UA79447C2 - Indole derivates, pharmaceutical composition based thereon, process for their preparation (variants), intermediate compound - Google Patents
Indole derivates, pharmaceutical composition based thereon, process for their preparation (variants), intermediate compound Download PDFInfo
- Publication number
- UA79447C2 UA79447C2 UA20040806742A UA20040806742A UA79447C2 UA 79447 C2 UA79447 C2 UA 79447C2 UA 20040806742 A UA20040806742 A UA 20040806742A UA 20040806742 A UA20040806742 A UA 20040806742A UA 79447 C2 UA79447 C2 UA 79447C2
- Authority
- UA
- Ukraine
- Prior art keywords
- pyridin
- hydroxy
- indol
- compound
- alkyl
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 287
- 238000000034 method Methods 0.000 title claims abstract description 34
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 230000008569 process Effects 0.000 title abstract description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title 1
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 121
- 239000002904 solvent Substances 0.000 claims description 100
- 239000002585 base Substances 0.000 claims description 86
- -1 4-methyl-1,4-diazepan-1-yl Chemical group 0.000 claims description 81
- 238000006243 chemical reaction Methods 0.000 claims description 80
- 125000000623 heterocyclic group Chemical group 0.000 claims description 72
- 125000005842 heteroatom Chemical group 0.000 claims description 46
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 46
- 125000000217 alkyl group Chemical group 0.000 claims description 45
- 229920006395 saturated elastomer Polymers 0.000 claims description 45
- 229910052736 halogen Inorganic materials 0.000 claims description 42
- 150000002367 halogens Chemical class 0.000 claims description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims description 40
- 239000001257 hydrogen Substances 0.000 claims description 39
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 37
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
- 150000003839 salts Chemical class 0.000 claims description 34
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 32
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 31
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 30
- 238000011282 treatment Methods 0.000 claims description 25
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
- 125000001072 heteroaryl group Chemical group 0.000 claims description 21
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 21
- 230000002265 prevention Effects 0.000 claims description 21
- 206010012289 Dementia Diseases 0.000 claims description 20
- 238000010992 reflux Methods 0.000 claims description 19
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 19
- 150000001412 amines Chemical class 0.000 claims description 18
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 17
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 17
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 17
- 229910052794 bromium Inorganic materials 0.000 claims description 17
- 239000003153 chemical reaction reagent Substances 0.000 claims description 17
- NKFLEFWUYAUDJV-UHFFFAOYSA-N pyridine-3-sulfonamide Chemical compound NS(=O)(=O)C1=CC=CN=C1 NKFLEFWUYAUDJV-UHFFFAOYSA-N 0.000 claims description 17
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 16
- 125000004429 atom Chemical group 0.000 claims description 16
- 239000000460 chlorine Substances 0.000 claims description 16
- 229910052801 chlorine Inorganic materials 0.000 claims description 16
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 16
- 208000024827 Alzheimer disease Diseases 0.000 claims description 15
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 15
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 15
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 claims description 15
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 15
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 15
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 14
- 229910052796 boron Inorganic materials 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 14
- 239000011737 fluorine Substances 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 239000012458 free base Substances 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 12
