, wherein the substitution position of the pyrazinyl in the benzene ring is position 3 or 4.
- a pharmaceutical composition comprising a compound according to any one of embodiments 1 to 32 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient .
- the pharmaceutical composition according to embodiment 33 which is a glycine transporter inhibitor.
- a pharmaceutical composition for the prevention or treatment of a disease selected from the group consisting of schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorders, depression, drug abuse, convulsion, tremor, and sleep disorders, comprising a compound according to any one of embodiments 1 to 32 or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient .
- monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur as endocyclic atoms refers to a monocyclic (e.g. 5- or 6- membered ) or bicyclic (e.g. the number of ring-forming atoms is 8 to 10) heterocyclic aromatic group having in its ring the same or different 1 or 2 atoms selected from nitrogen, oxygen and sulfur.
- Examples may include pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, furyl, isoxazolyl, thienyl, thiazolyl, indolyl, quinolyl and isoquinolyl.
- the phrase "monocyclic or bicyclic aromatic ring having 1 or 2 heteroatoms selected from nitrogen and sulfur as endocyclic atoms" refers to a monocyclic (e.g. 5- or 6- membered ) or bicyclic (e.g. the number of ring-forming atoms is 8 to 10) heterocyclic aromatic group having in its ring the same or different 1 or 2 atoms selected from nitrogen and sulfur.
- Examples may include pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, indolyl, quinolyl and isoquinolyl.
- monocyclic or bicycli ⁇ aromatic ring having 1 or 2 nitrogen atoms as endocyclic atoms refers to a monocyclic (e.g. 5- or 6-membered ) or bicyclic (e.g. the number of ring-forming atoms is 8 to 10) heterocyclic aromatic group having in its ring 1 or 2 nitrogen atoms.
- examples may include pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, indolyl, quinolyl and isoquinolyl.
- Ci_ 6 alkyl used herein means a linear or branched alkyl group having 1 to 6 carbon atoms , and examples may include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl.
- halogen halo-
- halogen means fluorine, chlorine , bromine , and iodine atoms .
- Ci_6 haloalkyl used herein means a halogen atom-substituted linear or branched alkyl group having 1 to 6 carbon atoms. Preferably, 1 to 3 halogen atoms are used for the substitution. Examples of the C 3. _ 6 haloalkyl may include fluoromethyl, difluoromethyl, trifluoromethyl and trichloromethyl .
- Ci_ 6 alkoxy used herein means a linear or branched alkoxy group having 1 to 6 carbon atoms, and examples may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutyloxy, pentyloxy, isopentyloxy and hexyloxy.
- C 3 - 8 cycloalkyl used herein means a saturated carbocyclic group having 3 to 8 carbon atoms, and examples may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
- Ci- 6 acyl used herein means a carbonyl group bound with a hydrogen atom or linear or branched Ci_ 5 alkyl or cyclic C 3 - 5 alkyl, and examples may include formyl, acetyl, propionyl, butyryl, isobutyryl, cyclopropylcarbonyl and cyclobutylcarbonyl .
- Ci_6 haloacyl used herein means a halogen atom-substituted linear or branched acyl group having 1 to 6 carbon atoms. Preferably, 1 to 3 halogen atoms are used for the substitution. Examples of the C 1 - 6 haloacyl may include fluoroacetyl, difluoroacetyl, trifluoroacetyl and trichloroacetyl .
- Ci. 6 haloalkoxy used herein means a halogen atom-substituted linear or branched alkoxy group having 1 to 6 carbon atoms. Preferably, 1 to 3 halogen atoms are used for the substitution. Examples may include fluoromethoxy, difluoromethoxy and trifluoromethoxy.
- C3- 6 alkenyl used herein means a linear or branched C 3 . 6 alkyl incorporating one double bond therein, and examples may include allyl and but-2-enyl.
- C2-7 alkoxycarbonyl refers to a group composed of the above-defined Ci_ 6 alkoxy and carbonyl attached to each other. Examples may include methoxycarbonyl and tert- butoxycarbonyl .
- pharmaceutically acceptable salt means an acid-addition salt that can be pharmaceutically accepted.
- the acid used may include: inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid and phosphoric acid; and organic acids such as acetic acid, oxalic acid, lactic acid, citric acid, malic acid, gluconic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.
- the conversion of the free form to the salt can be conducted in a conventional way.
- ring A is preferably, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, quinolyl, indolyl, imidazolyl, thienyl, thiazolyl (wherein the pyrazolyl and imidazolyl is unsubstituted or substituted with one Ci_ 6 alkyl group, the thiazolyl is unsubstituted or substituted with one or two Ci_ 6 alkyl groups , and the pyridyl is unsubstituted or substituted with halogen or Ci_ 6 alkoxy) , further preferably, unsubstituted or C 1 .
- pyrazolyl e.g., lH-pyrazol-4-yl, 1- methyl-lH-pyrazol-4-yl, l-ethyl-lH-pyrazol-4-yl, 1-isopropyl- lH-pyrazol-4-yl, l-propyl-lH-pyrazol-4-yl
- pyridyl which is unsubstituted or substituted with halogen or d_ 6 alkoxy
- pyrimidinyl e.g., pyrimidin-5-yl
- pyrazinyl e.g., pyrazin- 2-yl
- Ci_ 6 alkyl-substituted imidazolyl e.g., 3-methyl-3H- imidazol-4-yl
- a substitution position of ring A in the benzene ring is preferably, position 3 or 4 , more preferably, position 3.
