NO300774B1 - Nye triazolpyridazinforbindelser og farmasöytiske sammensetninger - Google Patents
Nye triazolpyridazinforbindelser og farmasöytiske sammensetninger Download PDFInfo
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- NO300774B1 NO300774B1 NO930974A NO930974A NO300774B1 NO 300774 B1 NO300774 B1 NO 300774B1 NO 930974 A NO930974 A NO 930974A NO 930974 A NO930974 A NO 930974A NO 300774 B1 NO300774 B1 NO 300774B1
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- -1 triazole pyridazine compounds Chemical class 0.000 title abstract description 70
- 239000008194 pharmaceutical composition Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 164
- 239000000203 mixture Substances 0.000 claims abstract description 80
- 150000003839 salts Chemical class 0.000 claims abstract description 72
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 33
- 239000000924 antiasthmatic agent Substances 0.000 claims abstract description 8
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 30
- 206010006482 Bronchospasm Diseases 0.000 claims description 13
- 230000007885 bronchoconstriction Effects 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 230000003266 anti-allergic effect Effects 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- 230000001088 anti-asthma Effects 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 3
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- OQGLMJWGJNCHNA-UHFFFAOYSA-N 2-ethyl-2-[(7-methyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)oxymethyl]butane-1-sulfonamide Chemical group C1=C(C)C(OCC(CC)(CC)CS(N)(=O)=O)=NN2N=CN=C21 OQGLMJWGJNCHNA-UHFFFAOYSA-N 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 14
- 150000002367 halogens Chemical class 0.000 abstract description 5
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 4
- 239000001257 hydrogen Substances 0.000 abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 3
- 125000003107 substituted aryl group Chemical group 0.000 abstract description 2
- 125000005346 substituted cycloalkyl group Chemical group 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 89
- 238000006243 chemical reaction Methods 0.000 description 68
- 238000005481 NMR spectroscopy Methods 0.000 description 67
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 50
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 42
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 40
- 238000000921 elemental analysis Methods 0.000 description 37
- 239000002904 solvent Substances 0.000 description 36
- 239000000243 solution Substances 0.000 description 34
- 239000011541 reaction mixture Substances 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 238000000034 method Methods 0.000 description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- 238000001816 cooling Methods 0.000 description 20
- 238000010828 elution Methods 0.000 description 18
- 239000003921 oil Substances 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 238000009835 boiling Methods 0.000 description 15
- XYGZNPKIOSSWBT-UHFFFAOYSA-N 6-chloro-7-methyl-[1,2,4]triazolo[1,5-b]pyridazine Chemical compound N1=C(Cl)C(C)=CC2=NC=NN21 XYGZNPKIOSSWBT-UHFFFAOYSA-N 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 13
- 239000013078 crystal Substances 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 11
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 11
- 239000012312 sodium hydride Substances 0.000 description 11
- 229910000104 sodium hydride Inorganic materials 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- 229910052801 chlorine Inorganic materials 0.000 description 9
- 239000005457 ice water Substances 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
- 229910052794 bromium Inorganic materials 0.000 description 8
- 239000012230 colorless oil Substances 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000012280 lithium aluminium hydride Substances 0.000 description 7
