CA1194871A - 1-phenyl-2(1h,3h)-indolone psycho-therapeutic agents - Google Patents
1-phenyl-2(1h,3h)-indolone psycho-therapeutic agentsInfo
- Publication number
- CA1194871A CA1194871A CA000436845A CA436845A CA1194871A CA 1194871 A CA1194871 A CA 1194871A CA 000436845 A CA000436845 A CA 000436845A CA 436845 A CA436845 A CA 436845A CA 1194871 A CA1194871 A CA 1194871A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- hydrogen
- compound
- indolone
- reaction
- Prior art date
- 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
Links
- OWPNVXATCSXTBK-UHFFFAOYSA-N 1-phenyl-3h-indol-2-one Chemical compound O=C1CC2=CC=CC=C2N1C1=CC=CC=C1 OWPNVXATCSXTBK-UHFFFAOYSA-N 0.000 title description 2
- 239000003814 drug Substances 0.000 title description 2
- 229940124597 therapeutic agent Drugs 0.000 title 1
- 238000000034 method Methods 0.000 claims description 168
- 150000001875 compounds Chemical class 0.000 claims description 145
- 229910052739 hydrogen Inorganic materials 0.000 claims description 141
- 239000001257 hydrogen Substances 0.000 claims description 136
- 235000013350 formula milk Nutrition 0.000 claims description 126
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 82
- -1 1,3-propylene, 1,4-butylene Chemical group 0.000 claims description 74
- 238000006243 chemical reaction Methods 0.000 claims description 63
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 47
- 239000007858 starting material Substances 0.000 claims description 38
- 150000002431 hydrogen Chemical class 0.000 claims description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- 239000012442 inert solvent Substances 0.000 claims description 35
- FGFUBBNNYLNVLJ-UHFFFAOYSA-N indolone Natural products C1=CC=C2C(=O)C=NC2=C1 FGFUBBNNYLNVLJ-UHFFFAOYSA-N 0.000 claims description 33
- QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical compound C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 claims description 30
- 238000002360 preparation method Methods 0.000 claims description 29
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 27
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 25
- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 18
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 17
- 125000001153 fluoro group Chemical group F* 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 17
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
- GRHZRAGCCPFBLA-UHFFFAOYSA-N 3-(dimethylaminomethylidene)-1h-indol-2-one Chemical compound C1=CC=C2C(=CN(C)C)C(=O)NC2=C1 GRHZRAGCCPFBLA-UHFFFAOYSA-N 0.000 claims description 11
- 150000001408 amides Chemical class 0.000 claims description 11
- 125000001246 bromo group Chemical group Br* 0.000 claims description 11
- 125000003282 alkyl amino group Chemical group 0.000 claims description 10
- 125000004414 alkyl thio group Chemical group 0.000 claims description 10
- 125000003277 amino group Chemical group 0.000 claims description 10
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000002883 imidazolyl group Chemical group 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- 229910052783 alkali metal Inorganic materials 0.000 claims description 7
- 125000005596 alkyl carboxamido group Chemical group 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 6
- 125000005518 carboxamido group Chemical group 0.000 claims description 6
- 239000002168 alkylating agent Substances 0.000 claims description 5
- 229940100198 alkylating agent Drugs 0.000 claims description 5
- 230000029936 alkylation Effects 0.000 claims description 5
- 238000005804 alkylation reaction Methods 0.000 claims description 5
- 125000002346 iodo group Chemical group I* 0.000 claims description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 5