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 12
- 201000011240 Frontotemporal dementia Diseases 0.000 claims description 12
- 208000010877 cognitive disease Diseases 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 10
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 10
- 102000001267 GSK3 Human genes 0.000 claims description 10
- 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 claims description 10
- 208000028698 Cognitive impairment Diseases 0.000 claims description 9
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 9
- OBLVPWTUALCMGD-UHFFFAOYSA-N pyridin-1-ium-3-carboxamide;chloride Chemical compound Cl.NC(=O)C1=CC=CN=C1 OBLVPWTUALCMGD-UHFFFAOYSA-N 0.000 claims description 9
- 229940124530 sulfonamide Drugs 0.000 claims description 9
- 241000124008 Mammalia Species 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
- 201000000980 schizophrenia Diseases 0.000 claims description 8
- 201000004384 Alopecia Diseases 0.000 claims description 7
- 208000000609 Pick Disease of the Brain Diseases 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 206010019196 Head injury Diseases 0.000 claims description 5
- 208000018737 Parkinson disease Diseases 0.000 claims description 5
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 5
- 230000001684 chronic effect Effects 0.000 claims description 5
- 206010027175 memory impairment Diseases 0.000 claims description 5
- 230000004770 neurodegeneration Effects 0.000 claims description 5
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 5
- 210000002682 neurofibrillary tangle Anatomy 0.000 claims description 5
- 125000001963 4 membered heterocyclic group Chemical group 0.000 claims description 4
- 208000020925 Bipolar disease Diseases 0.000 claims description 4
- 208000011990 Corticobasal Degeneration Diseases 0.000 claims description 4
- 201000010374 Down Syndrome Diseases 0.000 claims description 4
- 208000023105 Huntington disease Diseases 0.000 claims description 4
- 208000019022 Mood disease Diseases 0.000 claims description 4
- 208000036757 Postencephalitic parkinsonism Diseases 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 238000003682 fluorination reaction Methods 0.000 claims description 4
- 208000024963 hair loss Diseases 0.000 claims description 4
- 230000003676 hair loss Effects 0.000 claims description 4
- 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 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- 230000007170 pathology Effects 0.000 claims description 4
- 208000000170 postencephalitic Parkinson disease Diseases 0.000 claims description 4
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 208000000044 Amnesia Diseases 0.000 claims description 3
- 208000031091 Amnestic disease Diseases 0.000 claims description 3
- 206010067889 Dementia with Lewy bodies Diseases 0.000 claims description 3
- 201000002832 Lewy body dementia Diseases 0.000 claims description 3
- 201000004810 Vascular dementia Diseases 0.000 claims description 3
- 230000006986 amnesia Effects 0.000 claims description 3
- 239000003433 contraceptive agent Substances 0.000 claims description 3
- 230000007423 decrease Effects 0.000 claims description 3
- 208000017004 dementia pugilistica Diseases 0.000 claims description 3
- MTDZOMKWYKURBV-UHFFFAOYSA-N ethyl 6-(5-cyano-2-hydroxy-1H-indol-3-yl)pyridine-3-carboxylate Chemical compound N1=CC(C(=O)OCC)=CC=C1C1=C(O)NC2=CC=C(C#N)C=C12 MTDZOMKWYKURBV-UHFFFAOYSA-N 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 201000002212 progressive supranuclear palsy Diseases 0.000 claims description 3
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 3
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
- 208000006011 Stroke Diseases 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- ZSBINQQBBOUXFI-UHFFFAOYSA-N ethyl 6-(2-hydroxy-5-nitro-1H-indol-3-yl)pyridine-3-carboxylate Chemical compound N1=CC(C(=O)OCC)=CC=C1C1=C(O)NC2=CC=C([N+]([O-])=O)C=C12 ZSBINQQBBOUXFI-UHFFFAOYSA-N 0.000 claims description 2
- 210000001682 neurofibril Anatomy 0.000 claims description 2
- 230000003930 cognitive ability Effects 0.000 claims 4
- 230000006866 deterioration Effects 0.000 claims 3
- 206010068168 androgenetic alopecia Diseases 0.000 claims 2
- 201000002996 androgenic alopecia Diseases 0.000 claims 2
