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 PDF

Info

Publication number: UA79447C2
Authority: UA; Ukraine
Prior art keywords: pyridin; hydroxy; indol; compound; alkyl
Prior art date: 2002-03-28

Application number

UA20040806742A

Other languages

English (en)

Ukrainian (uk)

Inventor

Stefan Berg

Sven Hellberg

Martin Nylof

Yafeng Xue

Original Assignee

Astrazeneca Ab

Priority date (The priority date 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 date listed.)

2002-03-28

Filing date

2003-03-28

Publication date

2007-06-25

2003-03-28 Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab

2007-06-25 Publication of UA79447C2 publication Critical patent/UA79447C2/uk

Links

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
125000000842 isoxazolyl group Chemical group 0.000 description 5
239000002480 mineral oil Substances 0.000 description 5
235000010446 mineral oil Nutrition 0.000 description 5
125000002971 oxazolyl group Chemical group 0.000 description 5
125000003373 pyrazinyl group Chemical group 0.000 description 5
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LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
238000012360 testing method Methods 0.000 description 1
CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 description 1
125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
125000003831 tetrazolyl group Chemical group 0.000 description 1
229940124597 therapeutic agent Drugs 0.000 description 1
125000004568 thiomorpholinyl group Chemical group 0.000 description 1
SYRHIZPPCHMRIT-UHFFFAOYSA-N tin(4+) Chemical compound [Sn+4] SYRHIZPPCHMRIT-UHFFFAOYSA-N 0.000 description 1
210000001519 tissue Anatomy 0.000 description 1
238000000844 transformation Methods 0.000 description 1
125000005270 trialkylamine group Chemical group 0.000 description 1
125000001425 triazolyl group Chemical group 0.000 description 1
CFQJBWKKHCMCGJ-UHFFFAOYSA-N tributyl(pyridin-3-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CN=C1 CFQJBWKKHCMCGJ-UHFFFAOYSA-N 0.000 description 1
UKTDFYOZPFNQOQ-UHFFFAOYSA-N tributyl(thiophen-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CS1 UKTDFYOZPFNQOQ-UHFFFAOYSA-N 0.000 description 1
ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
238000001665 trituration Methods 0.000 description 1
208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
229920002554 vinyl polymer Polymers 0.000 description 1
238000005406 washing Methods 0.000 description 1

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- 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
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- 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
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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
- C07D405/14—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 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
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- 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

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Health & Medical Sciences (AREA)
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Engineering & Computer Science (AREA)
Chemical Kinetics & Catalysis (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Pharmacology & Pharmacy (AREA)
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Heart & Thoracic Surgery (AREA)
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Orthopedic Medicine & Surgery (AREA)
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UA20040806742A 2002-03-28 2003-03-28 Indole derivates, pharmaceutical composition based thereon, process for their preparation (variants), intermediate compound UA79447C2 (en)

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Application Number	Priority Date	Filing Date	Title
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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UA20040806742A UA79447C2 (en)	2002-03-28	2003-03-28	Indole derivates, pharmaceutical composition based thereon, process for their preparation (variants), intermediate compound

Country Status (31)

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US (2)	US7399780B2 (de)
EP (2)	EP1961748A3 (de)
JP (2)	JP3989444B2 (de)
KR (1)	KR101014525B1 (de)
CN (2)	CN100519550C (de)
AR (1)	AR038996A1 (de)
AT (1)	ATE416171T1 (de)
AU (1)	AU2003216026B2 (de)
BR (1)	BR0308196A (de)
CA (1)	CA2476343C (de)
CY (1)	CY1108823T1 (de)
DE (1)	DE60325032D1 (de)
DK (1)	DK1492785T3 (de)
ES (1)	ES2316784T3 (de)
IL (2)	IL163894A0 (de)
IS (1)	IS7471A (de)
MX (1)	MXPA04009163A (de)
MY (1)	MY144659A (de)
NO (1)	NO329884B1 (de)
NZ (1)	NZ534664A (de)
PL (1)	PL211096B1 (de)
PT (1)	PT1492785E (de)
RU (1)	RU2338742C2 (de)
SA (1)	SA03240054B1 (de)
SE (1)	SE0200979D0 (de)
SI (1)	SI1492785T1 (de)
TW (1)	TWI330081B (de)
UA (1)	UA79447C2 (de)
UY (1)	UY27740A1 (de)
WO (1)	WO2003082853A1 (de)
ZA (1)	ZA200407665B (de)

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Publication number	Publication date
KR20040094884A (ko)	2004-11-10
PL372966A1 (en)	2005-08-08
CY1108823T1 (el)	2014-04-09
EP1961748A2 (de)	2008-08-27
ES2316784T3 (es)	2009-04-16
CN1642938A (zh)	2005-07-20
AR038996A1 (es)	2005-02-02
AU2003216026A1 (en)	2003-10-13
NO20044432L (no)	2004-10-19
JP2007224051A (ja)	2007-09-06
UY27740A1 (es)	2003-10-31
DK1492785T3 (da)	2009-03-02
NO329884B1 (no)	2011-01-17
WO2003082853A8 (en)	2004-05-06
CA2476343C (en)	2011-05-03
CA2476343A1 (en)	2003-10-09
CN1923812A (zh)	2007-03-07
CN100519550C (zh)	2009-07-29
JP3989444B2 (ja)	2007-10-10
SI1492785T1 (sl)	2009-06-30
IL163894A (en)	2010-11-30
EP1961748A3 (de)	2009-10-07
US20050153987A1 (en)	2005-07-14
RU2004125146A (ru)	2005-06-27
TW200306180A (en)	2003-11-16
HK1071360A1 (en)	2005-07-15
IL163894A0 (en)	2005-12-18
US7399780B2 (en)	2008-07-15
RU2338742C2 (ru)	2008-11-20
PT1492785E (pt)	2009-02-02
WO2003082853A1 (en)	2003-10-09
SE0200979D0 (sv)	2002-03-28
BR0308196A (pt)	2005-01-11
NZ534664A (en)	2007-06-29
KR101014525B1 (ko)	2011-02-14
DE60325032D1 (de)	2009-01-15
TWI330081B (en)	2010-09-11
US20090149460A1 (en)	2009-06-11
ZA200407665B (en)	2005-08-29
MY144659A (en)	2011-10-31
AU2003216026B2 (en)	2008-12-11
SA03240054B1 (ar)	2009-04-04
EP1492785A1 (de)	2005-01-05
JP2005526814A (ja)	2005-09-08
MXPA04009163A (es)	2004-12-07
ATE416171T1 (de)	2008-12-15
EP1492785B9 (de)	2009-10-21
IS7471A (is)	2004-10-15
PL211096B1 (pl)	2012-04-30
EP1492785B1 (de)	2008-12-03

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