- R 1 is preferably, hydrogen or Ci_ 6 alkyl, more preferably, hydrogen or methyl.
- R 1 is hydrogen in light of the hepatic metabolic stability of the compound of the present invention.
- the hepatic metabolic stability was confirmed by a hepatic metabolic stability test , wherein a human liver microsome (obtained from XENOTECH LLC (Kansas City, KS, USA)) (1 mg of protein/mL) and the compound (5 ⁇ M) were added to 0.25 M phosphate buffer solution at pH 7.4 and preincubated at 37°C for 5 minutes, and reaction was then started by the addition of an NADPH production system and terminated 15 minutes later by the addition of a reaction stop solution, followed by measurement of the remaining compound by LC-MS.
- Ar 1 is preferably, (i) phenyl which has chloro, fluoro, or methyl at position 2 and has trifluoromethyl at position 3, 5 or 6 and/or chloro at position 3 or 6 (more preferably, phenyl which has chloro or methyl at position 2 and trifluoromethyl at position 3 or 5 , and may further have chloro at position 6); (ii) pyridin-2-yl having chloro at position 3 and trifluoromethyl at position 4 or pyridin-4-yl having chloro at position 3 and trifluoromethyl at position 2 or (iii) isoquinolin-1-yl.
- Ar 1 is 2-chloro-3- trifluoromethylphenyl , 3-chloro-2-methylphenyl, 2,3- dichlorophenyl , 2-methyl-3-trifluoromethylphenyl, 2-chloro-3- methylphenyl , 2-chloro-5-trifluoromethylphenyl, 2-methyl-5- trifluoromethylphenyl, 2 , 5-dichlorophenyl, 2,6-dichlorophenyl, 2,6-dichloro-3-trifluoromethylphenyl , 3-chloro-2-fluoro-6- trifluoromethylphenyl , 2 , 6-dimethylphenyl , 2,4,6- trichlorophenyl , 2-chloro-6-methylphenyl, 3-chloro-4- trifluoromethyl-pyridin-2-yl, 3-chloro-2-trifluoromethyl- pyridin-4-yl, and isoquinolin-1-yl, more preferably
- Ar 1 is, in particular, preferably, pyridin-2-yl having chloro at position 3 and trifluoromethyl at position 4 or pyridin-4-yl having chloro at position 3 and trifluoromethyl at position 2.
- Preferable compounds in the present invention are the compounds of formula [IA], [II], [III], [IIIA], [IV], [IVA], [V], [VA] and [VI] shown above.
- Examples of preferable specific compounds may include: 2-chloro-N-( (S) -( ( 2S) -l-methylpiperidin-2-yl) ( 4-pyridin-3- ylphenyl)methyl) -3- (trifluoromethyl)benzamide,
- Examples of more preferable specific compounds may include :
- Examples of further preferable specific compounds may include : 3-chloro-N- ( (S) -( 2S) -piperidin-2-yl(3-pyridin-3- ylphenyl)methyl) -4- ( trifluoromethyl)pyridine-2-carboxamide , 2-chloro-N-( (S) - (3- ( l-methyl-lH-pyrazol-4-yl)phenyl) ( (2S)- piperidin-2-yl)methyl ) -3- ( trifluoromethyl)benzamide , 2-chloro-N- ( (S) - ( 2S) -piperidin-2-yl( 3-pyrimidin-5- ylphenyl)methyl) -3- ( trifluoromethyl)benzamide,
- Examples of most preferable specific compounds may include :
- the compound represented by formula [I] can be produced by a variety of synthesis methods .
- the methods described below are just a few examples of production processes for the compound of the present invention, and the present invention is not intended to be limited to them.
- each step is optionally interchangeable, and in each step, a nitrogen atom and a hydroxyl group can be protected with a protective group, if necessary and then, the protective group can be removed when the protection is unnecessary.
- P 1 is a nitrogen protecting group by forming carbamate, such as a methoxycarbonyl , ethoxycarbonyl , tert- butoxycarbonyl or benzyloxycarbonyl group (see Theodora W. Greene and Peter G. M.
- P 2 is a protecting group for a phenolic hydroxyl group, such as a methyl, benzyl or tert-butyldimethylsilyl group (supra.);
- P 3 is an amino protecting group by forming an tertiary amino group, such as a methyl group or a benzyl or allyl group (supra.);
- P 4 is a protecting group for a hydroxyl group, such as a pivaloyl group (supra.);
- X 1 is a chlorine, bromine or iodine atom;
- R a is Ci_ 6 alkyl (wherein the Ci.
- X 6 alkyl is unsubstituted or substituted with a cyano group) ; and X 2 is a chlorine, bromine, or iodine atom or a methanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy or trifluoromethanesulfonyloxy group . All of other symbols are as already defined.
- an “inactive solvent” examples include: alcohols such as methanol, ethanol, isopropanol, n- butanol and ethylene glycol; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; hydrocarbons such as pentane, hexane, toluene, benzene and xylene; esters such as ethyl acetate and ethyl formate; ketones such as acetone and methyl ethyl ketone; halogenated carbon solvents such as chloroform and dichloromethane; amides such as dimethylformamide and N-methylpyrrolidone; acetonitrile, dimethyl sulfoxide and water; and mixed solvents thereof.