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 7
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 7
- 229940116357 potassium thiocyanate Drugs 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- LUIBHMKLKJNEQI-UHFFFAOYSA-N 3-hydroxy-2,2-dimethylpropane-1-sulfonamide Chemical compound OCC(C)(C)CS(N)(=O)=O LUIBHMKLKJNEQI-UHFFFAOYSA-N 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 241000700199 Cavia porcellus Species 0.000 description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 6
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- WDAXFOBOLVPGLV-UHFFFAOYSA-N ethyl isobutyrate Chemical compound CCOC(=O)C(C)C WDAXFOBOLVPGLV-UHFFFAOYSA-N 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- 239000011630 iodine Substances 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 5
- 125000003341 7 membered heterocyclic group Chemical group 0.000 description 5
- 102100033902 Endothelin-1 Human genes 0.000 description 5
- 101800004490 Endothelin-1 Proteins 0.000 description 5
- GWNVDXQDILPJIG-SHSCPDMUSA-N Leukotriene C4 Natural products CCCCCC=C/CC=C/C=C/C=C/C(SCC(NC(=O)CCC(N)C(=O)O)C(=O)NCC(=O)O)C(O)CCCC(=O)O GWNVDXQDILPJIG-SHSCPDMUSA-N 0.000 description 5
- 108010003541 Platelet Activating Factor Proteins 0.000 description 5
- 235000011054 acetic acid Nutrition 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 230000008030 elimination Effects 0.000 description 5
- 238000003379 elimination reaction Methods 0.000 description 5
- GWNVDXQDILPJIG-NXOLIXFESA-N leukotriene C4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@@H](C(=O)NCC(O)=O)NC(=O)CC[C@H](N)C(O)=O GWNVDXQDILPJIG-NXOLIXFESA-N 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- IBYHHJPAARCAIE-UHFFFAOYSA-N 1-bromo-2-chloroethane Chemical compound ClCCBr IBYHHJPAARCAIE-UHFFFAOYSA-N 0.000 description 4
- UYWWAXSGHPQSIU-UHFFFAOYSA-N 4-hydroxy-3,3-dimethylbutane-1-sulfonamide Chemical compound OCC(C)(C)CCS(N)(=O)=O UYWWAXSGHPQSIU-UHFFFAOYSA-N 0.000 description 4
- DCUYQKGXCADVJO-UHFFFAOYSA-N 6-chloro-2,7-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine Chemical compound C1=C(C)C(Cl)=NN2N=C(C)N=C21 DCUYQKGXCADVJO-UHFFFAOYSA-N 0.000 description 4
- 244000215068 Acacia senegal Species 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 229920000084 Gum arabic Polymers 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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
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- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000000205 acacia gum Substances 0.000 description 4
- 235000010489 acacia gum Nutrition 0.000 description 4
- 150000001340 alkali metals Chemical class 0.000 description 4
- 125000003282 alkyl amino group Chemical group 0.000 description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 4
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 4
- 230000003110 anti-inflammatory effect Effects 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- WHQLQYRFIHPMNA-UHFFFAOYSA-N ethyl acetate;oxolane Chemical compound C1CCOC1.CCOC(C)=O WHQLQYRFIHPMNA-UHFFFAOYSA-N 0.000 description 4
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 4
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- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 241000894007 species Species 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N 1-butanol Substances CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- SSQGPWQKKCMXMW-UHFFFAOYSA-N 4-ethyl-4-(hydroxymethyl)hexane-1-sulfonamide Chemical compound CCC(CC)(CO)CCCS(N)(=O)=O SSQGPWQKKCMXMW-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 208000009079 Bronchial Spasm Diseases 0.000 description 3
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- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 3
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 3
- MJGSLNIPTRPYJV-UHFFFAOYSA-N Ethyl 2-ethylbutanoate Chemical compound CCOC(=O)C(CC)CC MJGSLNIPTRPYJV-UHFFFAOYSA-N 0.000 description 3
