NO309268B1 - Azolderivat, farmasöytisk preparat inneholdende dette, og mellomprodukter for dets fremstilling - Google Patents
Azolderivat, farmasöytisk preparat inneholdende dette, og mellomprodukter for dets fremstilling Download PDFInfo
- Publication number
- NO309268B1 NO309268B1 NO971685A NO971685A NO309268B1 NO 309268 B1 NO309268 B1 NO 309268B1 NO 971685 A NO971685 A NO 971685A NO 971685 A NO971685 A NO 971685A NO 309268 B1 NO309268 B1 NO 309268B1
- Authority
- NO
- Norway
- Prior art keywords
- group
- propyl
- formula
- chlorophenylsulfonyl
- thiazolyl
- Prior art date
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- 150000007980 azole derivatives Chemical class 0.000 title claims abstract description 20
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 8
- 238000002360 preparation method Methods 0.000 title description 18
- 239000000543 intermediate Substances 0.000 title description 3
- -1 cyano, tetrazolyl Chemical group 0.000 claims abstract description 71
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 42
- 150000003839 salts Chemical class 0.000 claims abstract description 37
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 17
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 11
- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 claims abstract description 9
- 150000002617 leukotrienes Chemical class 0.000 claims abstract description 7
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 7
- 208000026935 allergic disease Diseases 0.000 claims abstract description 6
- 239000004480 active ingredient Substances 0.000 claims abstract description 5
- 125000004450 alkenylene group Chemical group 0.000 claims abstract description 5
- 230000003042 antagnostic effect Effects 0.000 claims abstract description 5
- 208000031225 myocardial ischemia Diseases 0.000 claims abstract description 4
- 230000000302 ischemic effect Effects 0.000 claims abstract 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 30
- 125000005843 halogen group Chemical group 0.000 claims description 25
- 239000012453 solvate Substances 0.000 claims description 19
- 208000006673 asthma Diseases 0.000 claims description 16
- 125000003277 amino group Chemical group 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 6
- 125000004434 sulfur atom Chemical group 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 208000030603 inherited susceptibility to asthma Diseases 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 4
- 230000003449 preventive effect Effects 0.000 claims description 4
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
- GXKYEUMGFUVOPM-UHFFFAOYSA-N 2-[2-[[3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]benzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetic acid Chemical compound CC(C)(C)C1=CSC(COC=2C=C(C=CC=2)C(=O)NC=2C(=CC=C(CCCS(=O)(=O)C=3C=CC(Cl)=CC=3)C=2)OCC(O)=O)=N1 GXKYEUMGFUVOPM-UHFFFAOYSA-N 0.000 claims description 3
- ZEZUDOUQZAREDI-UHFFFAOYSA-N 3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]-n-[5-[3-(4-chlorophenyl)sulfonylpropyl]-2-(2h-tetrazol-5-ylmethoxy)phenyl]benzamide Chemical compound CC(C)(C)C1=CSC(COC=2C=C(C=CC=2)C(=O)NC=2C(=CC=C(CCCS(=O)(=O)C=3C=CC(Cl)=CC=3)C=2)OCC2=NNN=N2)=N1 ZEZUDOUQZAREDI-UHFFFAOYSA-N 0.000 claims description 3
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 3
- 208000024780 Urticaria Diseases 0.000 claims description 3
- 201000010105 allergic rhinitis Diseases 0.000 claims description 3
- 201000010435 allergic urticaria Diseases 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical class NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 claims description 2
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 229940124597 therapeutic agent Drugs 0.000 claims 2
- CYOUETMLRDNEJT-UHFFFAOYSA-N 2-[4-[3-(4-chlorophenyl)sulfonylpropyl]-2-[[3-[(4-cyclobutyl-1,3-thiazol-2-yl)methoxy]benzoyl]amino]phenoxy]acetic acid Chemical compound C1=C(NC(=O)C=2C=C(OCC=3SC=C(N=3)C3CCC3)C=CC=2)C(OCC(=O)O)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 CYOUETMLRDNEJT-UHFFFAOYSA-N 0.000 claims 1
- KFKFSHXKMXWCHA-UHFFFAOYSA-N 3-(1,3-benzothiazol-2-ylmethoxy)-n-[5-[3-(4-chlorophenyl)sulfonylpropyl]-2-(2h-tetrazol-5-ylmethoxy)phenyl]benzamide Chemical compound C1=CC(Cl)=CC=C1S(=O)(=O)CCCC(C=C1NC(=O)C=2C=C(OCC=3SC4=CC=CC=C4N=3)C=CC=2)=CC=C1OCC1=NNN=N1 KFKFSHXKMXWCHA-UHFFFAOYSA-N 0.000 claims 1
- 208000018152 Cerebral disease Diseases 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 697
- 239000000203 mixture Substances 0.000 abstract description 73
