HU194168B - Process for producing 1-substituted, condensed indolo-3-carboxamide derivatives - Google Patents
Process for producing 1-substituted, condensed indolo-3-carboxamide derivatives Download PDFInfo
- Publication number
- HU194168B HU194168B HU854158A HU415885A HU194168B HU 194168 B HU194168 B HU 194168B HU 854158 A HU854158 A HU 854158A HU 415885 A HU415885 A HU 415885A HU 194168 B HU194168 B HU 194168B
- Authority
- HU
- Hungary
- Prior art keywords
- ethyl
- formula
- methyl
- mmol
- oxindole
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 15
- 229940053202 antiepileptics carboxamide derivative Drugs 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 239000012948 isocyanate Substances 0.000 claims abstract description 7
- 150000002513 isocyanates Chemical class 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 73
- -1 phenylacetyl Chemical group 0.000 claims description 42
- 150000001875 compounds Chemical class 0.000 claims description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 36
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 12
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000004212 difluorophenyl group Chemical group 0.000 claims description 6
- 125000006501 nitrophenyl group Chemical group 0.000 claims description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims 3
- 239000003849 aromatic solvent Substances 0.000 claims 2
- 239000000463 material Substances 0.000 claims 2
- 125000003944 tolyl group Chemical group 0.000 claims 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims 1
- 150000008046 alkali metal hydrides Chemical class 0.000 claims 1
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 abstract description 19
- 125000004095 oxindolyl group Chemical class N1(C(CC2=CC=CC=C12)=O)* 0.000 abstract description 6
- 239000002260 anti-inflammatory agent Substances 0.000 abstract description 5
- 229940121363 anti-inflammatory agent Drugs 0.000 abstract description 5
- 238000007098 aminolysis reaction Methods 0.000 abstract description 2
- 150000002576 ketones Chemical class 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 168
- 229910052757 nitrogen Inorganic materials 0.000 description 66
- 239000011541 reaction mixture Substances 0.000 description 60
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 58
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 51
- 239000000047 product Substances 0.000 description 48
- 239000000203 mixture Substances 0.000 description 43
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 34
- 239000000243 solution Substances 0.000 description 26
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- 238000004458 analytical method Methods 0.000 description 22
- 238000000921 elemental analysis Methods 0.000 description 21
- 239000012044 organic layer Substances 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 17
- 235000019341 magnesium sulphate Nutrition 0.000 description 17
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 16
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000005457 ice water Substances 0.000 description 13
- 238000010992 reflux Methods 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 11
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-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 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 9
