BG63433B1 - Бензопиранови производни, имащи антагонистично действие спрямо левкотриени - Google Patents
Бензопиранови производни, имащи антагонистично действие спрямо левкотриени Download PDFInfo
- Publication number
- BG63433B1 BG63433B1 BG102775A BG10277598A BG63433B1 BG 63433 B1 BG63433 B1 BG 63433B1 BG 102775 A BG102775 A BG 102775A BG 10277598 A BG10277598 A BG 10277598A BG 63433 B1 BG63433 B1 BG 63433B1
- Authority
- BG
- Bulgaria
- Prior art keywords
- benzopyran
- oxo
- compound
- phenyl
- group
- Prior art date
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- 230000003042 antagnostic effect Effects 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 308
- -1 5-tetrazolyl Chemical group 0.000 claims abstract description 133
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 77
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract description 76
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 36
- 239000001257 hydrogen Substances 0.000 claims abstract description 35
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 26
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 21
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims abstract description 10
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 8
- 125000004434 sulfur atom Chemical group 0.000 claims abstract description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims abstract description 3
- 125000003884 phenylalkyl group Chemical group 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 154
- 239000000203 mixture Substances 0.000 claims description 113
- 238000006243 chemical reaction Methods 0.000 claims description 34
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 32
- 238000002360 preparation method Methods 0.000 claims description 26
- 125000003836 4-phenylbutoxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 239000001301 oxygen Substances 0.000 claims description 24
- 125000001424 substituent group Chemical group 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 17
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 16
- 229910052801 chlorine Chemical group 0.000 claims description 15
- 150000002431 hydrogen Chemical class 0.000 claims description 15
- 239000000460 chlorine Chemical group 0.000 claims description 14
- 150000002617 leukotrienes Chemical class 0.000 claims description 13
- 239000011593 sulfur Substances 0.000 claims description 13
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 12
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 11
- ZZLXVXGOFGHKHP-UHFFFAOYSA-N 2-(2h-tetrazol-5-yl)chromen-4-one Chemical compound O1C2=CC=CC=C2C(=O)C=C1C=1N=NNN=1 ZZLXVXGOFGHKHP-UHFFFAOYSA-N 0.000 claims description 10
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 10
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 9
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 9
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 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 claims description 7
- 125000005228 aryl sulfonate group Chemical group 0.000 claims description 7
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 claims description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 4
- YBEGJIJGDLRCLU-UHFFFAOYSA-N 4-oxo-8-[[2-(phenylmethoxymethyl)-2,3-dihydro-1-benzofuran-5-carbonyl]amino]chromene-2-carboxylic acid Chemical compound C=12OC(C(=O)O)=CC(=O)C2=CC=CC=1NC(=O)C(C=C1C2)=CC=C1OC2COCC1=CC=CC=C1 YBEGJIJGDLRCLU-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 208000006673 asthma Diseases 0.000 claims description 4
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- FMCAFXHLMUOIGG-IWFBPKFRSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-formamido-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,5-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoic acid Chemical compound O=CN[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCSC)C(O)=O)CC1=CC(C)=C(O)C=C1C FMCAFXHLMUOIGG-IWFBPKFRSA-N 0.000 claims description 3