- 210000005056 cell body Anatomy 0.000 claims 2
- 230000003993 interaction Effects 0.000 claims 2
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 claims 1
- LLAZTZBIMDHGFQ-UHFFFAOYSA-N 6-(5-cyano-2-hydroxy-1H-indol-3-yl)-N-(2-pyrrolidin-1-ylethyl)pyridine-3-sulfonamide hydrochloride Chemical compound Cl.OC=1NC2=CC=C(C#N)C=C2C=1C(N=C1)=CC=C1S(=O)(=O)NCCN1CCCC1 LLAZTZBIMDHGFQ-UHFFFAOYSA-N 0.000 claims 1
- 241001482237 Pica Species 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 238000012876 topography Methods 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 267
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 225
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 169
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 162
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 136
- 239000000203 mixture Substances 0.000 description 104
- 238000005481 NMR spectroscopy Methods 0.000 description 86
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 84
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 76
- 239000000243 solution Substances 0.000 description 74
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 66
- 239000003480 eluent Substances 0.000 description 60
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 59
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 57
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 54
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 54
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 50
- 239000000741 silica gel Substances 0.000 description 48
- 229910002027 silica gel Inorganic materials 0.000 description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 39
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 38
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 36
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 36
- 239000011541 reaction mixture Substances 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- 235000017557 sodium bicarbonate Nutrition 0.000 description 33
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 33
- 239000012043 crude product Substances 0.000 description 30
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
- 239000000725 suspension Substances 0.000 description 29
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 27
- 239000012312 sodium hydride Substances 0.000 description 27
- 229910000104 sodium hydride Inorganic materials 0.000 description 27
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 26
- 239000003921 oil Substances 0.000 description 26
- 235000019198 oils Nutrition 0.000 description 26
- 239000007858 starting material Substances 0.000 description 26
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 24
- 239000010410 layer Substances 0.000 description 24
- 239000012044 organic layer Substances 0.000 description 24
- 239000007787 solid Substances 0.000 description 24
- 239000012265 solid product Substances 0.000 description 22
- 239000002244 precipitate Substances 0.000 description 21
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 20
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 19
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 19
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 18
- 239000007864 aqueous solution Substances 0.000 description 18
- 229910000027 potassium carbonate Inorganic materials 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- 239000006185 dispersion Substances 0.000 description 14
- NZOSLRYUVHMXTQ-UHFFFAOYSA-N 2-oxo-1,3-dihydroindole-5-carbonitrile Chemical compound N#CC1=CC=C2NC(=O)CC2=C1 NZOSLRYUVHMXTQ-UHFFFAOYSA-N 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- 229910000029 sodium carbonate Inorganic materials 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 229910000019 calcium carbonate Inorganic materials 0.000 description 12
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 12
- PGQOYAJLRDKANT-UHFFFAOYSA-N 1H-indol-5-yl cyanate Chemical compound N#COC1=CC=C2NC=CC2=C1 PGQOYAJLRDKANT-UHFFFAOYSA-N 0.000 description 11
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 11
- 230000002378 acidificating effect Effects 0.000 description 11
- 239000000908 ammonium hydroxide Substances 0.000 description 11