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
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- 229920002472 Starch Polymers 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
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- 230000037005 anaesthesia Effects 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- XAZHBYWCBFMIPF-UHFFFAOYSA-N ethyl 2,2-dimethyl-4-sulfamoylbutanoate Chemical compound CCOC(=O)C(C)(C)CCS(N)(=O)=O XAZHBYWCBFMIPF-UHFFFAOYSA-N 0.000 description 3
- ICLWTJIMXVISSR-UHFFFAOYSA-N gallamine Chemical compound CCN(CC)CCOC1=CC=CC(OCCN(CC)CC)=C1OCCN(CC)CC ICLWTJIMXVISSR-UHFFFAOYSA-N 0.000 description 3
- 229960003054 gallamine Drugs 0.000 description 3
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- 238000011597 hartley guinea pig Methods 0.000 description 3
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
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- 239000003937 drug carrier Substances 0.000 description 1
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- DJEVJSGKPPRHCZ-UHFFFAOYSA-N n'-(5-cyano-3,3-dimethylpentyl)sulfonyl-n,n-dimethylmethanimidamide Chemical compound CN(C)C=NS(=O)(=O)CCC(C)(C)CCC#N DJEVJSGKPPRHCZ-UHFFFAOYSA-N 0.000 description 1
- XKQIUMINCFAXLJ-UHFFFAOYSA-N n'-[4-ethyl-4-(hydroxymethyl)hexyl]sulfonyl-n,n-dimethylmethanimidamide Chemical compound CCC(CC)(CO)CCCS(=O)(=O)N=CN(C)C XKQIUMINCFAXLJ-UHFFFAOYSA-N 0.000 description 1
- STJCNEMCFZLJPU-UHFFFAOYSA-N n,n-diethyl-n'-[2-ethyl-2-(hydroxymethyl)butyl]sulfonylmethanimidamide Chemical compound CCN(CC)C=NS(=O)(=O)CC(CC)(CC)CO STJCNEMCFZLJPU-UHFFFAOYSA-N 0.000 description 1
- RGUOJYYIMVSCNC-UHFFFAOYSA-N n,n-dimethylformamide;2-methylpropanoic acid Chemical compound CN(C)C=O.CC(C)C(O)=O RGUOJYYIMVSCNC-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- CNUIZSGSHCFGFC-UHFFFAOYSA-N o-ethyl 5,5-dimethylhexanethioate Chemical compound CCOC(=S)CCCC(C)(C)C CNUIZSGSHCFGFC-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
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- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Immunology (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Plural Heterocyclic Compounds (AREA)
- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6178092 | 1992-03-18 | ||
| JP21890492 | 1992-08-18 | ||
| JP1456093 | 1993-02-01 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO930974D0 NO930974D0 (no) | 1993-03-17 |
| NO930974L NO930974L (no) | 1993-09-20 |
| NO300774B1 true NO300774B1 (no) | 1997-07-21 |
Family
ID=27280691
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO930974A NO300774B1 (no) | 1992-03-18 | 1993-03-17 | Nye triazolpyridazinforbindelser og farmasöytiske sammensetninger |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US5389633A (el) |
| EP (1) | EP0562439B1 (el) |
| CN (1) | CN1040874C (el) |
| AT (1) | ATE181075T1 (el) |
| AU (1) | AU654430B2 (el) |
| CA (1) | CA2091874A1 (el) |
| DE (1) | DE69325199T2 (el) |
| DK (1) | DK0562439T3 (el) |
| EE (1) | EE9400357A (el) |
| ES (1) | ES2132147T3 (el) |
| FI (1) | FI104076B (el) |
| GR (1) | GR3030817T3 (el) |
| HK (1) | HK1009700A1 (el) |
| HU (2) | HU218791B (el) |
| LT (1) | LT3200B (el) |
| LV (1) | LV10456B (el) |
| MY (1) | MY108967A (el) |
| NO (1) | NO300774B1 (el) |
| NZ (1) | NZ247171A (el) |
| PH (1) | PH29998A (el) |
| RU (1) | RU2130458C1 (el) |
| TW (1) | TW255891B (el) |
Families Citing this family (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5464853A (en) * | 1993-05-20 | 1995-11-07 | Immunopharmaceutics, Inc. | N-(5-isoxazolyl)biphenylsulfonamides, N-(3-isoxazolyl)biphenylsulfonamides and derivatives thereof that modulate the activity of endothelin |
| US5594021A (en) * | 1993-05-20 | 1997-01-14 | Texas Biotechnology Corporation | Thienyl-, furyl- and pyrrolyl sulfonamides and derivatives thereof that modulate the activity of endothelin |