- DIAKMWIJFVXOKU-UHFFFAOYSA-N 8-[[2-(benzylsulfanylmethyl)-2,3-dihydro-1-benzofuran-5-carbonyl]amino]-4-oxochromene-2-carboxylic acid Chemical compound C=12OC(C(=O)O)=CC(=O)C2=CC=CC=1NC(=O)C(C=C1C2)=CC=C1OC2CSCC1=CC=CC=C1 DIAKMWIJFVXOKU-UHFFFAOYSA-N 0.000 claims description 3
- 206010003225 Arteriospasm coronary Diseases 0.000 claims description 3
- 206010048962 Brain oedema Diseases 0.000 claims description 3
- 206010014824 Endotoxic shock Diseases 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 3
- 206010040070 Septic Shock Diseases 0.000 claims description 3
- 201000010105 allergic rhinitis Diseases 0.000 claims description 3
- 208000006752 brain edema Diseases 0.000 claims description 3
- 125000005518 carboxamido group Chemical group 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 230000002757 inflammatory effect Effects 0.000 claims description 3
- 208000030603 inherited susceptibility to asthma Diseases 0.000 claims description 3
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 claims description 3
- JZNOIAMUCZIVPJ-UHFFFAOYSA-N 2-(3-phenylpropyl)-3,4-dihydro-2h-chromene Chemical compound C1CC2=CC=CC=C2OC1CCCC1=CC=CC=C1 JZNOIAMUCZIVPJ-UHFFFAOYSA-N 0.000 claims description 2
- JEZLNWDWEMSICA-UHFFFAOYSA-N 6-fluoro-4-oxo-8-[[2-(3-phenylpropyl)-2,3-dihydro-1-benzofuran-5-carbonyl]amino]chromene-2-carboxylic acid Chemical compound C=12OC(C(=O)O)=CC(=O)C2=CC(F)=CC=1NC(=O)C(C=C1C2)=CC=C1OC2CCCC1=CC=CC=C1 JEZLNWDWEMSICA-UHFFFAOYSA-N 0.000 claims description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 claims description 2
- 206010006811 Bursitis Diseases 0.000 claims description 2
- 206010010744 Conjunctivitis allergic Diseases 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 208000002205 allergic conjunctivitis Diseases 0.000 claims description 2
- 230000000172 allergic effect Effects 0.000 claims description 2
- 230000036783 anaphylactic response Effects 0.000 claims description 2
- 208000003455 anaphylaxis Diseases 0.000 claims description 2
- 208000024998 atopic conjunctivitis Diseases 0.000 claims description 2
- 208000010668 atopic eczema Diseases 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 229910052796 boron Inorganic materials 0.000 claims description 2
- 230000000747 cardiac effect Effects 0.000 claims description 2
- 238000003776 cleavage reaction Methods 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 208000027866 inflammatory disease Diseases 0.000 claims description 2
- AGJSNMGHAVDLRQ-HUUJSLGLSA-N methyl (2s)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-amino-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,3-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoate Chemical compound SC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(=O)N[C@@H](CCSC)C(=O)OC)CC1=CC=C(O)C(C)=C1C AGJSNMGHAVDLRQ-HUUJSLGLSA-N 0.000 claims description 2
- 208000010125 myocardial infarction Diseases 0.000 claims description 2
- 208000031225 myocardial ischemia Diseases 0.000 claims description 2
- 201000008482 osteoarthritis Diseases 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 230000007017 scission Effects 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 230000001404 mediated effect Effects 0.000 claims 3
- 238000007796 conventional method Methods 0.000 claims 2
- 230000002526 effect on cardiovascular system Effects 0.000 claims 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims 1
- 208000004760 Tenosynovitis Diseases 0.000 claims 1
- 238000010306 acid treatment Methods 0.000 claims 1