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 9
- 239000002808 molecular sieve Substances 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Substances [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- VSMXLKGFTKFOSB-UHFFFAOYSA-N 1-ethyl-3h-indol-2-one Chemical compound C1=CC=C2N(CC)C(=O)CC2=C1 VSMXLKGFTKFOSB-UHFFFAOYSA-N 0.000 description 4
- WNZQDUSMALZDQF-UHFFFAOYSA-N 2-benzofuran-1(3H)-one Chemical compound C1=CC=C2C(=O)OCC2=C1 WNZQDUSMALZDQF-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- RFSNEPQSTGBYAX-UHFFFAOYSA-N ethyl 7-acetyl-2-oxo-1,3-dihydroindole-3-carboxylate Chemical compound C1=CC=C(C(C)=O)C2=C1C(C(=O)OCC)C(=O)N2 RFSNEPQSTGBYAX-UHFFFAOYSA-N 0.000 description 4
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 4
- 229920002554 vinyl polymer Polymers 0.000 description 4
- CEPCPXLLFXPZGW-UHFFFAOYSA-N 2,4-difluoroaniline Chemical compound NC1=CC=C(F)C=C1F CEPCPXLLFXPZGW-UHFFFAOYSA-N 0.000 description 3
- UYINJAQCJCYCGO-UHFFFAOYSA-N 2-oxo-3h-indole-1-carboxamide Chemical class C1=CC=C2N(C(=O)N)C(=O)CC2=C1 UYINJAQCJCYCGO-UHFFFAOYSA-N 0.000 description 3
- HFLGZTLNWGZCBU-UHFFFAOYSA-N 7-benzoyl-1-methyl-3h-indol-2-one Chemical compound C=12N(C)C(=O)CC2=CC=CC=1C(=O)C1=CC=CC=C1 HFLGZTLNWGZCBU-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-DYCDLGHISA-M Sodium hydroxide-d Chemical compound [Na+].[2H][O-] HEMHJVSKTPXQMS-DYCDLGHISA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 3
- 230000008961 swelling Effects 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- BAKCAJPZNKHTFX-UHFFFAOYSA-N (1-methylindol-7-yl)-phenylmethanone Chemical compound C=12N(C)C=CC2=CC=CC=1C(=O)C1=CC=CC=C1 BAKCAJPZNKHTFX-UHFFFAOYSA-N 0.000 description 2
- BJFCCDMOVSQLQF-UHFFFAOYSA-N 1-(1h-indol-7-yl)ethanone Chemical compound CC(=O)C1=CC=CC2=C1NC=C2 BJFCCDMOVSQLQF-UHFFFAOYSA-N 0.000 description 2
- HNENEALJPWJWJY-UHFFFAOYSA-N 2,4-difluoro-1-isocyanatobenzene Chemical compound FC1=CC=C(N=C=O)C(F)=C1 HNENEALJPWJWJY-UHFFFAOYSA-N 0.000 description 2
- MXVAMFYSKAUGSC-UHFFFAOYSA-N 2-(4-benzoyl-2-nitrophenyl)acetic acid Chemical compound C1=C([N+]([O-])=O)C(CC(=O)O)=CC=C1C(=O)C1=CC=CC=C1 MXVAMFYSKAUGSC-UHFFFAOYSA-N 0.000 description 2
- CFFMNUHNAJAPJY-UHFFFAOYSA-N 2-[(1-ethyl-2-oxo-3h-indol-5-yl)oxymethyl]benzoic acid Chemical compound C=1C=C2N(CC)C(=O)CC2=CC=1OCC1=CC=CC=C1C(O)=O CFFMNUHNAJAPJY-UHFFFAOYSA-N 0.000 description 2
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 description 2
- FBEJRZLRAAQFHZ-UHFFFAOYSA-N 5-(cyclopropanecarbonyl)-1-ethyl-3h-indol-2-one Chemical compound C=1C=C2N(CC)C(=O)CC2=CC=1C(=O)C1CC1 FBEJRZLRAAQFHZ-UHFFFAOYSA-N 0.000 description 2
- ZBBRHDRTJXCEOR-UHFFFAOYSA-N 5-acetyl-n-(2,4-difluorophenyl)-1-ethyl-2-oxo-3h-indole-3-carboxamide Chemical compound C12=CC(C(C)=O)=CC=C2N(CC)C(=O)C1C(=O)NC1=CC=C(F)C=C1F ZBBRHDRTJXCEOR-UHFFFAOYSA-N 0.000 description 2
- RGNSDWVDANBDBE-UHFFFAOYSA-N 5-benzoyl-1-ethyl-3h-indol-2-one Chemical compound C=1C=C2N(CC)C(=O)CC2=CC=1C(=O)C1=CC=CC=C1 RGNSDWVDANBDBE-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound 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 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 125000001589 carboacyl group Chemical group 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- GRTGGSXWHGKRSB-UHFFFAOYSA-N dichloromethyl methyl ether Chemical compound COC(Cl)Cl GRTGGSXWHGKRSB-UHFFFAOYSA-N 0.000 description 2