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- WAJSBPBBXCQDNV-UHFFFAOYSA-N 1-(3-fluoro-4-methoxyphenyl)-3-pyrrolidin-2-ylideneindol-2-one Chemical compound C1=C(F)C(OC)=CC=C1N(C1=O)C2=CC=CC=C2C1=C1NCCC1 WAJSBPBBXCQDNV-UHFFFAOYSA-N 0.000 claims description 4
- NRHPFUANXBJPPX-UHFFFAOYSA-N 1-(4-methoxyphenyl)-3-(1-methylpyrrolidin-2-ylidene)indol-2-one Chemical compound C1=CC(OC)=CC=C1N(C1=O)C2=CC=CC=C2C1=C1N(C)CCC1 NRHPFUANXBJPPX-UHFFFAOYSA-N 0.000 claims description 4
- 150000001449 anionic compounds Chemical class 0.000 claims description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 4
- 230000020335 dealkylation Effects 0.000 claims description 4
- 238000006900 dealkylation reaction Methods 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- OZZVVICMSONJND-UHFFFAOYSA-N 3-(1-methylpyrrolidin-2-ylidene)-1h-indol-2-one Chemical compound CN1CCCC1=C1C2=CC=CC=C2NC1=O OZZVVICMSONJND-UHFFFAOYSA-N 0.000 claims description 3
- PNDRDNIFVDEDDI-UHFFFAOYSA-N 5-ethoxy-3,4-dihydro-2h-pyrrole Chemical compound CCOC1=NCCC1 PNDRDNIFVDEDDI-UHFFFAOYSA-N 0.000 claims description 3
- 229910015845 BBr3 Inorganic materials 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- DWNXGZBXFDNKOR-UHFFFAOYSA-N 4-bromo-2-fluoro-1-methoxybenzene Chemical compound COC1=CC=C(Br)C=C1F DWNXGZBXFDNKOR-UHFFFAOYSA-N 0.000 claims description 2
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims 21
- 125000006536 (C1-C2)alkoxy group Chemical group 0.000 claims 14
- 230000001035 methylating effect Effects 0.000 claims 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 3
- IORXXINRTWZAFJ-UHFFFAOYSA-N 1-(3-chloro-4-methoxyphenyl)-3-(dimethylaminomethylidene)indol-2-one Chemical compound C1=C(Cl)C(OC)=CC=C1N1C2=CC=CC=C2C(=CN(C)C)C1=O IORXXINRTWZAFJ-UHFFFAOYSA-N 0.000 claims 3
- OFMIIEDWSUSJHA-UHFFFAOYSA-N 3-(dimethylaminomethylidene)-1-(3-fluoro-4-methoxyphenyl)indol-2-one Chemical compound C1=C(F)C(OC)=CC=C1N1C2=CC=CC=C2C(=CN(C)C)C1=O OFMIIEDWSUSJHA-UHFFFAOYSA-N 0.000 claims 3
- VZEPMNASMUXYAT-UHFFFAOYSA-N 1-(3-fluoro-4-methoxyphenyl)-3-(1-methylpyrrolidin-2-ylidene)indol-2-one Chemical compound C1=C(F)C(OC)=CC=C1N(C1=O)C2=CC=CC=C2C1=C1N(C)CCC1 VZEPMNASMUXYAT-UHFFFAOYSA-N 0.000 claims 2
- AVVRKHDJLFCZQE-UHFFFAOYSA-N 1-(3-fluoro-4-methoxyphenyl)-3h-indol-2-one Chemical compound C1=C(F)C(OC)=CC=C1N1C2=CC=CC=C2CC1=O AVVRKHDJLFCZQE-UHFFFAOYSA-N 0.000 claims 2
- IWVFFVBJTCPIIG-UHFFFAOYSA-N 2,2-dimethoxy-1-methylpyrrolidine Chemical compound COC1(OC)CCCN1C IWVFFVBJTCPIIG-UHFFFAOYSA-N 0.000 claims 1
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 claims 1
- XJMLPDPXMJKTCH-UHFFFAOYSA-N 2-chloro-4-iodo-1-methoxybenzene Chemical compound COC1=CC=C(I)C=C1Cl XJMLPDPXMJKTCH-UHFFFAOYSA-N 0.000 claims 1
- 230000011987 methylation Effects 0.000 claims 1
- 238000007069 methylation reaction Methods 0.000 claims 1
- 150000004040 pyrrolidinones Chemical class 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 23
- 230000000694 effects Effects 0.000 abstract description 13
- 201000000980 schizophrenia Diseases 0.000 abstract description 13
- 239000003176 neuroleptic agent Substances 0.000 abstract description 6
- 230000003389 potentiating effect Effects 0.000 abstract description 5
- 206010015037 epilepsy Diseases 0.000 abstract description 4
- 239000003445 gaba agent Substances 0.000 abstract description 3
- 208000019901 Anxiety disease Diseases 0.000 abstract description 2
- 230000036506 anxiety Effects 0.000 abstract description 2
- XRKBWYMXJJLQTN-UHFFFAOYSA-N 1-phenyl-3-pyrrolidin-2-ylideneindol-2-one Chemical class O=C1N(C=2C=CC=CC=2)C2=CC=CC=C2C1=C1CCCN1 XRKBWYMXJJLQTN-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 186