- 208000026935 allergic disease Diseases 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 238000005342 ion exchange Methods 0.000 claims 1
- AGJSNMGHAVDLRQ-IWFBPKFRSA-N methyl (2s)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-amino-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,3-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoate Chemical compound SC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCSC)C(=O)OC)CC1=CC=C(O)C(C)=C1C AGJSNMGHAVDLRQ-IWFBPKFRSA-N 0.000 claims 1
- GEVOPWHFLXDHRY-UHFFFAOYSA-N n-[4-oxo-2-(2h-tetrazol-5-yl)chromen-8-yl]-2-(3-phenylpropyl)-2,3-dihydro-1-benzofuran-5-carboxamide Chemical compound C=1C=C2OC(CCCC=3C=CC=CC=3)CC2=CC=1C(=O)NC1=CC=CC(C(C=2)=O)=C1OC=2C1=NN=NN1 GEVOPWHFLXDHRY-UHFFFAOYSA-N 0.000 claims 1
- QEZXEUXLGHLVQM-UHFFFAOYSA-N n-[4-oxo-2-(2h-tetrazol-5-yl)chromen-8-yl]-2-(phenylmethoxymethyl)-2,3-dihydro-1-benzofuran-5-carboxamide Chemical compound C=1C=C2OC(COCC=3C=CC=CC=3)CC2=CC=1C(=O)NC1=CC=CC(C(C=2)=O)=C1OC=2C1=NN=NN1 QEZXEUXLGHLVQM-UHFFFAOYSA-N 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
- 206010039073 rheumatoid arthritis Diseases 0.000 claims 1
- 150000001562 benzopyrans Chemical class 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 4
- 208000024172 Cardiovascular disease Diseases 0.000 abstract description 2
- 230000003266 anti-allergic effect Effects 0.000 abstract description 2
- 125000004430 oxygen atom Chemical group O* 0.000 abstract description 2
- 239000002260 anti-inflammatory agent Substances 0.000 abstract 1
- 230000001741 anti-phlogistic effect Effects 0.000 abstract 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 abstract 1
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 132
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 114
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 111
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 84
- 239000002904 solvent Substances 0.000 description 79
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 76
- 239000000243 solution Substances 0.000 description 75
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 66
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 61
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 61
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 57
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 55
- 239000000741 silica gel Substances 0.000 description 55
- 229910002027 silica gel Inorganic materials 0.000 description 55
- 239000007787 solid Substances 0.000 description 54
- 238000004587 chromatography analysis Methods 0.000 description 51
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 47
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- 239000003208 petroleum Substances 0.000 description 32
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 27
- 230000008018 melting Effects 0.000 description 26
- 238000002844 melting Methods 0.000 description 26
- 239000007858 starting material Substances 0.000 description 24
- 239000000047 product Substances 0.000 description 21
- 238000010992 reflux Methods 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 238000002425 crystallisation Methods 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 17
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- 239000002585 base Substances 0.000 description 16
- 230000008025 crystallization Effects 0.000 description 16
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 16
- 238000001704 evaporation Methods 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- PUSKHXMZPOMNTQ-UHFFFAOYSA-N ethyl 2,1,3-benzoselenadiazole-5-carboxylate Chemical compound CCOC(=O)C1=CC=C2N=[Se]=NC2=C1 PUSKHXMZPOMNTQ-UHFFFAOYSA-N 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 239000012298 atmosphere Substances 0.000 description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 9
