ES2320905T3 - Nuevas 5-acilindolinonas con contenido en alquilo, su preparacion y su uso como medicamentos. - Google Patents

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Publication number

ES2320905T3

ES2320905T3 ES05715811T ES05715811T ES2320905T3 ES 2320905 T3 ES2320905 T3 ES 2320905T3 ES 05715811 T ES05715811 T ES 05715811T ES 05715811 T ES05715811 T ES 05715811T ES 2320905 T3 ES2320905 T3 ES 2320905T3

Authority

ES

Spain

Prior art keywords

alkyl

group

amino

carbonyl

alkoxy

Prior art date

2004-03-12

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Expired - Lifetime

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• 238000002360 preparation method Methods 0.000 title claims description 26
• 239000003814 drug Substances 0.000 title claims description 9
• 229940079593 drug Drugs 0.000 title claims description 6
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 216
• -1 nitro, cyano, amino Chemical group 0.000 claims abstract description 99
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 85
• 150000001875 compounds Chemical class 0.000 claims abstract description 75
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 45
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 34
• 239000000203 mixture Substances 0.000 claims abstract description 26
• 125000003118 aryl group Chemical group 0.000 claims abstract description 22
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 22
• 239000000460 chlorine Substances 0.000 claims abstract description 20
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 19
• 229910052801 chlorine Inorganic materials 0.000 claims abstract description 19
• 125000006842 cycloalkyleneimino group Chemical group 0.000 claims abstract description 19
• 125000001424 substituent group Chemical group 0.000 claims abstract description 19
• 150000003839 salts Chemical class 0.000 claims abstract description 18
• 125000004429 atom Chemical group 0.000 claims abstract description 17
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 16
• 239000011737 fluorine Substances 0.000 claims abstract description 16
• 229910052731 fluorine Inorganic materials 0.000 claims abstract description 16
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 16
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 16
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 15
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 15
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 14
• 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 14
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 14
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 13
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims abstract description 13
• 125000005842 heteroatom Chemical group 0.000 claims abstract description 12
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 10
• 229910052794 bromium Inorganic materials 0.000 claims abstract description 10
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 10
• 239000001301 oxygen Substances 0.000 claims abstract description 10
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 10
• 125000006698 (C1-C3) dialkylamino group Chemical group 0.000 claims abstract description 9
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 9
• 125000003277 amino group Chemical group 0.000 claims abstract description 9
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 8
• 125000005129 aryl carbonyl group Chemical group 0.000 claims abstract description 8
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
• 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims abstract description 7
• 229910052740 iodine Inorganic materials 0.000 claims abstract description 7
• 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 7
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 7
• 125000006602 (C1-C3) alkylsulfonylamino group Chemical group 0.000 claims abstract description 6
• KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims abstract description 6
• 125000005100 aryl amino carbonyl group Chemical group 0.000 claims abstract description 6
• 125000005222 heteroarylaminocarbonyl group Chemical group 0.000 claims abstract description 6
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 5
• 125000003342 alkenyl group Chemical group 0.000 claims abstract description 5
• 125000000304 alkynyl group Chemical group 0.000 claims abstract description 5
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 5
• 125000006597 (C1-C3) alkylcarbonylamino group Chemical group 0.000 claims abstract description 4
• 229910052799 carbon Inorganic materials 0.000 claims abstract description 4
• 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 4
• 239000011630 iodine Substances 0.000 claims abstract description 4
• 125000001624 naphthyl group Chemical group 0.000 claims abstract description 4
• 125000000168 pyrrolyl group Chemical group 0.000 claims abstract description 4
• 125000006563 (C1-3) alkylaminocarbonyl group Chemical group 0.000 claims abstract description 3
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims abstract description 3
• 125000001769 aryl amino group Chemical group 0.000 claims abstract description 3
• 125000004658 aryl carbonyl amino group Chemical group 0.000 claims abstract description 3
• 125000004657 aryl sulfonyl amino group Chemical group 0.000 claims abstract description 3
• 125000004104 aryloxy group Chemical group 0.000 claims abstract description 3