| US5962490A (en) | 1987-09-25 | 1999-10-05 | Texas Biotechnology Corporation | Thienyl-, furyl- and pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin |
| US5514691A (en) * | 1993-05-20 | 1996-05-07 | Immunopharmaceutics, Inc. | N-(4-halo-isoxazolyl)-sulfonamides and derivatives thereof that modulate the activity of endothelin |
| US5591761A (en) * | 1993-05-20 | 1997-01-07 | Texas Biotechnology Corporation | Thiophenyl-, furyl-and pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin |
| US5571821A (en) * | 1993-05-20 | 1996-11-05 | Texas Biotechnology Corporation | Sulfonamides and derivatives thereof that modulate the activity of endothelin |
| US5736509A (en) * | 1990-12-14 | 1998-04-07 | Texas Biotechnology Corporation | Cyclic peptide surface feature mimics of endothelin |
| US5482939A (en) * | 1992-03-18 | 1996-01-09 | Takeda Chemical Industries, Ltd. | Triazolopyridazine compounds, their production and use |
| EP0620224B1 (en) * | 1993-04-12 | 1998-07-15 | Takeda Chemical Industries, Ltd. | Triazolopyridazine derivatives, their production and use |
| US6613804B2 (en) | 1993-05-20 | 2003-09-02 | Encysive Pharmaceuticals, Inc. | Biphenylsulfonamides and derivatives thereof that modulate the activity of endothelin |
| US6342610B2 (en) | 1993-05-20 | 2002-01-29 | Texas Biotechnology Corp. | N-aryl thienyl-, furyl-, and pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin |
| US6030991A (en) * | 1993-05-20 | 2000-02-29 | Texas Biotechnology Corp. | Benzenesulfonamides and the use thereof to modulate the activity of endothelin |
| TW304878B (el) * | 1993-09-21 | 1997-05-11 | Takeda Pharm Industry Co Ltd | |
| AU695377B2 (en) * | 1994-09-16 | 1998-08-13 | Takeda Chemical Industries Ltd. | Triazolopyridazines process and intermediates for their preparation and their use as medicaments |
| US5977117A (en) * | 1996-01-05 | 1999-11-02 | Texas Biotechnology Corporation | Substituted phenyl compounds and derivatives thereof that modulate the activity of endothelin |
| US5958905A (en) | 1996-03-26 | 1999-09-28 | Texas Biotechnology Corporation | Phosphoramidates, phosphinic amides and related compounds and the use thereof to modulate the activity of endothelin |
| US5804585A (en) | 1996-04-15 | 1998-09-08 | Texas Biotechnology Corporation | Thieno-pyridine sulfonamides derivatives thereof and related compounds that modulate the activity of endothelin |
| WO1998049167A1 (en) * | 1997-04-25 | 1998-11-05 | Takeda Chemical Industries, Ltd. | Condensed pyridazine derivatives, their production and use |
| US5783705A (en) * | 1997-04-28 | 1998-07-21 | Texas Biotechnology Corporation | Process of preparing alkali metal salys of hydrophobic sulfonamides |
| TR200101905T2 (tr) | 1997-04-28 | 2002-06-21 | Texas Biotechnology Corporation | Endotelin ile ilgili hastalıkların tedavisinde kullanılan sülfanoamidler. |
| CA2319426A1 (en) * | 1998-03-04 | 1999-09-10 | Kenichirou Kiyoshima | Triazolo-pyridazine derivatives for the treatment of chronic obstructive pulmonary diseases |
| AU6003099A (en) | 1998-10-06 | 2000-04-26 | Takeda Chemical Industries Ltd. | Fused pyridazine compounds, process for the preparation of the same and uses thereof |
| ATE256128T1 (de) | 1998-10-21 | 2003-12-15 | Takeda Chemical Industries Ltd | Kondensierte pyridazinderivate, verfahren zu ihrer herstellung und ihre anwendung |
| ES2553588T3 (es) * | 2008-02-05 | 2015-12-10 | Sanofi | Sales de triazolio como inhibidores de PAR1, su preparación y uso como medicamento |
| CN102791715B (zh) | 2009-12-31 | 2016-04-27 | 卡洛斯三世国家癌症研究中心基金会 | 用作激酶抑制剂的三环化合物 |
| WO2012098387A1 (en) | 2011-01-18 | 2012-07-26 | Centro Nacional De Investigaciones Oncológicas (Cnio) | 6, 7-ring-fused triazolo [4, 3 - b] pyridazine derivatives as pim inhibitors |
| WO2013005057A1 (en) | 2011-07-07 | 2013-01-10 | Centro Nacional De Investigaciones Oncológicas (Cnio) | New compounds |