- MYHLFAGJBNGCLE-UHFFFAOYSA-N dimethyl 1-ethyl-2-oxo-3h-indole-3,5-dicarboxylate Chemical compound COC(=O)C1=CC=C2N(CC)C(=O)C(C(=O)OC)C2=C1 MYHLFAGJBNGCLE-UHFFFAOYSA-N 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- SJNJERVZPASIFJ-UHFFFAOYSA-N ethyl 2-(2-amino-4-benzoylphenyl)acetate Chemical compound C1=C(N)C(CC(=O)OCC)=CC=C1C(=O)C1=CC=CC=C1 SJNJERVZPASIFJ-UHFFFAOYSA-N 0.000 description 2
- XLWFXOWSCOJHIJ-UHFFFAOYSA-N ethyl 2-(4-benzoyl-2-nitrophenyl)acetate Chemical compound C1=C([N+]([O-])=O)C(CC(=O)OCC)=CC=C1C(=O)C1=CC=CC=C1 XLWFXOWSCOJHIJ-UHFFFAOYSA-N 0.000 description 2
- TWUIQAPIXFMUOE-UHFFFAOYSA-N ethyl 5-(cyclopropanecarbonyl)-1-ethyl-2-oxo-3h-indole-3-carboxylate Chemical compound C1=C2C(C(=O)OCC)C(=O)N(CC)C2=CC=C1C(=O)C1CC1 TWUIQAPIXFMUOE-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- YQXSAMMOFCKADF-UHFFFAOYSA-N methyl 1-ethyl-2-oxo-3h-indole-5-carboxylate Chemical compound COC(=O)C1=CC=C2N(CC)C(=O)CC2=C1 YQXSAMMOFCKADF-UHFFFAOYSA-N 0.000 description 2
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 150000005623 oxindoles Chemical class 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 2
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- OWHHXUSYXDDFOJ-UHFFFAOYSA-N ethyl 3-[(2,4-difluorophenyl)carbamoyl]-1-ethyl-2-oxo-3h-indole-5-carboxylate Chemical compound C12=CC(C(=O)OCC)=CC=C2N(CC)C(=O)C1C(=O)NC1=CC=C(F)C=C1F OWHHXUSYXDDFOJ-UHFFFAOYSA-N 0.000 description 1
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- 238000006460 hydrolysis reaction Methods 0.000 description 1
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- SQQMAOCOWKFBNP-UHFFFAOYSA-L manganese(II) sulfate Chemical compound [Mn+2].[O-]S([O-])(=O)=O SQQMAOCOWKFBNP-UHFFFAOYSA-L 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
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- 229910044991 metal oxide Inorganic materials 0.000 description 1
- FBBDOOHMGLLEGJ-UHFFFAOYSA-N methane;hydrochloride Chemical compound C.Cl FBBDOOHMGLLEGJ-UHFFFAOYSA-N 0.000 description 1
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- RGJFWTBTCRJGAO-UHFFFAOYSA-N methyl 1-ethyl-5-(4-methylbenzoyl)-2-oxo-3h-indole-3-carboxylate Chemical compound C=1C=C2N(CC)C(=O)C(C(=O)OC)C2=CC=1C(=O)C1=CC=C(C)C=C1 RGJFWTBTCRJGAO-UHFFFAOYSA-N 0.000 description 1
- SIGOIUCRXKUEIG-UHFFFAOYSA-N methyl 2-dimethoxyphosphorylacetate Chemical compound COC(=O)CP(=O)(OC)OC SIGOIUCRXKUEIG-UHFFFAOYSA-N 0.000 description 1
- ARIZWXYQSBBGPE-UHFFFAOYSA-N methyl 3-(1-ethyl-2-oxo-3h-indol-5-yl)propanoate Chemical compound COC(=O)CCC1=CC=C2N(CC)C(=O)CC2=C1 ARIZWXYQSBBGPE-UHFFFAOYSA-N 0.000 description 1
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- 229960002702 piroxicam Drugs 0.000 description 1
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- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
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- 230000003389 potentiating effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- 150000003839 salts Chemical class 0.000 description 1
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- 239000000375 suspending agent Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/70—[b]- or [c]-condensed containing carbocyclic rings other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—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 two hetero rings