- 230000008020 evaporation Effects 0.000 description 9
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 229940002520 2'-hydroxyacetophenone Drugs 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- NLLYXOVHEQVWJF-UHFFFAOYSA-N 1-(3-amino-2-hydroxyphenyl)ethanone Chemical compound CC(=O)C1=CC=CC(N)=C1O NLLYXOVHEQVWJF-UHFFFAOYSA-N 0.000 description 6
- JECYUBVRTQDVAT-UHFFFAOYSA-N 2-acetylphenol Chemical compound CC(=O)C1=CC=CC=C1O JECYUBVRTQDVAT-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical compound BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical group C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical group ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 5
- 239000011591 potassium Substances 0.000 description 5
- 229910052700 potassium Inorganic materials 0.000 description 5
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- 210000004165 myocardium Anatomy 0.000 description 1
- UUGGPISNCZNLTB-UHFFFAOYSA-N n-(2-cyano-4-oxochromen-8-yl)-2-(3-phenylpropyl)-2,3-dihydro-1-benzofuran-5-carboxamide Chemical compound C=1C=CC(C(C=C(O2)C#N)=O)=C2C=1NC(=O)C(C=C1C2)=CC=C1OC2CCCC1=CC=CC=C1 UUGGPISNCZNLTB-UHFFFAOYSA-N 0.000 description 1
- UMZLDZKBMKEBFM-UHFFFAOYSA-N n-(2-cyano-4-oxochromen-8-yl)-2-(phenylmethoxymethyl)-2,3-dihydro-1-benzofuran-5-carboxamide Chemical compound C=1C=CC(C(C=C(O2)C#N)=O)=C2C=1NC(=O)C(C=C1C2)=CC=C1OC2COCC1=CC=CC=C1 UMZLDZKBMKEBFM-UHFFFAOYSA-N 0.000 description 1
- RUTWMSYHBAJAKT-UHFFFAOYSA-N n-(3-acetyl-2-hydroxyphenyl)-2-(benzylsulfanylmethyl)-2,3-dihydro-1-benzofuran-5-carboxamide Chemical compound CC(=O)C1=CC=CC(NC(=O)C=2C=C3CC(CSCC=4C=CC=CC=4)OC3=CC=2)=C1O RUTWMSYHBAJAKT-UHFFFAOYSA-N 0.000 description 1
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- GZGBWROZWUSXKG-UHFFFAOYSA-N n-(3-acetyl-2-hydroxyphenyl)-2-[(4-fluorophenyl)methoxymethyl]-2,3-dihydro-1-benzofuran-5-carboxamide Chemical compound CC(=O)C1=CC=CC(NC(=O)C=2C=C3CC(COCC=4C=CC(F)=CC=4)OC3=CC=2)=C1O GZGBWROZWUSXKG-UHFFFAOYSA-N 0.000 description 1
- YXXUCHQPCFWZNE-UHFFFAOYSA-N n-(3-acetyl-2-hydroxyphenyl)-4-chloro-2-(3-phenylpropyl)-2,3-dihydro-1-benzofuran-5-carboxamide Chemical compound CC(=O)C1=CC=CC(NC(=O)C=2C(=C3CC(CCCC=4C=CC=CC=4)OC3=CC=2)Cl)=C1O YXXUCHQPCFWZNE-UHFFFAOYSA-N 0.000 description 1
- DKBLWPFTSWIQPS-UHFFFAOYSA-N n-(3-acetyl-2-hydroxyphenyl)-4-methoxybenzenesulfonamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)NC1=CC=CC(C(C)=O)=C1O DKBLWPFTSWIQPS-UHFFFAOYSA-N 0.000 description 1
- OIYMJVKJPZZFHN-UHFFFAOYSA-N n-(3-acetyl-2-hydroxyphenyl)-7-chloro-2-(3-phenylpropyl)-2,3-dihydro-1-benzofuran-5-carboxamide Chemical compound CC(=O)C1=CC=CC(NC(=O)C=2C=C(Cl)C=3OC(CCCC=4C=CC=CC=4)CC=3C=2)=C1O OIYMJVKJPZZFHN-UHFFFAOYSA-N 0.000 description 1
- IXDDTIWKWFXUQY-UHFFFAOYSA-N n-(3-acetyl-5-fluoro-2-hydroxyphenyl)-2-(3-phenylpropyl)-2,3-dihydro-1-benzofuran-5-carboxamide Chemical compound CC(=O)C1=CC(F)=CC(NC(=O)C=2C=C3CC(CCCC=4C=CC=CC=4)OC3=CC=2)=C1O IXDDTIWKWFXUQY-UHFFFAOYSA-N 0.000 description 1
- VCXLXRGPCSYNLU-UHFFFAOYSA-N n-(phenylmethoxymethyl)-3,4-dihydro-2h-chromene-6-carboxamide Chemical compound C=1C=C2OCCCC2=CC=1C(=O)NCOCC1=CC=CC=C1 VCXLXRGPCSYNLU-UHFFFAOYSA-N 0.000 description 1
- DYSILEHECFITEM-UHFFFAOYSA-N n-[4-oxo-2-(2h-tetrazol-5-yl)chromen-8-yl]-2-(phenylmethoxymethyl)-3,4-dihydro-2h-chromene-6-carboxamide Chemical compound C=1C=C2OC(COCC=3C=CC=CC=3)CCC2=CC=1C(=O)NC1=CC=CC(C(C=2)=O)=C1OC=2C=1N=NNN=1 DYSILEHECFITEM-UHFFFAOYSA-N 0.000 description 1
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- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 150000002901 organomagnesium compounds Chemical class 0.000 description 1