- alcohols such as methanol, ethanol, isopropanol, n- butanol and ethylene glycol
- ethers such as die
- Examples of a “base” include: amines such as triethylamine , N,N-diisopropylethylamine, pyridine, 1,8- diazabicyclo[ 5.4.0]undec-7-ene, N,N-dimethylaniline, N,N- diethylaniline and 4-dimethylaminopyridine; inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide and sodium hydride; metal alcoholates such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; metal amides such as sodium amide, lithium diisopropylamide , lithium hexamethyldisilazide, sodium hexamethyldisilazide and potassium hexamethyldisilazide; alkyllithium such as n-butyllithium, sec-butyllithium, tert- buty
- an “acid” examples include: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid and acetic acid.
- a compound (2) can be obtained by amidation reaction of a compound (1) with N,0-dimethylhydroxyamine in the presence or absence of a base in an inactive solvent .
- the amidation reaction can be practiced by many standard procedures generally known by those skilled in the art, and examples may include: amidation via a mixed anhydride using ethyl chlorocarbonate, isobutyl chlorocarbonate , or pivaloyl chloride; and amidation using a condensing agent such as l-(3,3-dimethylaminopropyl)-3-ethylcarbodiimide, 1,3- dicyclohexylcarbodiimide , diphenylphosphorylazide, diethyl cyanophosphate , carbonyldiimidazole, or benzotriazol-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) .
- Step 2 A compound (3) can be converted into a metal reagent with a metal or alkyllithium reagent and then reacted with the compound (2) in an inactive solvent to thereby obtain a compound ( 4 ) .
- the metal may include magnesium and zinc
- examples of the alkyllithium reagent may include n-butyllithium, sec-butyllithium, tert- butyllithium and phenyllithium reagents .
- Step 3 The compound ( 4 ) can be reacted with a reducing agent in an inactive solvent to thereby obtain a compound ( 5 ) .
- the reducing agent is a reagent that can convert carbonyl groups into hydroxyl groups through reduction, and examples may include lithium borohydride, sodium borohydride, calcium borohydride, lithium triethylborohydride, lithium tri- sec-butylborohydride, potassium tri-sec-butylborohydride, zinc borohydride, borane, lithium trimethoxyborohydride, lithium triacetoxyborohydride , tetramethylammonium borohydride , lithium aluminum hydride, sodium aluminum hydride, sodium bis ( 2-methoxyethoxy) aluminum hydride, diisobutylaluminum hydride and trichlorosilane.
- Step 4 A compound (6) can be obtained by hydrolysis of the compound (5) with an acid or base or deprotection reaction described in Theodora W. Greene and Peter G. M. Wuts "Protective Groups in Organic Synthesis Third Edition" in an inactive solvent.
- Step 5 The compound ( 6 ) can be reacted with an allylating agent such as allyl chloride or allyl bromide or a benzylating agent such as benzyl chloride or benzyl bromide in the presence or absence of a base in an inactive solvent to thereby obtain a compound (7).
- an allylating agent such as allyl chloride or allyl bromide
- a benzylating agent such as benzyl chloride or benzyl bromide
- Step 6 When P 3 is a methyl group , the compound ( 5 ) can be reacted with a reducing agent in an inactive solvent to thereby obtain a compound (7).
- the reducing agent is a reagent that can convert carbamate into methyl groups through reduction, and examples may include borane, lithium aluminum hydride, sodium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride and diisobutylaluminum hydride .
- Step 7 The compound ( 7 ) can be reacted with a sulfonylating agent in the presence or absence of a base in an inactive solvent and then reacted with ammonia to thereby obtain a compound (8).
- the sulfonylating agent is a reagent that can sulfonylate hydroxyl groups, and examples may include p- toluenesulfonyl chloride, methanesulfonyl chloride, p- toluenesulfonic acid anhydrides , methanesulfonic acid anhydrides , trifluoromethanesulfonic acid anhydrides and N- phenylbis ( trifluoromethanesulfonimide) .
- Step 8 The compound (10) can be obtained by amidation reaction of the compounds ( 8 ) with a compound ( 9 ) in the presence or absence of a base in an inactive solvent .
- Step 9 The compound (10) can be (1) reacted with, for example, boron tribromide, aluminum (III) bromide, or aluminum (III) chloride in an inactive solvent (when P 2 is a methyl group); or (2) reacted with, for example, boron tribromide, aluminum (III) bromide, or aluminum (III) chloride in an inactive solvent or hydrogenated with a palladium or platinum catalyst (when P 2 is a benzyl group) to thereby obtain a compound (11).
- the palladium catalyst may include palladium black, palladium carbon and palladium hydroxide
- examples of the platinum catalyst may include platinum oxide.
- the compound (11) can be obtained by removing P 2 through deprotection reaction described in Theodora W. Greene and Peter G. M. Wuts "Protective Groups in Organic Synthesis Third Edition".
- Step 10 The compound (11) can be reacted with a triflating agent in the presence or absence of a base in an inactive solvent to thereby obtain a compound (12).
- the triflating agent may include trifluoromethanesulfonic acid anhydrides and N- phenylbis (trifluoromethanesulfonimide) .
- Step 11 The compound (12) can be reacted with a boric acid- or boric acid ester-substituted ring A by use of a palladium catalyst and, if necessary, a ligand for a palladium catalyst, in the presence or absence of a base in an inactive solvent to thereby obtain a compound (13) of the present invention.