- 239000000463 material Substances 0.000 description 11
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 10
- 239000000872 buffer Substances 0.000 description 10
- 239000012299 nitrogen atmosphere Substances 0.000 description 10
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 9
- 239000005695 Ammonium acetate Substances 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 9
- 229940043376 ammonium acetate Drugs 0.000 description 9
- 235000019257 ammonium acetate Nutrition 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 238000002953 preparative HPLC Methods 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- 150000003973 alkyl amines Chemical class 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 8
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 238000009835 boiling Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- 229910052744 lithium Inorganic materials 0.000 description 7
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- 150000001340 alkali metals Chemical class 0.000 description 6
- 239000001530 fumaric acid Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 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 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- RPCLPGKRXFYJKP-UHFFFAOYSA-N 2-chloro-5-(chloromethyl)-1-oxidopyridin-1-ium Chemical compound [O-][N+]1=CC(CCl)=CC=C1Cl RPCLPGKRXFYJKP-UHFFFAOYSA-N 0.000 description 5
- XRZSTVZROYQDLJ-UHFFFAOYSA-N 4-[(6-chloro-1-oxidopyridin-1-ium-3-yl)methyl]morpholine Chemical compound C1=C(Cl)[N+]([O-])=CC(CN2CCOCC2)=C1 XRZSTVZROYQDLJ-UHFFFAOYSA-N 0.000 description 5
- AWOFOOPKKDKSFM-UHFFFAOYSA-N 5-(furan-2-yl)-1,3-dihydroindol-2-one Chemical compound C=1C=C2NC(=O)CC2=CC=1C1=CC=CO1 AWOFOOPKKDKSFM-UHFFFAOYSA-N 0.000 description 5
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
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Classifications
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- 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
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- 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
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- 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
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Landscapes
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| SE0200979A SE0200979D0 (sv) | 2002-03-28 | 2002-03-28 | New compounds |
| PCT/SE2003/000508 WO2003082853A1 (en) | 2002-03-28 | 2003-03-28 | New compounds |
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| UA79447C2 true UA79447C2 (en) | 2007-06-25 |
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| UA20040806742A UA79447C2 (en) | 2002-03-28 | 2003-03-28 | Indole derivates, pharmaceutical composition based thereon, process for their preparation (variants), intermediate compound |
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| SE0302546D0 (sv) * | 2003-09-24 | 2003-09-24 | Astrazeneca Ab | New compounds |
| US20040067985A1 (en) * | 2002-10-04 | 2004-04-08 | Fortuna Haviv | Method of inhibiting angiogenesis |
| EP1812439B2 (en) | 2004-10-15 | 2017-12-06 | Takeda Pharmaceutical Company Limited | Kinase inhibitors |
| US8046280B2 (en) * | 2005-06-10 | 2011-10-25 | Pioneer Hi-Bred International, Inc. | Method for using environmental classification to assist in financial management and services |
| EP2258358A3 (en) | 2005-08-26 | 2011-09-07 | Braincells, Inc. | Neurogenesis with acetylcholinesterase inhibitor |
| US7678363B2 (en) | 2005-08-26 | 2010-03-16 | Braincells Inc | Methods of treating psychiatric conditions comprising administration of muscarinic agents in combination with SSRIs |
| US8119655B2 (en) | 2005-10-07 | 2012-02-21 | Takeda Pharmaceutical Company Limited | Kinase inhibitors |
| EP1940389A2 (en) | 2005-10-21 | 2008-07-09 | Braincells, Inc. | Modulation of neurogenesis by pde inhibition |
| US20070112017A1 (en) | 2005-10-31 | 2007-05-17 | Braincells, Inc. | Gaba receptor mediated modulation of neurogenesis |
| SA07280004B1 (ar) * | 2006-02-02 | 2011-10-29 | استرازينيكا ايه بي | ملح سترات من مركب 2- هيدروكسي –3- [5- (مورفولين –4- يل ميثيل) بيريدين –2- يل] 1h- إندول –5- كربونيتريل سترات |
| US20090221576A1 (en) * | 2006-02-02 | 2009-09-03 | Astrazeneca Ab Global Intellectual Property | Pharmaceutical Use of 2-Hydroxy-3-[5-(Morpholin-4-Ylmethyl) Pyridin-2-YL]-1H-IN-Dole-5-Carbonitrile as a Free Base or Salts |