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 105
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 83
- 239000000047 product Substances 0.000 description 78
- 229940093499 ethyl acetate Drugs 0.000 description 60
- 235000019439 ethyl acetate Nutrition 0.000 description 60
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 49
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 37
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- 239000000203 mixture Substances 0.000 description 28
- 238000004587 chromatography analysis Methods 0.000 description 27
- 229910001868 water Inorganic materials 0.000 description 26
- 239000007787 solid Substances 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 14
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 9
- 238000001953 recrystallisation Methods 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 125000003118 aryl group Chemical group 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- DKIDEFUBRARXTE-UHFFFAOYSA-N 3-mercaptopropanoic acid Chemical compound OC(=O)CCS DKIDEFUBRARXTE-UHFFFAOYSA-N 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 7
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 229960001701 chloroform Drugs 0.000 description 7
- 230000003371 gabaergic effect Effects 0.000 description 7
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 7
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 206010010904 Convulsion Diseases 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical class C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- FBZVZUSVGKOWHG-UHFFFAOYSA-N 1,1-dimethoxy-n,n-dimethylethanamine Chemical compound COC(C)(OC)N(C)C FBZVZUSVGKOWHG-UHFFFAOYSA-N 0.000 description 4
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000002249 anxiolytic agent Substances 0.000 description 4
- 230000000949 anxiolytic effect Effects 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 230000036461 convulsion Effects 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 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 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000006254 arylation reaction Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229940000425 combination drug Drugs 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 150000005624 indolones Chemical class 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- UZZNUBBBIPNJQU-UHFFFAOYSA-N 1-(4-methoxyphenyl)-3h-indol-2-one Chemical compound C1=CC(OC)=CC=C1N1C2=CC=CC=C2CC1=O UZZNUBBBIPNJQU-UHFFFAOYSA-N 0.000 description 2
- MPEOPBCQHNWNFB-UHFFFAOYSA-N 1-chloro-2-iodobenzene Chemical compound ClC1=CC=CC=C1I MPEOPBCQHNWNFB-UHFFFAOYSA-N 0.000 description 2
- JMLWXCJXOYDXRN-UHFFFAOYSA-N 1-chloro-3-iodobenzene Chemical compound ClC1=CC=CC(I)=C1 JMLWXCJXOYDXRN-UHFFFAOYSA-N 0.000 description 2
- RSHBAGGASAJQCH-UHFFFAOYSA-N 1-iodo-3-methoxybenzene Chemical compound COC1=CC=CC(I)=C1 RSHBAGGASAJQCH-UHFFFAOYSA-N 0.000 description 2
- XRTDVSABOWNTDF-UHFFFAOYSA-N 3-(imidazol-1-ylmethylidene)-1-phenylindol-2-one Chemical compound O=C1N(C=2C=CC=CC=2)C2=CC=CC=C2C1=CN1C=CN=C1 XRTDVSABOWNTDF-UHFFFAOYSA-N 0.000 description 2
- STXAVEHFKAXGOX-UHFFFAOYSA-N 3-bromobenzonitrile Chemical group BrC1=CC=CC(C#N)=C1 STXAVEHFKAXGOX-UHFFFAOYSA-N 0.000 description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 2
- QJPJQTDYNZXKQF-UHFFFAOYSA-N 4-bromoanisole Chemical compound COC1=CC=C(Br)C=C1 QJPJQTDYNZXKQF-UHFFFAOYSA-N 0.000 description 2
- CENVPIZOTHULGJ-UHFFFAOYSA-N 6-chloro-1,3-dihydroindol-2-one Chemical compound ClC1=CC=C2CC(=O)NC2=C1 CENVPIZOTHULGJ-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 101150041968 CDC13 gene Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