| WO2013004984A1 (en) | 2011-07-07 | 2013-01-10 | Centro Nacional De Investigaciones Oncologicas (Cnio) | Tricyclic compounds for use as kinase inhibitors |
| WO2013005041A1 (en) | 2011-07-07 | 2013-01-10 | Centro Nacional De Investigaciones Oncológicas (Cnio) | Tricyclic heterocyclic compounds as kinase inhibitors |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3915968A (en) | 1973-09-21 | 1975-10-28 | Lepetit Spa | Triazolopyridazines |
| US4136182A (en) | 1976-05-26 | 1979-01-23 | The Dow Chemical Company | Triazolopyridazines used to alleviate bronchial spasms |
| PH27291A (en) * | 1989-01-31 | 1993-05-04 | Takeda Chemical Industries Ltd | Imidazolpyrimidazines their production and use |
| EP0440119A1 (en) * | 1990-01-31 | 1991-08-07 | Takeda Chemical Industries, Ltd. | Imidazopyridazine compounds, their production and use |
| EP0444549B1 (en) * | 1990-03-01 | 1995-01-25 | Takeda Chemical Industries, Ltd. | Imidazopyridazines their production and use |
-
1993
- 1993-03-05 LT LTIP390A patent/LT3200B/lt not_active IP Right Cessation
- 1993-03-06 TW TW082101665A patent/TW255891B/zh active
- 1993-03-10 MY MYPI93000429A patent/MY108967A/en unknown
- 1993-03-12 RU RU93004584A patent/RU2130458C1/ru active
- 1993-03-16 NZ NZ247171A patent/NZ247171A/en unknown
- 1993-03-16 AU AU35269/93A patent/AU654430B2/en not_active Ceased
- 1993-03-17 AT AT93104367T patent/ATE181075T1/de not_active IP Right Cessation
- 1993-03-17 DK DK93104367T patent/DK0562439T3/da active
- 1993-03-17 PH PH45897A patent/PH29998A/en unknown
- 1993-03-17 US US08/032,296 patent/US5389633A/en not_active Expired - Fee Related
- 1993-03-17 HU HU9300759A patent/HU218791B/hu not_active IP Right Cessation
- 1993-03-17 LV LVP-93-189A patent/LV10456B/en unknown
- 1993-03-17 DE DE69325199T patent/DE69325199T2/de not_active Expired - Fee Related
- 1993-03-17 NO NO930974A patent/NO300774B1/no not_active IP Right Cessation
- 1993-03-17 EP EP93104367A patent/EP0562439B1/en not_active Expired - Lifetime
- 1993-03-17 CA CA002091874A patent/CA2091874A1/en not_active Abandoned
- 1993-03-17 FI FI931190A patent/FI104076B/fi active
- 1993-03-17 ES ES93104367T patent/ES2132147T3/es not_active Expired - Lifetime
- 1993-03-18 CN CN93103370A patent/CN1040874C/zh not_active Expired - Fee Related
-
1994
- 1994-11-10 EE EE9400357A patent/EE9400357A/xx unknown
-
1995
- 1995-05-31 HU HU95P/P00146P patent/HU211326A9/hu unknown
-
1998
- 1998-09-08 HK HK98110535A patent/HK1009700A1/xx not_active IP Right Cessation
-
1999
- 1999-07-20 GR GR990401905T patent/GR3030817T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| LTIP390A (lt) | 1994-08-25 |
| MY108967A (en) | 1996-11-30 |
| RU2130458C1 (ru) | 1999-05-20 |
| DK0562439T3 (da) | 1999-11-15 |
| HU218791B (hu) | 2000-12-28 |
| ATE181075T1 (de) | 1999-06-15 |
| US5389633A (en) | 1995-02-14 |
| HU9300759D0 (en) | 1993-06-28 |
| TW255891B (el) | 1995-09-01 |
| CA2091874A1 (en) | 1993-09-19 |
| FI931190A0 (fi) | 1993-03-17 |
| PH29998A (en) | 1996-10-29 |
| EP0562439A1 (en) | 1993-09-29 |
| GR3030817T3 (en) | 1999-11-30 |
| EE9400357A (et) | 1996-04-15 |
| HK1009700A1 (en) | 1999-06-04 |
| LT3200B (en) | 1995-03-27 |
| LV10456B (en) | 1995-10-20 |
| FI931190A (fi) | 1993-09-19 |
| DE69325199T2 (de) | 1999-12-16 |
| FI104076B1 (fi) | 1999-11-15 |
| AU654430B2 (en) | 1994-11-03 |
| DE69325199D1 (de) | 1999-07-15 |
| LV10456A (lv) | 1995-02-20 |
| EP0562439B1 (en) | 1999-06-09 |
| CN1077958A (zh) | 1993-11-03 |
| CN1040874C (zh) | 1998-11-25 |
| NO930974L (no) | 1993-09-20 |
| ES2132147T3 (es) | 1999-08-16 |
| AU3526993A (en) | 1993-09-23 |
| NO930974D0 (no) | 1993-03-17 |
| FI104076B (fi) | 1999-11-15 |
| HU211326A9 (en) | 1995-11-28 |
| NZ247171A (en) | 1994-09-27 |
| HUT65935A (en) | 1994-08-29 |
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| MM1K | Lapsed by not paying the annual fees |
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