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- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000013014 purified material Substances 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000013391 scatchard analysis Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
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- 201000004415 tendinitis Diseases 0.000 description 1
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- 125000001391 thioamide group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 150000003595 thromboxanes Chemical class 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
- DYVOLUUJJDFBFC-UHFFFAOYSA-N tripotassium butan-1-olate Chemical compound [K+].[K+].[K+].CCCC[O-].CCCC[O-].CCCC[O-] DYVOLUUJJDFBFC-UHFFFAOYSA-N 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
- C07C45/54—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition of compounds containing doubly bound oxygen atoms, e.g. esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/24—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Life Sciences & Earth Sciences (AREA)
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- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
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- Pain & Pain Management (AREA)
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- Otolaryngology (AREA)
- Ophthalmology & Optometry (AREA)
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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES009600682A ES2127106B1 (es) | 1996-03-21 | 1996-03-21 | Derivados benzopiranicos con accion antagonista de los leucotrienos, procedimiento para su preparacion y utilizacion de los mismos. |
| PCT/EP1997/001418 WO1997034885A1 (en) | 1996-03-21 | 1997-03-20 | Benzopyran derivatives having leukotriene-antagonistic action |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| BG102775A BG102775A (en) | 1999-08-31 |
| BG63433B1 true BG63433B1 (bg) | 2002-01-31 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| BG102775A BG63433B1 (bg) | 1996-03-21 | 1998-09-17 | Бензопиранови производни, имащи антагонистично действие спрямо левкотриени |
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|---|---|
| US (1) | US5990142A (cs) |
| EP (1) | EP0888327B1 (cs) |
| JP (1) | JP3914575B2 (cs) |
| KR (1) | KR100378892B1 (cs) |
| CN (1) | CN1182129C (cs) |
| AT (1) | ATE219073T1 (cs) |
| AU (1) | AU707282B2 (cs) |
| BG (1) | BG63433B1 (cs) |
| BR (1) | BR9708215A (cs) |
| CA (1) | CA2249402C (cs) |
| CU (1) | CU22777A3 (cs) |
| CZ (1) | CZ296260B6 (cs) |
| DE (1) | DE69713300T2 (cs) |
| DK (1) | DK0888327T3 (cs) |
| EA (1) | EA001680B1 (cs) |
| EE (1) | EE03526B1 (cs) |
| ES (2) | ES2127106B1 (cs) |
| GE (1) | GEP20012416B (cs) |
| HU (1) | HUP9901326A3 (cs) |
| IL (1) | IL126296A (cs) |
| NO (1) | NO319612B1 (cs) |
| NZ (1) | NZ331953A (cs) |
| PL (1) | PL189562B1 (cs) |
| PT (1) | PT888327E (cs) |
| RS (1) | RS49588B (cs) |
| SI (1) | SI0888327T1 (cs) |
| SK (1) | SK282979B6 (cs) |
| TR (1) | TR199801857T2 (cs) |
| UA (1) | UA65535C2 (cs) |
| WO (1) | WO1997034885A1 (cs) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2001038582A1 (en) | 1999-11-24 | 2001-05-31 | The Research Foundation Of State University Of New York | CATALYTIC RNAs WITH AMINOACYLATION ACTIVITY |
| AU2003213136A1 (en) * | 2002-02-15 | 2003-09-09 | The Research Foundation Of State University Of New York At Buffalo | RIBOZYMES WITH BROAD tRNA AMINOACYLATION ACTIVITY |
| US7851486B2 (en) | 2002-10-17 | 2010-12-14 | Decode Genetics Ehf. | Susceptibility gene for myocardial infarction, stroke, and PAOD; methods of treatment |
| AU2003301305A1 (en) * | 2002-10-17 | 2004-05-04 | Decode Genetics Ehf. | Susceptibility gene for myocardial infarction; methods of treatment |
| ITTO20030140U1 (it) * | 2003-09-16 | 2005-03-17 | Interfila Srl | Matita cosmetica |