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- JIKUXBYRTXDNIY-UHFFFAOYSA-N n-methyl-n-phenylformamide Chemical compound O=CN(C)C1=CC=CC=C1 JIKUXBYRTXDNIY-UHFFFAOYSA-N 0.000 description 1
- 239000004533 oil dispersion Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 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
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000036647 reaction Effects 0.000 description 1
- 229940069435 retaine Drugs 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000012265 solid product Substances 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
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Neurology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Neurosurgery (AREA)
- Public Health (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Anesthesiology (AREA)
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Dental Preparations (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/420,544 US4476307A (en) | 1982-09-20 | 1982-09-20 | Heteroylidene indolone compounds |
| US420,544 | 1982-09-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1194871A true CA1194871A (en) | 1985-10-08 |
Family
ID=23666904
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000436845A Expired CA1194871A (en) | 1982-09-20 | 1983-09-16 | 1-phenyl-2(1h,3h)-indolone psycho-therapeutic agents |
Country Status (24)
| Country | Link |
|---|---|
| US (1) | US4476307A (en, 2012) |
| EP (1) | EP0104860B1 (en, 2012) |
| JP (1) | JPS5976058A (en, 2012) |
| KR (1) | KR860001270B1 (en, 2012) |
| AT (1) | ATE25972T1 (en, 2012) |
| AU (1) | AU543115B2 (en, 2012) |
| CA (1) | CA1194871A (en, 2012) |
| DD (1) | DD213211A5 (en, 2012) |
| DE (1) | DE3370325D1 (en, 2012) |
| DK (1) | DK157010C (en, 2012) |
| ES (3) | ES525737A0 (en, 2012) |
| FI (1) | FI77446C (en, 2012) |
| GR (1) | GR79732B (en, 2012) |
| HU (1) | HU189747B (en, 2012) |
| IE (1) | IE55923B1 (en, 2012) |
| IL (1) | IL69758A (en, 2012) |
| NO (1) | NO161557C (en, 2012) |
| NZ (1) | NZ205638A (en, 2012) |
| PH (1) | PH18297A (en, 2012) |
| PL (3) | PL141609B1 (en, 2012) |
| PT (1) | PT77360B (en, 2012) |
| SU (1) | SU1272983A3 (en, 2012) |
| YU (4) | YU189283A (en, 2012) |
| ZA (1) | ZA836933B (en, 2012) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4879391A (en) * | 1982-09-20 | 1989-11-07 | Pfizer Inc. | 1-Phenyl-2(1H,3H)-indolone psychotherapeutic agents |
| US4760083A (en) * | 1986-04-10 | 1988-07-26 | E. I. Dupont De Nemours & Company | 3,3-disubstituted indolines |
| HU217072B (hu) * | 1989-01-10 | 1999-11-29 | Pfizer Inc. | 1-Heteroaril-oxindol-3-karboxamid-származékok, azok előállítása, és az azokat tartalmazó gyógyszerkészítmények |
| US5078756A (en) * | 1990-01-12 | 1992-01-07 | Major Thomas O | Apparatus and method for purification and recovery of refrigerant |
| US5158969A (en) * | 1991-08-21 | 1992-10-27 | Neurosearch A/S | Indole derivatives as potassium channel blockers |
| US5760250A (en) * | 1991-11-05 | 1998-06-02 | Zeneca Limited | Process for the preparation of 3-(α-methoxy)methylenebenzofuranones and intermediates therefor |
| DE19949209A1 (de) * | 1999-10-13 | 2001-04-19 | Boehringer Ingelheim Pharma | In 5-Stellung substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel |
| JP2005508336A (ja) * | 2001-09-27 | 2005-03-31 | アラーガン、インコーポレイテッド | キナーゼ阻害物質としての３−（アリールアミノ）メチレン−１，３−ジヒドロ−２ｈ−インドール−２−オン類 |
| US20050101788A1 (en) * | 2002-03-27 | 2005-05-12 | Jacopo Zanon | Method for manufacture of sertindole |
| FR2847811B1 (fr) * | 2002-11-29 | 2005-01-07 | Oreal | Composition filtrante contenant au moins un derive du dibenzoylmethane et au moins un derive de 3-(2-azacycloalkylidene)-1,3-dihydro-indol-2-one;procede de photostabilisation |