- examples of the palladium catalyst may include Pd(OAc) 2 , Pd 2 (dba) 3 , Pd(PPh 3 J 4 , PEPPSI-Ipr( trade mark) , and Pd(dppf)Cl 2
- examples of the ligand may include triphenylphosphine, 2 , 2-bis(diphenylphosphino) -1, 1-binaphthyl (BINAP), 2-(di-tert-butylphosphino)biphenyl and 9 , 9-dimethyl- 4,5-bis(diphenylphosphino)xanthene (Xantphos) .
- the compound (13) can be (1) subjected to deprotection reaction with N,N-dimethylbarbituric acid and a palladium catalyst (in this context, examples of the palladium catalyst may include Pd(OAc) 2 , Pd 2 (dba) 3 , and Pd(PPh 3 J 4 ) (when P 3 is an allyl group); or (2) subjected to deprotection reaction through hydrogenation with a palladium or platinum catalyst (in this context, examples of the palladium catalyst may include palladium black, palladium carbon, and palladium hydroxide, and examples of the platinum catalyst may include platinum oxide) (when P 3 is a benzyl group) to thereby obtain a compound (14) of the present invention.
- a palladium catalyst in this context, examples of the palladium catalyst may include Pd(OAc) 2 , Pd 2 (dba) 3 , and Pd(PPh 3 J 4 ) (when P 3 is an allyl group); or (2) subjected to
- the compound (14) of the present invention can be obtained by removing P 3 through deprotection reaction described in Theodora W. Greene and Peter G. M. Wuts "Protective Groups in Organic Synthesis Third Edition"
- Step 13 The compound (4) can be converted into a compound (15) by the same procedure as in Step 9 in the general production process 1.
- Step 14 The compound (15) can be converted into a compound (16) by the same procedure as in Step 10 in the general production process 1.
- Step 15 The compound (16) can be converted into a compound
- Step 16 The compound (17) can be converted into a compound
- Step 17 The compound (18) can be converted into a compound
- Step 18 The compound (19) can be converted into a compound
- Step 19 When P 3 is a methyl group, the compound (18) can be converted into the compound (20) by the same procedure as in Step 6 in the general production process 1.
- Step 20 The compound (20) can be converted into a compound
- Step 23 The compound (14) of the present invention can be reacted with a compound (22) in the presence or absence of a base in an inactive solvent to thereby obtain a compound (23)
- the intermediate (18) can also be produced according to a general production process 4 below.
- Step: 24 The compound (17) can be reacted with bispinacolborane using a palladium catalyst and, if necessary, a ligand for a palladium catalyst, in the presence or absence of a base in an inactive solvent to thereby obtain a compound (24).
- examples of the palladium catalyst may include Pd(OAc) 2 , Pd 2 (dba) 3 , Pd(PPh 3 ) 4 , PEPPSI-Ipr( trade mark) and Pd(dppf)C1 2
- examples of the ligand may include triphenylphosphine, 2,2-bis (diphenylphosphino) - 1 , 1-binaphthyl (BINAP), 2-(di-tert-butylphosphino)biphenyl, 9 , 9-dimethyl-4, 5- bis (diphenylphosphino)xanthene (Xantphos), and 1,1'- bisdiphenylphosphinoferrocene (dppf ) .
- Step 25 The compound (24) can be reacted with a halogen- substituted ring A in the same way as in Step 11 in the general production process 1 to thereby obtain the compound (18).
- Step 26 The compound (24) can be converted into a compound (30) through reaction with a halogenating reagent such as copper (II) bromide, bromine, iodine, N-bromosuccinimide, or N-iodosuc ⁇ inimide, reaction with iodine or iodine monochloride in the presence of a base such as sodium hydroxide or sodium methoxide, reaction with chloramine-T and sodium iodide, or reaction with 1 , 3-dibromo-5 , 5-dimethylhydantoin, in an inactive solvent .
- a halogenating reagent such as copper (II) bromide, bromine, iodine, N-bromosuccinimide, or N-iodosuc ⁇ inimide
- reaction with iodine or iodine monochloride in the presence of a base such as sodium hydroxide or sodium methoxide
- the intermediate (7) can also be produced according to a general production process 5 below. [General production process 5]
- Step 27 When P 4 is a pivaloyl group, the compound (5) can be reacted with pivaloyl chloride in the presence or absence of a base in an inactive solvent to thereby obtain a compound (25).
- the compound (25) can be obtained by the procedure described in Theodora W. Greene and Peter G. M. Wuts "Protective Groups in Organic Synthesis Third Edition" .
- Step 28 The compound (25) can be converted into a compound
- Step 29 The compound (26) can be converted into a compound
- Step 30 When P 4 is a pivaloyl group, the compound (7) can be obtained by carrying out deprotection with a reducing agent such as lithium aluminum hydride, sodium bis (2- methoxyethoxy) aluminum hydride, or diisobutylaluminum hydride in an inactive solvent or carrying out deprotection by the procedure described in Theodora W. Greene and Peter G. M. Wuts "Protective Groups in Organic Synthesis Third Edition" . When P 4 is any of other protecting groups, the compound (7) can be obtained by the deprotection procedure described in this literature .