| WO2005032544A1 (en) | 2003-09-19 | 2005-04-14 | Galileo Pharmaceuticals, Inc. | Treatment of mitochondrial diseases |
| CN100475781C (zh) * | 2004-02-13 | 2009-04-08 | 沃尼尔·朗伯有限责任公司 | 雄激素受体调节剂 |
| EA009902B1 (ru) * | 2004-02-13 | 2008-04-28 | УОРНЕР-ЛАМБЕРТ КОМПАНИ Эл-Эл-Си | Модуляторы рецепторов андрогенов |
| US7507860B2 (en) | 2004-04-13 | 2009-03-24 | Pfizer Inc. | Androgen modulators |
| EP1781598A1 (en) * | 2004-07-08 | 2007-05-09 | Warner-Lambert Company LLC | Androgen modulators |
| BRPI0514469A (pt) * | 2004-08-18 | 2008-06-10 | Warner Lambert Co | moduladores de androgênio |
| TW200724139A (en) | 2005-05-05 | 2007-07-01 | Warner Lambert Co | Androgen modulators |
| US20090170886A1 (en) * | 2005-08-08 | 2009-07-02 | Pfizer Inc | Androgen modulators |
| US8188260B2 (en) * | 2005-12-06 | 2012-05-29 | The University Of Tokyo | Versatile acylation catalytic RNAs and uses thereof |
| ITMI20061606A1 (it) * | 2006-08-09 | 2008-02-10 | Dipharma Spa | Procedimento per la preparazione di composti nitrilici |
| CN102304052A (zh) * | 2011-07-28 | 2012-01-04 | 浙江大学 | 一种制备5-溴-2-羟基-3-硝基苯乙酮的方法 |
| CN103980257B (zh) * | 2014-05-28 | 2016-04-27 | 苏州开元民生科技股份有限公司 | 8-硝基-2-四氮唑基-4-羰基苯并吡喃的合成方法 |
| CN104402711A (zh) * | 2014-11-12 | 2015-03-11 | 平湖优康药物研发有限公司 | 一种抗哮喘药物普伦斯特中间体的合成工艺 |
| CN113651788B (zh) * | 2021-09-16 | 2023-11-21 | 东华理工大学 | 一种3-胺烷基色酮化合物及其制备方法 |
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| US4977162A (en) * | 1989-07-13 | 1990-12-11 | Rorer Pharmaceutical Corporation | Quinolinyl-chromone derivatives and use for treatment of hypersensitive ailments |
| JPH0395144A (ja) * | 1989-08-04 | 1991-04-19 | Ono Pharmaceut Co Ltd | アミノフェノール誘導体の製造方法 |
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1996
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1997
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- 1997-03-20 PT PT97914280T patent/PT888327E/pt unknown
- 1997-03-20 ES ES97914280T patent/ES2176719T3/es not_active Expired - Lifetime
- 1997-03-20 DE DE69713300T patent/DE69713300T2/de not_active Expired - Fee Related
- 1997-03-20 AT AT97914280T patent/ATE219073T1/de not_active IP Right Cessation
- 1997-03-20 SI SI9730340T patent/SI0888327T1/xx unknown
- 1997-03-20 EA EA199800738A patent/EA001680B1/ru unknown
- 1997-03-20 HU HU9901326A patent/HUP9901326A3/hu unknown
- 1997-03-20 DK DK97914280T patent/DK0888327T3/da active
- 1997-03-20 GE GEAP19974493A patent/GEP20012416B/en unknown
- 1997-03-20 PL PL97329027A patent/PL189562B1/pl not_active IP Right Cessation
- 1997-03-20 SK SK1272-98A patent/SK282979B6/sk not_active IP Right Cessation
- 1997-03-20 NZ NZ331953A patent/NZ331953A/xx not_active IP Right Cessation
- 1997-03-20 UA UA98094930A patent/UA65535C2/uk unknown
- 1997-03-20 KR KR10-1998-0707399A patent/KR100378892B1/ko not_active Expired - Fee Related
- 1997-03-20 JP JP53315997A patent/JP3914575B2/ja not_active Expired - Fee Related
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- 1997-03-20 EE EE9800318A patent/EE03526B1/xx not_active IP Right Cessation
- 1997-03-20 CZ CZ0299598A patent/CZ296260B6/cs not_active IP Right Cessation
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- 1997-03-20 TR TR1998/01857T patent/TR199801857T2/xx unknown
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- 1997-03-20 CN CNB971931933A patent/CN1182129C/zh not_active Expired - Fee Related
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1998
- 1998-09-17 BG BG102775A patent/BG63433B1/bg unknown
- 1998-09-17 NO NO19984330A patent/NO319612B1/no not_active IP Right Cessation
- 1998-09-18 RS YUP-407/98A patent/RS49588B/sr unknown
- 1998-09-18 CU CU1998130A patent/CU22777A3/es not_active IP Right Cessation
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