- C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/666,953 US4644005A (en) | 1984-10-31 | 1984-10-31 | Oxindole antiinflammatory agents |
| US06/762,998 US4686224A (en) | 1984-10-31 | 1985-08-06 | Oxindole antiinflammatory agents |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HUT39428A HUT39428A (en) | 1986-09-29 |
| HU194168B true HU194168B (en) | 1988-01-28 |
Family
ID=27099577
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HU854158A HU194168B (en) | 1984-10-31 | 1985-10-30 | Process for producing 1-substituted, condensed indolo-3-carboxamide derivatives |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US4686224A (en, 2012) |
| EP (1) | EP0181136B1 (en, 2012) |
| KR (1) | KR870001269B1 (en, 2012) |
| AU (1) | AU555051B2 (en, 2012) |
| CA (1) | CA1247099A (en, 2012) |
| DE (1) | DE3585719D1 (en, 2012) |
| DK (1) | DK163990C (en, 2012) |
| ES (1) | ES8707731A1 (en, 2012) |
| FI (1) | FI81340C (en, 2012) |
| GR (1) | GR852629B (en, 2012) |
| HU (1) | HU194168B (en, 2012) |
| IE (1) | IE58207B1 (en, 2012) |
| IL (1) | IL76854A (en, 2012) |
| PH (3) | PH20985A (en, 2012) |
| PL (2) | PL150842B1 (en, 2012) |
| PT (1) | PT81393B (en, 2012) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU217072B (hu) * | 1989-01-10 | 1999-11-29 | Pfizer Inc. | 1-Heteroaril-oxindol-3-karboxamid-származékok, azok előállítása, és az azokat tartalmazó gyógyszerkészítmények |
| HU215112B (hu) * | 1989-01-10 | 1998-12-28 | Pfizer Inc. | Eljárás gyulladáscsökkentő 1-heteroaril-3-acil-2-oxindol-származékok előállítására |
| JPH0717589B2 (ja) * | 1990-01-22 | 1995-03-01 | ファイザー製薬株式会社 | 新規１，３―ジカルボニル化合物およびその組成物 |
| CH687764A5 (de) * | 1992-07-02 | 1997-02-14 | Lonza Ag Gampel Wallis Geschof | Verfahren zur Herstellung von 7-Acylindolen. |
| US5449788A (en) * | 1994-01-28 | 1995-09-12 | Catalytica, Inc. | Process for preparing 2-oxindole-1-carboxamides |
| GB9414139D0 (en) * | 1994-07-13 | 1994-08-31 | Smithkline Beecham Plc | Novel compounds |
| CN102050758A (zh) | 2000-09-14 | 2011-05-11 | 田边三菱制药株式会社 | 酰胺衍生物及其制备药物的用途 |
| JP2004529110A (ja) | 2001-03-06 | 2004-09-24 | アストラゼネカ アクチボラグ | 脈管損傷活性を有するインドール誘導体 |
| DE60234057D1 (de) | 2001-07-25 | 2009-11-26 | Raptor Pharmaceutical Inc | Zusammensetzungen und verfahren zur modulation des transports durch die blut-hirn-schranke |
| WO2005041957A1 (en) * | 2003-10-29 | 2005-05-12 | Pfizer Products Inc. | Oxindole derivatives and their use as phosphodiesterase type 2 inhibitors |
| DK1889198T3 (da) | 2005-04-28 | 2015-02-09 | Proteus Digital Health Inc | Farma-informatiksystem |
| JP2010503710A (ja) | 2006-09-18 | 2010-02-04 | ラプトール ファーマシューティカル インコーポレイテッド | 受容体関連タンパク質（ｒａｐ）結合体の投与による肝障害の処置 |
| NZ616673A (en) | 2009-02-20 | 2014-08-29 | To Bbb Holding B V | Glutathione-based drug delivery system |
| MX2011011833A (es) | 2009-05-06 | 2012-01-27 | Lab Skin Care Inc | Composiciones de administración dérmica que comprenden complejos de partículas de fosfato de calcio-agente activo y métodos para utilizar las mismas. |
| US20120077778A1 (en) | 2010-09-29 | 2012-03-29 | Andrea Bourdelais | Ladder-Frame Polyether Conjugates |
| CN104130176A (zh) * | 2014-06-13 | 2014-11-05 | 天津科技大学 | 一种1,5-二取代吲哚酮类衍生物及其应用 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE756447A (fr) * | 1969-10-15 | 1971-03-22 | Pfizer | Oxindolecarboxamides |