- a reducing agent such as lithium aluminum hydride, sodium bis (2- methoxyethoxy) aluminum hydride, or diisobutylaluminum hydride in an inactive solvent
- the intermediate (18) can also be produced according to a general production process 6 below.
- General production process 6 [General production process 6]
- Step 31 A compound (28) can be converted into a metal reagent by the procedure shown in Step 2 in the general production process 1 and then reacted with the compound (2) to thereby obtain a compound (29).
- Step 32 The compound (18) can be obtained by the same procedure as in Step 3 in the general production process 1. [General production process 7]
- Step 33 The compound (2) can be reacted with a compound (31) by the same procedure as in Step 2 in the general production process 1 to thereby convert into a compound (32).
- Step 34 The compound (32) can be reacted with hydroxylamine hydrochloride in an inactive solvent to thereby convert into a compound (33) .
- Step 35 The compound (33) can be converted into a compound
- Step 36 The compound (34) can be converted into a compound
- examples of the metal catalyst may include: palladium catalysts such as palladium hydroxide, palladium carbon and palladium black; nickel catalysts such as Raney nickel; and platinum catalysts such as platinum oxide.
- Examples of the reducing agent may include: boron reagents such as boron hydride (BH 3 ) , sodium borohydride (NaBH 4 ) and sodium cyanoborohydride (NaBH 3 CN) ; aluminum reagents such as lithium aluminum hydride (LiAlH 4 ); metals such as zinc, magnesium and sodium; samarium iodide; and lithium naphthalenide .
- boron reagents such as boron hydride (BH 3 ) , sodium borohydride (NaBH 4 ) and sodium cyanoborohydride (NaBH 3 CN)
- aluminum reagents such as lithium aluminum hydride (LiAlH 4 )
- metals such as zinc, magnesium and sodium
- samarium iodide samarium iodide
- lithium naphthalenide .
- Step 38 The compound (36) can be converted into the compound (14) of the present invention by the same procedure as in Step 4 in the general production process 1.
- Step 39 The compound (30) can be converted into a compound
- Step 40 The compound (37) can be converted into a compound
- Step 41 The compound (38) can be converted into a compound
- Step 42 The compound (39) can be converted into a compound
- Step 43 The compound (40) can be converted into a compound (41) by the same procedure as in Step 12 in the general production process 1.
- Step 44 The compound (41) can be converted into a compound
- Step 45 The compound (42) can be converted into a compound
- Step 46 The compound (43) can be converted into the compound (14) of the present invention by the same procedure as in Step 4 in the general production process 1.
- the compound of the present invention may have plural asymmetric centers.
- the compound can exist in any of the forms of an optically active substance and a racemic body thereof and may further include plural diastereoisomers . All of these forms are encompassed within the scope of the present invention.
- Individual isomers may be obtained by a method known in the art, for example, the use of optically active starting materials or intermediates, optically selective or diasteroselective reaction in the production of intermediates or final products, or chromatographic separation in the production of intermediates or final products.
- the compound of the present invention forms a hydrate or solvate, these compounds are also encompassed within the scope of the present invention.
- the compound of the present invention can be administered orally or parenterally .
- Examples of the dosage form thereof include tablets, capsules, granules, powdered medicines, powders, troches, ointments, creams, emulsions, suspensions, suppositories, and injections. Any of these preparations can be produced by a routine pharmaceutical technique (e.g., methods specified by Japanese Pharmacopoeia, 14th ed. ) . These dosage forms can be selected appropriately according to the conditions and age of a patient and the purpose of treatment .
- compositions can be produced by incorporating pharmacologically acceptable carriers , that is , excipients (e.g., crystalline cellulose, starch, lactose, and mannitol), binders (e.g., hydroxypropylcellulose and polyvinyl pyrrolidone) , lubricants (e.g., magnesium stearate and talc), disintegrants (e.g., carboxymethylcellulose calcium), and various other pharmacologically acceptable additives, into a composition comprising the compound of the present invention.
- excipients e.g., crystalline cellulose, starch, lactose, and mannitol
- binders e.g., hydroxypropylcellulose and polyvinyl pyrrolidone
- lubricants e.g., magnesium stearate and talc
- disintegrants e.g., carboxymethylcellulose calcium
- the dosage of the compound of the present invention is 1 to 2000 mg/day in the treatment of an adult, which is administered at a single or divided daily dose. This dosage can be increased or decreased appropriately according to the age, body weight, and conditions of a patient.
- “Silica gel” and “NH-silica gel” used for purification using column chromatography were silica gel 6ON (Kanto Chemical Co., Inc.) and Chromatorex NH (Fuji Silysia) , respectively.
- TLC (silica gel) and TLC (NH-silica gel) used for purification using TLC were Silica gel 60F254 (Merck Ltd. ) and TLC Plate NH (Fuji Silysia) .
- MS spectrum Shimadzu LCMS-20IOEV or micromass Platform LC
- BOP reagent benzotriazol-1- yloxytris (dimethylamino)phosphonium hexafluorophosphate
- TBS tert-butyldimethylsilyl
- Tf trifluoromethanesulfonyl
- Triethylamine (218 g) and N, O-dimethylhydroxyamine hydrochloride (84 g) were added to a chloroform solution (1200 ml) of (S) -l-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (165 g) .
- a BOP reagent (334 g) was gradually added thereto .
- the mixture was stirred overnight at room temperature.
- the reaction mixture was concentrated under reduced pressure, and the concentrate was diluted with ethyl acetate and sequentially washed with 0.5 M hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, water, and saturated brine .