| WO2007089193A1 (en) * | 2006-02-02 | 2007-08-09 | Astrazeneca Ab | A process for preparing 2-hydroxy-3- [5- (morpholin-4-ylmethyl)pyridin-2-yl] lh-indole-5-carbonitrile as a free base or salts thereof |
| WO2007100282A1 (en) * | 2006-02-28 | 2007-09-07 | Astrazeneca Ab | New salts of an indole derivative and their use in medicine |
| US20100216734A1 (en) | 2006-03-08 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
| WO2007120102A1 (en) * | 2006-04-19 | 2007-10-25 | Astrazeneca Ab | New substituted oxindole derivatives |
| AU2007249399A1 (en) | 2006-05-09 | 2007-11-22 | Braincells, Inc. | Neurogenesis by modulating angiotensin |
| US20100184806A1 (en) | 2006-09-19 | 2010-07-22 | Braincells, Inc. | Modulation of neurogenesis by ppar agents |
| US20080086340A1 (en) * | 2006-10-04 | 2008-04-10 | Pioneer Hi-Bred International, Inc. | Crop quality insurance |
| EA200970361A1 (ru) | 2006-10-09 | 2010-02-26 | Такеда Фармасьютикал Компани Лимитед | Ингибиторы киназы |
| EP2091943B1 (en) | 2006-10-21 | 2013-11-20 | AbbVie Deutschland GmbH & Co KG | Heterocyclic compounds and their use as glycogen synthase kinase 3 inhibitors |
| US8417534B2 (en) | 2006-12-29 | 2013-04-09 | Pioneer Hi-Bred International, Inc. | Automated location-based information recall |
| US8101750B2 (en) | 2007-04-18 | 2012-01-24 | Astrazeneca Ab | Process for the manufacturing of the compound 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]1H-indole-5-carbonitrile 701 |
| WO2009017454A1 (en) * | 2007-07-30 | 2009-02-05 | Astrazeneca Ab | New therapeutic combination of a gsk3 inhibitor and an a7-nicotinic agonist 960 |
| WO2009017453A1 (en) * | 2007-07-30 | 2009-02-05 | Astrazeneca Ab | New therapeutic combination of an antipsychotic and a gsk3 inhibitor 958 |
| WO2009017455A1 (en) * | 2007-07-30 | 2009-02-05 | Astrazeneca Ab | A new combination of (a) an alpha-4-beta-2 -neuronal nicotinic agonist and (b) a gsk3 inhibitor |
| WO2009017452A1 (en) * | 2007-07-30 | 2009-02-05 | Astrazeneca Ab | New crystalline forms of 2 -hydroxy- 3- [5- (morpholin- 4- ylmethyl) pyridin-2-yl] ih- indole- 5 -carbonitrile citrate |
| HUE030774T2 (hu) * | 2007-09-06 | 2017-05-29 | Boston Biomedical Inc | Kinázinhibitorokból álló készítmények és felhasználásuk a rák és a kinázokhoz kapcsolódó más betegségek kezelésére |
| US20090291982A1 (en) * | 2008-05-22 | 2009-11-26 | Astrazeneca Ab | New Substituted Oxindole Derivative 352 |
| WO2010099217A1 (en) | 2009-02-25 | 2010-09-02 | Braincells, Inc. | Modulation of neurogenesis using d-cycloserine combinations |
| TW201040191A (en) | 2009-03-27 | 2010-11-16 | Abbott Gmbh & Co Kg | Heterocyclic compounds and their use as glycogen synthase kinase-3 inhibitors |
| WO2010143803A2 (en) * | 2009-06-08 | 2010-12-16 | Industry Foundation Of Chonnam National University | New nicotinamide derivatives with anti-androgen effects, processes of preparing, and antiandrogens comprising the same |
| JP2011178752A (ja) * | 2010-03-03 | 2011-09-15 | Nagoya Univ | 含窒素複素環化合物及びその製造方法 |
| WO2012041814A1 (en) | 2010-09-27 | 2012-04-05 | Abbott Gmbh & Co. Kg | Heterocyclic compounds and their use as glycogen synthase kinase-3 inhibitors |
| MX2013006467A (es) | 2010-12-09 | 2013-10-01 | Amgen Inc | Compuestos biciclicos como inhibidores pim. |
| MX2013006694A (es) | 2010-12-21 | 2013-07-29 | Bayer Ip Gmbh | Procedimiento para producir oxindoles sustituidos con triazinilo. |
| US9090592B2 (en) | 2010-12-30 | 2015-07-28 | AbbVie Deutschland GmbH & Co. KG | Heterocyclic compounds and their use as glycogen synthase kinase-3 inhibitors |
| EP2688886A1 (en) | 2011-03-22 | 2014-01-29 | Amgen Inc. | Azole compounds as pim inhibitors |
| HUE049377T2 (hu) | 2013-03-14 | 2020-09-28 | Brigham & Womens Hospital Inc | Készítmények és eljárások epiteliális õssejtek expanziójára és tenyésztésére |
| JP2017524739A (ja) | 2014-07-17 | 2017-08-31 | アンセルムＩｎｓｅｒｍ | 神経筋接合部関連疾患の処置方法 |
| CN107073042A (zh) | 2014-09-03 | 2017-08-18 | 布里格海姆妇女医院公司 | 用于产生内耳毛细胞来治疗听力损失的组合物、系统和方法 |
| WO2016207366A1 (en) | 2015-06-26 | 2016-12-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment of viral infections |