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 7
- 239000001257 hydrogen Substances 0.000 abstract description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 5
- 208000014644 Brain disease Diseases 0.000 abstract description 3
- 150000002431 hydrogen Chemical class 0.000 abstract 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract 1
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- 239000001301 oxygen Substances 0.000 abstract 1
- 239000011593 sulfur Substances 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 177
- 239000000243 solution Substances 0.000 description 122
- 238000006243 chemical reaction Methods 0.000 description 103
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 84
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 69
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 64
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 58
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 55
- 101150041968 CDC13 gene Proteins 0.000 description 53
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 53
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
- 238000004949 mass spectrometry Methods 0.000 description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 39
- 238000000034 method Methods 0.000 description 37
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
- 238000001816 cooling Methods 0.000 description 35
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 35
- 238000004519 manufacturing process Methods 0.000 description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 31
- 238000000921 elemental analysis Methods 0.000 description 31
- 239000012267 brine Substances 0.000 description 30
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 28
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 27
- 239000013078 crystal Substances 0.000 description 26
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 24
- 238000002844 melting Methods 0.000 description 24
- 230000008018 melting Effects 0.000 description 24
- 239000012044 organic layer Substances 0.000 description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 24
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 22
- 239000003795 chemical substances by application Substances 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- 239000000047 product Substances 0.000 description 21
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- 238000010992 reflux Methods 0.000 description 20
- 239000007787 solid Substances 0.000 description 20
- 235000019441 ethanol Nutrition 0.000 description 19
- 238000003756 stirring Methods 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 238000001914 filtration Methods 0.000 description 17
- 230000000694 effects Effects 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 239000003480 eluent Substances 0.000 description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 15
- 238000010898 silica gel chromatography Methods 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 14
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 14
- 235000015165 citric acid Nutrition 0.000 description 13
- 230000009467 reduction Effects 0.000 description 13
- 238000006722 reduction reaction Methods 0.000 description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- LQANGKSBLPMBTJ-BRSNVKEHSA-N (z)-7-[(1s,2s,3r,4r)-3-[(e,3s)-3-hydroxyoct-1-enyl]-5-oxabicyclo[2.2.1]heptan-2-yl]hept-5-enoic acid Chemical compound C1[C@@H]2CO[C@H]1[C@H](/C=C/[C@@H](O)CCCCC)[C@H]2C\C=C/CCCC(O)=O LQANGKSBLPMBTJ-BRSNVKEHSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 238000011282 treatment Methods 0.000 description 8
- 239000000427 antigen Substances 0.000 description 7
- 102000036639 antigens Human genes 0.000 description 7
- 108091007433 antigens Proteins 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 230000007062 hydrolysis Effects 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 238000007112 amidation reaction Methods 0.000 description 6
- QSKWJTXWJJOJFP-UHFFFAOYSA-N chloroform;ethoxyethane Chemical compound ClC(Cl)Cl.CCOCC QSKWJTXWJJOJFP-UHFFFAOYSA-N 0.000 description 6
- 238000006266 etherification reaction Methods 0.000 description 6
- YEESKJGWJFYOOK-IJHYULJSSA-N leukotriene D4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@H](N)C(=O)NCC(O)=O YEESKJGWJFYOOK-IJHYULJSSA-N 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 239000011343 solid material Substances 0.000 description 6