- the organic layer was dried over anhydrous magnesium sulfate.
- L-Selectride (trade mark) (I M tetrahydrofuran solution, 200 ml) was added dropwise thereto over 40 minutes. The mixture was stirred at the same temperature for 3 hours. Then, 15% aqueous hydrogen peroxide solution (200 ml) was added dropwise thereto over 15 minutes , and the mixture was stirred at room temperature for 30 minutes . The organic solvent was evapolated under reduced pressure. Ethyl acetate and water were added to the resulting solution, and the organic layer was separated with a separating funnel. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure.
- Triethylamine (0.7 ml) was added to a chloroform solution (15 ml) of (S) -((2S) -l-allylpiperidin-2-yl) ( 4-pyridin-3-yl phenyl)methanol (1.1 g) .
- methanesulfonyl chloride (0.31 ml) was added dropwise thereto.
- the mixture was stirred under ice cooling for 30 minutes .
- the reaction solution was concentrated under reduced pressure. The residue was dissolved in 8 M ammonia/methanol solution (8 ml).
- Reaction was carried out in a microwave reactor at 120 0 C for 20 minutes.
- the reaction solution was concentrated under reduced pressure.
- Lithium aluminum hydride (3.3 g) was suspended in dry tetrahydrofuran (100 ml). A tetrahydrofuran solution (30 ml) of (S)-( (2S) -l-allylpyrrolidin-2-yl) ( 3-methoxyphenyl)methyl pivalate (26 g) was added thereto, and the mixture was stirred at room temperature for 1 hour. Water and 10% aqueous sodium hydroxide solution were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. Insoluble matter was filtered off with a funnel firmly covered with anhydrous magnesium sulfate.
- the chloroform layer was dried over anhydrous sodium sulfate, and passed through an NH-silica gel for removing the drying agent and preliminary purification.
- the filtrate was concentrated under reduced pressure.
- the residue was dissolved in chloroform (8 ml).
- tert-Butyl Dicarbonate (1.2 ml) was added thereto, and the mixture was stirred at room temperature for 3 hours .
- 1,3-Dibromobenzene (148.3 g) was dissolved in tetrahydrofuran (680 ml) under a nitrogen atmosphere. 2.64 M Hexane solution (175 ml) of n-butyllithium was added dropwise to this solution at -70 0 C or lower. The mixture was stirred at the same temperature for 30 minutes. A tetrahydrofuran solution (230 ml) of tert-butyl (2S) -2- ( (methoxy(methyl) amino) carbony1)piperidine- 1- carboxylate (114 g) was added dropwise thereto at -70 0 C or lower. The mixture was stirred at the same temperature for 2 hours.
- Triethylamine (5.8 ml) was added thereto, and di-tert-butyl dicarbonate (9.5 ml) was added dropwise to this mixture. The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the residue. This ethyl acetate layer was washed with 5% aqueous potassium bisulfate solution and a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure.
- 3-ylphenyl) methanamine (0.30 g) was added thereto, and the mixture was stirred at room temperature for 4 hours .
- Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added thereto, and the organic layer was separated with a separating funnel.
- the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine.
- the organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure.
- 3-ylphenyl) methanamine (0.30 g) was added thereto, and the mixture was stirred overnight at room temperature.
- Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added thereto, and the organic layer was separated with a separating funnel.
- the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine.
- the organic layer was dried over anhydrous magnesium sulfate .
- the drying agent was filtered off , and the filtrate was concentrated under reduced pressure.
- the obtained purified product was dissolved in ethyl acetate (8 ml) and 4 M HCl/ethyl acetate solution (1 ml) was added to the acetate solution under ice cooling. The resulting solution was stirred at room temperature for 1 hour. The precipitate was collected by filtration to obtain the title compound (0.24 g) as a colorless solid.
- the obtained purified product was dissolved in ethyl acetate (2 ml) and 4 M HCl/ethyl acetate solution (0.15 ml) was added to the ethyl acetate solution under ice cooling. The solvent was distilled off under reduced pressure to obtain the colorless, amorphous title compound (0.11 g) .
- the aqueous layer was extracted with ethyl acetate , and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure.
- the obtained purified product was dissolved in ethyl acetate (2 ml) and 4 M HCl/ethyl acetate solution (0.2 ml) was added to the ethyl acetate solution under ice cooling. The resulting solution was stirred at room temperature for 30 minutes . The precipitate was collected by filtration to obtain the title compound (0.12 g) .
- the obtained purified product was dissolved in ethyl acetate (2 ml) and methanol (1 ml) and 4 M HCl/ethyl acetate solution (2 ml) was added to the ethyl acetate solution under ice cooling. The solvent was distilled off under reduced pressure to obtain the title compound (0.14 g) .
- the obtained purified product was dissolved in ethyl acetate (4 ml) and 4 M HCl/ethyl acetate solution (1 ml) was added to the mixture. The resulting solution was stirred at room temperature for 30 minutes and concentrated under reduced pressure. The residue was solidified with a mixed solvent of chloroform (1 ml) and diisopropyl ether (3 ml). The obtained solid was collected by filtration to obtain the title compound (0.14 g) .
- the obtained compound was dissolved in ethyl acetate (2 ml) and 4 M HCl/ethyl acetate solution (0.2 ml) was added to the ethyl acetate solution.