• 125000005241 heteroarylamino group Chemical group 0.000 claims abstract description 3
• 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims abstract description 3
• 125000005224 heteroarylcarbonylamino group Chemical group 0.000 claims abstract description 3
• 125000005553 heteroaryloxy group Chemical group 0.000 claims abstract description 3
• 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 3
• 125000005544 phthalimido group Chemical group 0.000 claims abstract description 3
• 239000002253 acid Substances 0.000 claims description 44
• 239000000126 substance Substances 0.000 claims description 24
• 238000006243 chemical reaction Methods 0.000 claims description 17
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 15
• 125000004076 pyridyl group Chemical group 0.000 claims description 13
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
• 238000000034 method Methods 0.000 claims description 10
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
• 125000002883 imidazolyl group Chemical group 0.000 claims description 9
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
• 206010012601 diabetes mellitus Diseases 0.000 claims description 8
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
• 125000006239 protecting group Chemical group 0.000 claims description 8
• 239000011593 sulfur Substances 0.000 claims description 8
• 239000003795 chemical substances by application Substances 0.000 claims description 7
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
• 208000024827 Alzheimer disease Diseases 0.000 claims description 6
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
• 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 6
• 150000007513 acids Chemical class 0.000 claims description 5
• 150000001412 amines Chemical class 0.000 claims description 5
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
• 208000012902 Nervous system disease Diseases 0.000 claims description 4
• 208000025966 Neurological disease Diseases 0.000 claims description 4
• 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 4
• 125000001246 bromo group Chemical group Br* 0.000 claims description 4
• 150000007529 inorganic bases Chemical class 0.000 claims description 4
• 150000007530 organic bases Chemical class 0.000 claims description 4
• 208000020925 Bipolar disease Diseases 0.000 claims description 3
• 230000003412 degenerative effect Effects 0.000 claims description 3
• 125000002541 furyl group Chemical group 0.000 claims description 3
• 125000005843 halogen group Chemical group 0.000 claims description 3
• 125000001041 indolyl group Chemical group 0.000 claims description 3
• PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 3
• 150000003951 lactams Chemical group 0.000 claims description 3
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
• NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 2
• PRRYKQCBNLEMKK-UHFFFAOYSA-N 5-acetyl-3-[(3,4-difluorophenyl)-(2,2-dimethylhydrazinyl)methylidene]-1h-indol-2-one Chemical compound O=C1NC2=CC=C(C(C)=O)C=C2C1=C(NN(C)C)C1=CC=C(F)C(F)=C1 PRRYKQCBNLEMKK-UHFFFAOYSA-N 0.000 claims description 2
• GEDCCZDGOSWMCN-UHFFFAOYSA-N 5-acetyl-3-[8-(dimethylamino)oct-2-en-4-ylidene]-1h-indol-2-one Chemical compound C1=C(C(C)=O)C=C2C(=C(CCCCN(C)C)C=CC)C(=O)NC2=C1 GEDCCZDGOSWMCN-UHFFFAOYSA-N 0.000 claims description 2
• RRIMEAIVEAJAJM-UHFFFAOYSA-N 5-acetyl-3-[phenyl(propylamino)methylidene]-1h-indol-2-one Chemical compound O=C1NC2=CC=C(C(C)=O)C=C2C1=C(NCCC)C1=CC=CC=C1 RRIMEAIVEAJAJM-UHFFFAOYSA-N 0.000 claims description 2
• HFWLYTNHGAQFOU-UHFFFAOYSA-N 5-acetyl-3-[phenyl-(3-pyridin-3-ylpropylamino)methylidene]-1h-indol-2-one Chemical compound C12=CC(C(=O)C)=CC=C2NC(=O)C1=C(C=1C=CC=CC=1)NCCCC1=CC=CN=C1 HFWLYTNHGAQFOU-UHFFFAOYSA-N 0.000 claims description 2
• OYSQUGVVMMVTHE-UHFFFAOYSA-N 5-acetyl-3-[phenyl-(propan-2-ylamino)methylidene]-1h-indol-2-one Chemical compound O=C1NC2=CC=C(C(C)=O)C=C2C1=C(NC(C)C)C1=CC=CC=C1 OYSQUGVVMMVTHE-UHFFFAOYSA-N 0.000 claims description 2
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
• 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 2
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
• 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 2
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
• 125000005111 carboxyalkoxy group Chemical group 0.000 claims description 2
• 125000004181 carboxyalkyl group Chemical group 0.000 claims description 2
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
• 239000003085 diluting agent Substances 0.000 claims description 2
• 208000035475 disorder Diseases 0.000 claims description 2
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 2
• 229910052739 hydrogen Inorganic materials 0.000 claims description 2
• 239000001257 hydrogen Substances 0.000 claims description 2
• 125000001841 imino group Chemical group [H]N=* 0.000 claims description 2
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
• 230000003902 lesion Effects 0.000 claims description 2
• HCXMWFUMXGBEQA-UHFFFAOYSA-N methyl 4-[[(5-acetyl-2-oxo-1h-indol-3-ylidene)-(2,3-dihydro-1,4-benzodioxin-6-yl)methyl]amino]butanoate Chemical compound O1CCOC2=CC(C(=C3C4=CC(=CC=C4NC3=O)C(C)=O)NCCCC(=O)OC)=CC=C21 HCXMWFUMXGBEQA-UHFFFAOYSA-N 0.000 claims description 2
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
• 150000007522 mineralic acids Chemical class 0.000 claims description 2
• 125000002757 morpholinyl group Chemical group 0.000 claims description 2