| GB201519573D0 (en) | 2015-11-05 | 2015-12-23 | King S College London | Combination |
| JP2019506153A (ja) | 2016-01-08 | 2019-03-07 | マサチューセッツ インスティテュート オブ テクノロジー | 分化した腸内分泌細胞およびインスリン産生細胞の作製 |
| US11260130B2 (en) | 2016-03-02 | 2022-03-01 | Frequency Therapeutics, Inc. | Solubilized compositions for controlled proliferation of stem cells / generating inner ear hair cells using a GSK3 inhibitor: IV |
| US10213511B2 (en) | 2016-03-02 | 2019-02-26 | Frequency Therapeutics, Inc. | Thermoreversible compositions for administration of therapeutic agents |
| US10201540B2 (en) | 2016-03-02 | 2019-02-12 | Frequency Therapeutics, Inc. | Solubilized compositions for controlled proliferation of stem cells / generating inner ear hair cells using GSK3 inhibitors: I |
| RU2648820C2 (ru) * | 2016-04-14 | 2018-03-28 | Общество с ограниченной ответственностью "Научно-исследовательский центр "Парк активных молекул" | Средство, обладающее противоклоногенной активностью в отношении опухолевых клеток человека |
| AU2017386417B2 (en) | 2016-12-30 | 2022-07-14 | Frequency Therapeutics, Inc. | 1H-pyrrole-2,5-dione compounds and methods of using them to induce self-renewal of stem/progenitor supporting cells |
| CN108440401A (zh) * | 2018-04-13 | 2018-08-24 | 华东理工大学 | 5-[(4-乙基哌嗪-1-基)甲基]吡啶-2-胺的制备方法 |
| EP3837351A1 (en) | 2018-08-17 | 2021-06-23 | Frequency Therapeutics, Inc. | Compositions and methods for generating hair cells by downregulating foxo |
| AU2019321641A1 (en) | 2018-08-17 | 2021-04-15 | Frequency Therapeutics, Inc. | Compositions and methods for generating hair cells by upregulating Jag-1 |
| JP2022520671A (ja) | 2019-02-08 | 2022-03-31 | フリークエンシー・セラピューティクス・インコーポレイテッド | 耳障害を治療するためのバルプロ酸化合物及びｗｎｔ作動薬 |
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| NZ192948A (en) * | 1979-03-09 | 1982-02-23 | Ishihara Sangyo Kaisha | Preparation of beta-trifuloromethyl-pyridine derivatives directly from beta-picoline |
| US5710158A (en) | 1991-05-10 | 1998-01-20 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Aryl and heteroaryl quinazoline compounds which inhibit EGF and/or PDGF receptor tyrosine kinase |
| US5565580A (en) | 1994-01-27 | 1996-10-15 | Neurosearch A/S | Glutamate Antagonists |
| JP2890267B2 (ja) | 1994-02-23 | 1999-05-10 | ファイザー インク． | ４−ヘテロサイクリル−置換キナゾリン誘導体、その調製法および抗癌剤としてのその使用法 |
| TW574214B (en) | 1994-06-08 | 2004-02-01 | Pfizer | Corticotropin releasing factor antagonists |
| GB9707800D0 (en) * | 1996-05-06 | 1997-06-04 | Zeneca Ltd | Chemical compounds |
| DE69838172T2 (de) * | 1997-08-22 | 2008-04-10 | Astrazeneca Ab | Oxindolylchinazolinderivate als angiogenesehemmer |
| AU5301199A (en) | 1998-08-20 | 2000-03-14 | Sumitomo Pharmaceuticals Company, Limited | Oxindole derivatives as growth hormone releasers |
| WO2000071129A1 (en) | 1999-05-21 | 2000-11-30 | Bristol-Myers Squibb Company | Pyrrolotriazine inhibitors of kinases |
| AU770600B2 (en) * | 1999-10-07 | 2004-02-26 | Amgen, Inc. | Triazine kinase inhibitors |
| US6455525B1 (en) | 1999-11-04 | 2002-09-24 | Cephalon, Inc. | Heterocyclic substituted pyrazolones |
| EP1136493A1 (en) | 2000-03-23 | 2001-09-26 | Sanofi-Synthelabo | 2-(Thienopyridinyl)pyrimidone, 2-(furopyridinyl)pyrimidone 2-(isoquinolinyl)pyrimidone, 2-(pyridoindolyl)pyrimidone and 2-(benzofuropyridinyl)pyrimidone derivatives |
| ATE284885T1 (de) * | 2000-07-27 | 2005-01-15 | Hoffmann La Roche | 3-indolyl-4-phenyl-1h-pyrrol-2,5-dion derivate als glycogen synthase kinase 3beta inhibitoren |
| HUP0303559A3 (en) | 2000-10-13 | 2006-02-28 | Bristol Myers Squibb Co | Selective maxi-k-potassium channel openers functional under conditions of high intracellular calcium concentration and uses thereof |
| SE0104341D0 (sv) * | 2001-12-20 | 2001-12-20 | Astrazeneca Ab | New use |
| SE0104340D0 (sv) * | 2001-12-20 | 2001-12-20 | Astrazeneca Ab | New compounds |
| TW200301123A (en) * | 2001-12-21 | 2003-07-01 | Astrazeneca Uk Ltd | New use |
| DE60221283T2 (de) * | 2001-12-21 | 2008-03-20 | Astrazeneca Ab | Verwendung von oxindolderivaten zur behandlung von mit demenz in zusammenhang stehenden krankheiten, alzheimer-krankheit und mit glycogensynthasekinase-3 assoziierten leiden |
| SE0302546D0 (sv) * | 2003-09-24 | 2003-09-24 | Astrazeneca Ab | New compounds |
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