- the solvent was distilled off under reduced pressure.
- the glycine uptake experiment was conducted according to the method described in Neuron, 8, 927-935, 1992.
- Glioma T98G cells which expressed human glycine transporter-1 (GIyTl) were used.
- the T98G cells were seeded at a density of 2.0 x 10 4 cells/well onto a 96-well plate and cultured overnight in a carbon dioxide incubator.
- the test compound was dissolved in 100% DMSO and then dissolved in 10 mM HEPES buffer solution (pH 7.4) containing 150 mM sodium chloride, 1 mM calcium chloride, 5 mM potassium chloride, 1 mM magnesium chloride, 10 mM glucose, and 0.2% bovine serum albumin.
- test compound and [ 3 H] glycine were added to the cells and reacted at room temperature for 15 minutes.
- the labeled glycine solution was aspirated with a manifold.
- the cells were then lysed with 0.5 M sodium hydroxide solution.
- An intracellular glycine amount was determined by measuring radio activity in the cell lysate with a liquid scintillation counter.
- a glycine uptake amount in the presence of 10 ⁇ M ALX5407 is defined as nonspecific uptake, and a specific uptake amount was determined by subtracting the nonspecific uptake amount from a total uptake amount in the absence of 10 ⁇ M ALX5407.
- Glycine uptake inhibitory activity (IC 50 value) was calculated from an inhibition curve at test compound concentrations of 10 '10 to 10 "6 .
- the compound of the present invention has glycine transporter-1 (GIyTl) inhibitory activity and is thus effective for the prevention or treatment of glycine transporter-related diseases, specifically, schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorders (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, posttraumatic stress disorder, particular phobias, acute stress disorder, etc.), depression, drug abuse, convulsion, tremor, or sleep disorders.
- GIPl glycine transporter-1
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Psychiatry (AREA)
- Food Science & Technology (AREA)
- Pain & Pain Management (AREA)
- Manufacturing & Machinery (AREA)
- Hospice & Palliative Care (AREA)
- Addiction (AREA)
- Anesthesiology (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
L'invention concerne un composé représenté par la formule (I) ou un sel pharmaceutiquement acceptable de ce composé, ou un hydrate de ce composé ou de son sel, servant à la prévention ou au traitement de maladies telles que la schizophrénie, la maladie d'Alzheimer, le dysfonctionnement cognitif, la démence, les troubles de l'anxiété (état d'anxiété généralisé, état de panique, trouble obsessionnel compulsif, état d'anxiété social, état de stress post-traumatique, phobies particulières, état de stress grave etc.), la dépression, l'abus de drogues, les convulsions, les tremblements et les troubles du sommeil, sur la base de l'effet d'inhibition de l'absorption de glycine.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006-220267 | 2006-08-11 | ||
JP2006220267A JP2009179562A (ja) | 2006-08-11 | 2006-08-11 | グリシントランスポーター阻害剤 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2008018639A2 true WO2008018639A2 (fr) | 2008-02-14 |
WO2008018639A3 WO2008018639A3 (fr) | 2008-04-03 |
Family
ID=39033397
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2007/065988 WO2008018639A2 (fr) | 2006-08-11 | 2007-08-10 | Inhibiteur de transporteurs de glycine |
Country Status (3)
Country | Link |
---|---|
JP (1) | JP2009179562A (fr) |
AR (1) | AR062325A1 (fr) |
WO (1) | WO2008018639A2 (fr) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010087762A1 (fr) * | 2009-01-28 | 2010-08-05 | Astrazeneca Ab | Composés 2-aza-bicyclo[2.2.1]heptane et leurs utilisations |
WO2010087761A1 (fr) * | 2009-01-28 | 2010-08-05 | Astrazeneca Ab | Composés 2-aza-bicyclo[2.2.2]octane et leurs utilisations |
FR2943056A1 (fr) * | 2009-03-16 | 2010-09-17 | Sanofi Aventis | Derives de n-°2-aza-bicyclo°2.1.1!hex-1-yl)-aryl-methyl!- heterobenzamide, leur preparation et leur application en therapeutique |
WO2010106269A3 (fr) * | 2009-03-16 | 2010-12-02 | Sanofi-Aventis | Derives de n-[(2-aza-bicyclo[2.1.1]hex-1-yl)-aryl-methyl]-heterobenzamide, leur preparation et leur application en therapeutique |
EP2679585A1 (fr) * | 2011-02-21 | 2014-01-01 | Taisho Pharmaceutical Co., Ltd. | Inhibiteur de transport de glycine |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003089411A1 (fr) * | 2002-04-19 | 2003-10-30 | Sanofi-Aventis | Derives de n-[phenyl(piperidin-2-yl)methyl] benzamide, leur preparation et leur application en therapeutique |