| FR2847813A1 (fr) * | 2002-11-29 | 2004-06-04 | Oreal | Compositions cosmetiques photoprotectrices contenant des derives de 3-(2-azacycloalkylidene)-1,3-dihydro-indol-2-one et utilisations |
| MX2007014114A (es) | 2005-05-10 | 2008-03-14 | Intermune Inc | Derivados de piridona para modular el sistema de proteina cinasa activada por estres. |
| JP5627574B2 (ja) | 2008-06-03 | 2014-11-19 | インターミューン， インコーポレイテッド | 炎症性および線維性疾患を治療するための化合物および方法 |
| HRP20141067T1 (hr) | 2008-12-19 | 2015-01-02 | Nippon Soda Co., Ltd. | Derivat 1-heterodiena i sredstvo za kontrolu štetnih organizama |
| CN102596931B (zh) | 2009-11-12 | 2014-07-02 | 日本曹达株式会社 | 1-杂原子二烯衍生物和有害生物防除剂 |
| AR092742A1 (es) | 2012-10-02 | 2015-04-29 | Intermune Inc | Piridinonas antifibroticas |
| HK1215170A1 (zh) | 2012-11-14 | 2016-08-19 | The Johns Hopkins University | 治療精神分裂症的方法和組合物 |
| KR102373700B1 (ko) | 2014-04-02 | 2022-03-11 | 인터뮨, 인크. | 항섬유성 피리디논 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3506683A (en) * | 1963-10-07 | 1970-04-14 | Upjohn Co | 3-(2-pyrrolidinylidene)-3h-indoles |
| GB1237008A (en) * | 1968-12-18 | 1971-06-30 | Pfizer Ltd | Novel indoline derivatives |
| US3723457A (en) * | 1969-09-30 | 1973-03-27 | Eisai Co Ltd | Indoline-2-one derivatives and preparation thereof |
| GB1374414A (en) * | 1972-06-12 | 1974-11-20 | Sterling Drug Inc | 1-acyl-3-amino-alkyl-indoles and their preparation |
| DE2557342A1 (de) * | 1975-12-19 | 1977-06-30 | Hoechst Ag | Basisch substituierte indolderivate und verfahren zu ihrer herstellung |
-
1982
- 1982-09-20 US US06/420,544 patent/US4476307A/en not_active Expired - Fee Related
-
1983
- 1983-09-16 CA CA000436845A patent/CA1194871A/en not_active Expired
- 1983-09-18 IL IL69758A patent/IL69758A/xx unknown
- 1983-09-19 ES ES525737A patent/ES525737A0/es active Granted
- 1983-09-19 KR KR1019830004396A patent/KR860001270B1/ko not_active Expired
- 1983-09-19 HU HU833235A patent/HU189747B/hu unknown
- 1983-09-19 NO NO833367A patent/NO161557C/no unknown
- 1983-09-19 NZ NZ205638A patent/NZ205638A/en unknown
- 1983-09-19 AU AU19252/83A patent/AU543115B2/en not_active Ceased
- 1983-09-19 DD DD83254923A patent/DD213211A5/de unknown
- 1983-09-19 PT PT77360A patent/PT77360B/pt not_active IP Right Cessation
- 1983-09-19 SU SU833646758A patent/SU1272983A3/ru active
- 1983-09-19 DE DE8383305484T patent/DE3370325D1/de not_active Expired
- 1983-09-19 GR GR72470A patent/GR79732B/el unknown
- 1983-09-19 AT AT83305484T patent/ATE25972T1/de not_active IP Right Cessation
- 1983-09-19 ZA ZA836933A patent/ZA836933B/xx unknown
- 1983-09-19 IE IE2193/83A patent/IE55923B1/en not_active IP Right Cessation
- 1983-09-19 FI FI833335A patent/FI77446C/fi not_active IP Right Cessation
- 1983-09-19 DK DK425383A patent/DK157010C/da not_active IP Right Cessation
- 1983-09-19 EP EP83305484A patent/EP0104860B1/en not_active Expired
- 1983-09-20 PL PL1983243826A patent/PL141609B1/pl unknown
- 1983-09-20 PL PL1983250768A patent/PL141370B1/pl unknown
- 1983-09-20 PL PL1983250769A patent/PL141876B1/pl unknown
- 1983-09-20 PH PH29565A patent/PH18297A/en unknown
- 1983-09-20 JP JP58174025A patent/JPS5976058A/ja active Granted
- 1983-09-20 YU YU01892/83A patent/YU189283A/xx unknown
-
1984
- 1984-04-25 ES ES531908A patent/ES531908A0/es active Granted
- 1984-04-25 ES ES531907A patent/ES8505950A1/es not_active Expired
-
1986
- 1986-10-01 YU YU01692/86A patent/YU169286A/xx unknown
- 1986-10-01 YU YU01693/86A patent/YU169386A/xx unknown
- 1986-10-01 YU YU01691/86A patent/YU169186A/xx unknown
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| Date | Code | Title | Description |
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| MKEC | Expiry (correction) | ||
| MKEX | Expiry |