| US3749731A (en) * | 1971-07-08 | 1973-07-31 | Warner Lambert Co | 2-oxo-n-(2-thiazolyl)-3-indoline-carboxamide |
| DE3114351A1 (de) * | 1981-04-09 | 1982-11-04 | Hoechst Ag, 6000 Frankfurt | "oxindol-derivate, verfahren zu ihrer herstellung und sie enthaltende arzneimittel mit neuroanaboler wirkung" |
| AU8509882A (en) * | 1981-06-30 | 1983-01-06 | Merck & Co., Inc. | Tricyclic derivatives of substituted pyrrole acids |
| DE3582890D1 (de) * | 1984-02-07 | 1991-06-20 | Pfizer | 2-oxindolzwischenprodukte. |
| PT80116B (pt) * | 1984-03-19 | 1987-10-20 | Pfizer | Processo para a producao de 2-oxindole-1-carboxamidas e de intermediarios para esse efeito |
| US4556672A (en) * | 1984-03-19 | 1985-12-03 | Pfizer Inc. | 3-Substituted 2-oxindole-1-carboxamides as analgesic and anti-inflammatory agents |
-
1985
- 1985-08-06 US US06/762,998 patent/US4686224A/en not_active Expired - Lifetime
- 1985-10-28 IL IL76854A patent/IL76854A/xx not_active IP Right Cessation
- 1985-10-29 PL PL1985262327A patent/PL150842B1/pl unknown
- 1985-10-29 DE DE8585307794T patent/DE3585719D1/de not_active Expired - Lifetime
- 1985-10-29 PT PT81393A patent/PT81393B/pt not_active IP Right Cessation
- 1985-10-29 EP EP85307794A patent/EP0181136B1/en not_active Expired - Lifetime
- 1985-10-29 PL PL1985255990A patent/PL145239B1/pl unknown
- 1985-10-30 KR KR1019850008037A patent/KR870001269B1/ko not_active Expired
- 1985-10-30 FI FI854258A patent/FI81340C/fi not_active IP Right Cessation
- 1985-10-30 AU AU49189/85A patent/AU555051B2/en not_active Ceased
- 1985-10-30 DK DK497685A patent/DK163990C/da active
- 1985-10-30 CA CA000494220A patent/CA1247099A/en not_active Expired
- 1985-10-30 HU HU854158A patent/HU194168B/hu not_active IP Right Cessation
- 1985-10-31 GR GR852629A patent/GR852629B/el unknown
- 1985-10-31 PH PH33000A patent/PH20985A/en unknown
- 1985-11-01 IE IE270385A patent/IE58207B1/en not_active IP Right Cessation
-
1986
- 1986-04-30 ES ES554609A patent/ES8707731A1/es not_active Expired
- 1986-12-05 PH PH34562A patent/PH23130A/en unknown
- 1986-12-05 PH PH34563A patent/PH24091A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IE852703L (en) | 1986-04-30 |
| EP0181136B1 (en) | 1992-03-25 |
| DK163990C (da) | 1992-09-21 |
| AU4918985A (en) | 1986-05-08 |
| PL145239B1 (en) | 1988-08-31 |
| KR860003260A (ko) | 1986-05-21 |
| PL150842B1 (en) | 1990-07-31 |
| DK163990B (da) | 1992-04-27 |
| IL76854A (en) | 1989-05-15 |
| DE3585719D1 (de) | 1992-04-30 |
| PT81393A (en) | 1985-11-01 |
| FI854258L (fi) | 1986-05-01 |
| PH20985A (en) | 1987-06-18 |
| ES554609A0 (es) | 1987-08-16 |
| EP0181136A2 (en) | 1986-05-14 |
| PL262327A1 (en) | 1987-11-02 |
| AU555051B2 (en) | 1986-09-11 |
| EP0181136A3 (en) | 1987-10-28 |
| CA1247099A (en) | 1988-12-20 |
| PH24091A (en) | 1990-03-05 |
| IE58207B1 (en) | 1993-07-28 |
| GR852629B (en, 2012) | 1986-03-04 |
| IL76854A0 (en) | 1986-02-28 |
| FI854258A0 (fi) | 1985-10-30 |
| US4686224A (en) | 1987-08-11 |
| ES8707731A1 (es) | 1987-08-16 |
| PL255990A1 (en) | 1987-03-23 |
| FI81340C (fi) | 1990-10-10 |
| HUT39428A (en) | 1986-09-29 |
| KR870001269B1 (ko) | 1987-06-30 |
| DK497685D0 (da) | 1985-10-30 |
| DK497685A (da) | 1986-05-01 |
| PH23130A (en) | 1989-05-05 |
| FI81340B (fi) | 1990-06-29 |
| PT81393B (pt) | 1988-02-17 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| HMM4 | Cancellation of final prot. due to non-payment of fee |