• FSQQJBYLRCHDQO-UHFFFAOYSA-N n-[3-[[(5-acetyl-2-oxo-1h-indol-3-ylidene)-phenylmethyl]amino]propyl]methanesulfonamide Chemical compound C12=CC(C(=O)C)=CC=C2NC(=O)C1=C(NCCCNS(C)(=O)=O)C1=CC=CC=C1 FSQQJBYLRCHDQO-UHFFFAOYSA-N 0.000 claims description 2
• 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
• 125000005476 oxopyrrolidinyl group Chemical group 0.000 claims description 2
• 125000004193 piperazinyl group Chemical group 0.000 claims description 2
• 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 2
• 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 claims description 2
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
• 125000005140 aralkylsulfonyl group Chemical group 0.000 claims 1
• 239000003701 inert diluent Substances 0.000 claims 1
• 201000001119 neuropathy Diseases 0.000 claims 1
• 230000007823 neuropathy Effects 0.000 claims 1
• 150000007524 organic acids Chemical class 0.000 claims 1
• 235000005985 organic acids Nutrition 0.000 claims 1
• 208000033808 peripheral neuropathy Diseases 0.000 claims 1
• 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 claims 1
• 125000004448 alkyl carbonyl group Chemical group 0.000 abstract 7
• 125000006594 (C1-C3) alkylsulfony group Chemical group 0.000 abstract 2
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 abstract 2
• MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 abstract 2
• 125000006576 di-(C1-C3-alkyl)-aminocarbonyl group Chemical group 0.000 abstract 2
• 125000004434 sulfur atom Chemical group 0.000 abstract 2
• 125000006559 (C1-C3) alkylamino group Chemical group 0.000 abstract 1
• 125000006656 (C2-C4) alkenyl group Chemical group 0.000 abstract 1
• 125000006650 (C2-C4) alkynyl group Chemical group 0.000 abstract 1
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 abstract 1
• 125000002993 cycloalkylene group Chemical group 0.000 abstract 1
• ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 abstract 1
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 228
• 238000001819 mass spectrum Methods 0.000 description 87
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 66
• 239000000741 silica gel Substances 0.000 description 60
• 229910002027 silica gel Inorganic materials 0.000 description 60
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
• OGDZTLONCPVKCE-UHFFFAOYSA-N 1,5-diacetyl-3h-indol-2-one Chemical compound CC(=O)C1=CC=C2N(C(=O)C)C(=O)CC2=C1 OGDZTLONCPVKCE-UHFFFAOYSA-N 0.000 description 41
• 102000001267 GSK3 Human genes 0.000 description 25
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 25
• 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 description 24
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 22
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
• 239000013543 active substance Substances 0.000 description 17
• 235000002639 sodium chloride Nutrition 0.000 description 17
• 239000003112 inhibitor Substances 0.000 description 15
• 150000002148 esters Chemical class 0.000 description 14
• 238000003756 stirring Methods 0.000 description 14
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
• 230000000694 effects Effects 0.000 description 12
• JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical group C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 11
• 239000003826 tablet Substances 0.000 description 11
• 210000004027 cell Anatomy 0.000 description 9
• 239000012141 concentrate Substances 0.000 description 9
• 239000008103 glucose Substances 0.000 description 9
• 239000002244 precipitate Substances 0.000 description 9
• 239000000243 solution Substances 0.000 description 9
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 8
• 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 8
• 229920002527 Glycogen Polymers 0.000 description 8
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
• 229940096919 glycogen Drugs 0.000 description 8
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
• 239000002585 base Substances 0.000 description 7
• 201000010099 disease Diseases 0.000 description 7
• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 7
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
• 229910021529 ammonia Inorganic materials 0.000 description 6
• 239000005557 antagonist Substances 0.000 description 6
• 238000004587 chromatography analysis Methods 0.000 description 6
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
• 108010001483 Glycogen Synthase Proteins 0.000 description 5
• 230000015572 biosynthetic process Effects 0.000 description 5
• 239000008280 blood Substances 0.000 description 5
• 210000004369 blood Anatomy 0.000 description 5
• 239000008298 dragée Substances 0.000 description 5
• 239000003480 eluent Substances 0.000 description 5
• 230000026731 phosphorylation Effects 0.000 description 5
• 238000006366 phosphorylation reaction Methods 0.000 description 5
• 235000011121 sodium hydroxide Nutrition 0.000 description 5
• 239000000725 suspension Substances 0.000 description 5
• 238000003786 synthesis reaction Methods 0.000 description 5
• 102000013498 tau Proteins Human genes 0.000 description 5
• 108010026424 tau Proteins Proteins 0.000 description 5
• KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 4
• CMULJQRPNMIROG-UHFFFAOYSA-N 5-acetyl-3-[1,3-benzodioxol-5-yl-[3-(methylamino)propylamino]methylidene]-1h-indol-2-one Chemical compound C1=C2OCOC2=CC(C(=C2C3=CC(=CC=C3NC2=O)C(C)=O)NCCCNC)=C1 CMULJQRPNMIROG-UHFFFAOYSA-N 0.000 description 4
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
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