- 241000700199 Cavia porcellus Species 0.000 description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 229960004592 isopropanol Drugs 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 230000003381 solubilizing effect Effects 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000010998 test method Methods 0.000 description 5
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- 229920002554 vinyl polymer Polymers 0.000 description 5
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- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- QLNHAPDKHQUIOD-UHFFFAOYSA-N 2-amino-4-[3-(4-chlorophenyl)sulfonylpropyl]phenol;hydrochloride Chemical compound Cl.C1=C(O)C(N)=CC(CCCS(=O)(=O)C=2C=CC(Cl)=CC=2)=C1 QLNHAPDKHQUIOD-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- JLCHNBRGUPQWKF-UHFFFAOYSA-J [OH-].[C+4].[OH-].[OH-].[OH-] Chemical compound [OH-].[C+4].[OH-].[OH-].[OH-] JLCHNBRGUPQWKF-UHFFFAOYSA-J 0.000 description 4
- 230000008485 antagonism Effects 0.000 description 4
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- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 150000002148 esters Chemical group 0.000 description 4
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 239000003701 inert diluent Substances 0.000 description 4
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- 150000007529 inorganic bases Chemical class 0.000 description 4
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- 229910052763 palladium Inorganic materials 0.000 description 4
- 210000004623 platelet-rich plasma Anatomy 0.000 description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 4
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 4
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- BRZUSLILZCEYJF-UHFFFAOYSA-N 4-[3-(4-chlorophenyl)sulfonylpropyl]-2-nitrophenol Chemical compound C1=C([N+]([O-])=O)C(O)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 BRZUSLILZCEYJF-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- BAUYHBQYTHPONS-UHFFFAOYSA-N ethyl 2-[2-[[3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]-4-nitrobenzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(OCC=3SC=C(N=3)C(C)(C)C)C(=CC=2)[N+]([O-])=O)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 BAUYHBQYTHPONS-UHFFFAOYSA-N 0.000 description 1
- GTGDWMXBABMGII-UHFFFAOYSA-N ethyl 2-[2-[[3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]-5-chlorobenzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(OCC=3SC=C(N=3)C(C)(C)C)C=C(Cl)C=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 GTGDWMXBABMGII-UHFFFAOYSA-N 0.000 description 1
- VUPUKQYIXOPPOG-UHFFFAOYSA-N ethyl 2-[2-[[3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]benzenecarbothioyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=S)C=2C=C(OCC=3SC=C(N=3)C(C)(C)C)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 VUPUKQYIXOPPOG-UHFFFAOYSA-N 0.000 description 1
- YCSCHKXKZQFVCB-UHFFFAOYSA-N ethyl 2-[2-[[3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]benzoyl]-methylamino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(N(C)C(=O)C=2C=C(OCC=3SC=C(N=3)C(C)(C)C)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 YCSCHKXKZQFVCB-UHFFFAOYSA-N 0.000 description 1
- UPWNQNLQQNVHND-UHFFFAOYSA-N ethyl 2-[2-[[3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]benzoyl]amino]-6-chloro-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(OCC=3SC=C(N=3)C(C)(C)C)C=CC=2)C(OCC(=O)OCC)=C(Cl)C=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 UPWNQNLQQNVHND-UHFFFAOYSA-N 0.000 description 1
- RQEFUKKJNAPNMA-UHFFFAOYSA-N ethyl 2-[2-[[3-[(4-tert-butyl-5-methyl-1,3-thiazol-2-yl)methoxy]benzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(OCC=3SC(C)=C(N=3)C(C)(C)C)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 RQEFUKKJNAPNMA-UHFFFAOYSA-N 0.000 description 1
- HFPWWLJUBDCBQP-UHFFFAOYSA-N ethyl 2-[2-[[3-[(5-chloro-1,3-benzothiazol-2-yl)methoxy]benzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(OCC=3SC4=CC=C(Cl)C=C4N=3)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 HFPWWLJUBDCBQP-UHFFFAOYSA-N 0.000 description 1
- HPZSJOKHDBLBLM-UHFFFAOYSA-N ethyl 2-[2-[[3-[(6-chloro-1,3-benzothiazol-2-yl)methoxy]benzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(OCC=3SC4=CC(Cl)=CC=C4N=3)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 HPZSJOKHDBLBLM-UHFFFAOYSA-N 0.000 description 1
- UMODLGUQGCHOIY-UHFFFAOYSA-N ethyl 2-[2-[[3-[2-(1,3-benzothiazol-2-yl)ethyl]benzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(CCC=3SC4=CC=CC=C4N=3)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 UMODLGUQGCHOIY-UHFFFAOYSA-N 0.000 description 1