WO2006134341A1 (fr) * | 2005-06-13 | 2006-12-21 | Merck Sharp & Dohme Limited | Agents therapeutiques |
-
2006
- 2006-08-11 JP JP2006220267A patent/JP2009179562A/ja active Pending
-
2007
- 2007-08-10 AR ARP070103550A patent/AR062325A1/es unknown
- 2007-08-10 WO PCT/JP2007/065988 patent/WO2008018639A2/fr active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003089411A1 (fr) * | 2002-04-19 | 2003-10-30 | Sanofi-Aventis | Derives de n-[phenyl(piperidin-2-yl)methyl] benzamide, leur preparation et leur application en therapeutique |
WO2006134341A1 (fr) * | 2005-06-13 | 2006-12-21 | Merck Sharp & Dohme Limited | Agents therapeutiques |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010087762A1 (fr) * | 2009-01-28 | 2010-08-05 | Astrazeneca Ab | Composés 2-aza-bicyclo[2.2.1]heptane et leurs utilisations |
WO2010087761A1 (fr) * | 2009-01-28 | 2010-08-05 | Astrazeneca Ab | Composés 2-aza-bicyclo[2.2.2]octane et leurs utilisations |
CN102405222A (zh) * | 2009-01-28 | 2012-04-04 | 阿斯利康(瑞典)有限公司 | 2-氮杂-二环[2.2.1]庚烷化合物及其用途 |
FR2943056A1 (fr) * | 2009-03-16 | 2010-09-17 | Sanofi Aventis | Derives de n-°2-aza-bicyclo°2.1.1!hex-1-yl)-aryl-methyl!- heterobenzamide, leur preparation et leur application en therapeutique |
WO2010106269A3 (fr) * | 2009-03-16 | 2010-12-02 | Sanofi-Aventis | Derives de n-[(2-aza-bicyclo[2.1.1]hex-1-yl)-aryl-methyl]-heterobenzamide, leur preparation et leur application en therapeutique |
EP2679585A1 (fr) * | 2011-02-21 | 2014-01-01 | Taisho Pharmaceutical Co., Ltd. | Inhibiteur de transport de glycine |
EP2679585A4 (fr) * | 2011-02-21 | 2014-08-06 | Taisho Pharmaceutical Co Ltd | Inhibiteur de transport de glycine |
Also Published As
Publication number | Publication date |
---|---|
WO2008018639A3 (fr) | 2008-04-03 |
AR062325A1 (es) | 2008-10-29 |
JP2009179562A (ja) | 2009-08-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2509955B1 (fr) | Dérivés de pyrazole en tant que modulateurs du canal calcique activé par la libération du calcium | |
JP5161869B2 (ja) | 11−β−ヒドロキシステロイドデヒドロゲナーゼ1の阻害剤としての、シクロヘキシルピラゾール−ラクタム誘導体 | |
JP5269765B2 (ja) | 11−β−ヒドロキシステロイドデヒドロゲナーゼ1の阻害剤 | |
CA2753434C (fr) | Activateurs solubles de guanylate cyclase | |
JP5324427B2 (ja) | 11−β−ヒドロキシステロイドデヒドロゲナーゼ1の阻害剤 | |
DE60312998T2 (de) | 1-amido-4-phenyl-4-benzyloxymethyl-piperidin derivative und verwandte verbindungen als neurokinin-1 (nk-1) antagonsisten zur behandlung von erbrechen, depressionen, angstzustände und husten | |
CA2932010C (fr) | Derive d'uree ou sel pharmacologiquement acceptable de celui-ci | |
CA2611376C (fr) | Agents therapeutiques | |
EP3634958B1 (fr) | Agonistes du récepteur 2 du peptide formylé et agonistes du récepteur 1 du peptide formylé à base de cyclopropyle d'urée | |
CA3018346A1 (fr) | 6-hydroxy-4-oxo-1,4-dihydropyrimidine-5-carboxamides utilises en tant qu'agonistes de l'apj | |
US8623898B2 (en) | Glycine transporter inhibiting substances | |
AU2009245715A1 (en) | Trisubstituted pyrazoles as acetylcholine receptor modulators | |
US20050176772A1 (en) | Pharmaceutically active compounds | |
JP2011517680A (ja) | オレキシン関連障害の治療に使用するピリジン誘導体 | |
CA2562100A1 (fr) | Derives de la 1-amino-phthalazine, leur preparation, et leur application en therapeutique | |
AU2005213538A1 (en) | Piperidinylcarbonyl-pyrrolidines and their use as melanocortin agonists | |
WO2009026407A1 (fr) | Composés pyrroliques ayant une activité agoniste de récepteur de sphingosine-1-phosphate ou une activité biologique antagoniste | |
CA2787248A1 (fr) | Compose de piperazine ayant un effet inhibiteur des prostaglandines | |
EP3634956A1 (fr) | Agonistes du récepteur 2 du peptide formylé et agonistes du récepteur 1 du peptide formylé à base de pipéridinone d'aryle hétérocyclique | |
WO2008018639A2 (fr) | Inhibiteur de transporteurs de glycine | |
EP3442967A1 (fr) | Nouveaux n-[(hétéroaryloxy)propanyl]hétéroaryl carboxamides | |
JP2013502448A (ja) | オレキシンアンタゴニストとして用いられるピペリジン誘導体 | |
KR101827660B1 (ko) | 플루오로페닐 피라졸 화합물 | |
KR20240045222A (ko) | 3,4-메틸렌다이옥시메스암페타민 및 관련 환각제, 그리고 이들의 용도 | |
JPH07233162A (ja) | イミダゾリジノン誘導体とその酸付加塩及び老年性痴呆症の治療薬 |
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: 07805937 Country of ref document: EP Kind code of ref document: A2 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
NENP | Non-entry into the national phase |
Ref country code: RU |
|
NENP | Non-entry into the national phase |
Ref country code: JP |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 07805937 Country of ref document: EP Kind code of ref document: A2 |