- OCGMXMGKQMTSRC-UHFFFAOYSA-N ethyl 2-[2-[[3-[2-(4-tert-butyl-1,3-thiazol-2-yl)ethyl]benzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(CCC=3SC=C(N=3)C(C)(C)C)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 OCGMXMGKQMTSRC-UHFFFAOYSA-N 0.000 description 1
- CRWDBKJXBOPUNJ-UHFFFAOYSA-N ethyl 2-[2-[[3-[2-(5-chloro-1,3-benzothiazol-2-yl)ethenyl]benzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(C=CC=3SC4=CC=C(Cl)C=C4N=3)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 CRWDBKJXBOPUNJ-UHFFFAOYSA-N 0.000 description 1
- BYBBAPDPGSPCAB-UHFFFAOYSA-N ethyl 2-[2-[[3-amino-5-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]benzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(OCC=3SC=C(N=3)C(C)(C)C)C=C(N)C=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 BYBBAPDPGSPCAB-UHFFFAOYSA-N 0.000 description 1
- YHBYEFGMZNPOFW-UHFFFAOYSA-N ethyl 2-[2-[[4-[2-(1,3-benzothiazol-2-yl)ethenyl]benzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=CC(C=CC=3SC4=CC=CC=C4N=3)=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 YHBYEFGMZNPOFW-UHFFFAOYSA-N 0.000 description 1
- QCAKVSBEXLPVMB-UHFFFAOYSA-N ethyl 2-[2-[[6-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]pyridine-2-carbonyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2N=C(OCC=3SC=C(N=3)C(C)(C)C)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 QCAKVSBEXLPVMB-UHFFFAOYSA-N 0.000 description 1
- CVNIKNBIKUFMCI-UHFFFAOYSA-N ethyl 2-[4-[3-(4-chlorophenyl)sulfonylpropyl]-2-[[3-[(4-phenyl-1,3-thiazol-2-yl)methoxy]benzoyl]amino]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(OCC=3SC=C(N=3)C=3C=CC=CC=3)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 CVNIKNBIKUFMCI-UHFFFAOYSA-N 0.000 description 1
- PXZHUHLSJFWQAT-UHFFFAOYSA-N ethyl 2-[4-[3-(4-chlorophenyl)sulfonylpropyl]-2-[[3-[2-(4-cyclopropyl-1,3-thiazol-2-yl)ethenyl]benzoyl]amino]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(C=CC=3SC=C(N=3)C3CC3)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 PXZHUHLSJFWQAT-UHFFFAOYSA-N 0.000 description 1
- RLXQTXKPFSJUOW-UHFFFAOYSA-N ethyl 2-[4-[3-(4-chlorophenyl)sulfonylpropyl]-2-[[3-[2-[4-(4-methylphenyl)-1,3-thiazol-2-yl]ethenyl]benzoyl]amino]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(C=CC=3SC=C(N=3)C=3C=CC(C)=CC=3)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 RLXQTXKPFSJUOW-UHFFFAOYSA-N 0.000 description 1
- HGBNSZFJEWCDTI-UHFFFAOYSA-N ethyl 2-[4-[3-(4-chlorophenyl)sulfonylpropyl]-2-[[3-[[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]methoxy]benzoyl]amino]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(OCC=3SC4=CC=C(C=C4N=3)C(F)(F)F)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 HGBNSZFJEWCDTI-UHFFFAOYSA-N 0.000 description 1
- NLIHMEONDFZKAE-UHFFFAOYSA-N ethyl 2-[6-[[3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]benzoyl]amino]-2,3-dichloro-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(CCCS(=O)(=O)C=2C=CC(Cl)=CC=2)C(Cl)=C(Cl)C(OCC(=O)OCC)=C1NC(=O)C(C=1)=CC=CC=1OCC1=NC(C(C)(C)C)=CS1 NLIHMEONDFZKAE-UHFFFAOYSA-N 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
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- 238000001640 fractional crystallisation Methods 0.000 description 1
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- BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical compound NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
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- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- YECBIJXISLIIDS-UHFFFAOYSA-N mepyramine Chemical compound C1=CC(OC)=CC=C1CN(CCN(C)C)C1=CC=CC=N1 YECBIJXISLIIDS-UHFFFAOYSA-N 0.000 description 1
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- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- IWVKTOUOPHGZRX-UHFFFAOYSA-N methyl 2-methylprop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.COC(=O)C(C)=C IWVKTOUOPHGZRX-UHFFFAOYSA-N 0.000 description 1
- XZZKYJDVQQEAGL-UHFFFAOYSA-N methyl 3-(3-amino-3-sulfanylidenepropoxy)benzoate Chemical compound COC(=O)C1=CC=CC(OCCC(N)=S)=C1 XZZKYJDVQQEAGL-UHFFFAOYSA-N 0.000 description 1
- RCPISXSXCHGBNQ-UHFFFAOYSA-N methyl 3-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-ylmethoxy)benzoate Chemical compound COC(=O)C1=CC=CC(OCC=2SC=3CCCCC=3N=2)=C1 RCPISXSXCHGBNQ-UHFFFAOYSA-N 0.000 description 1
- LFVLVWOACUGFQP-UHFFFAOYSA-N methyl 3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]-4-chlorobenzoate Chemical compound COC(=O)C1=CC=C(Cl)C(OCC=2SC=C(N=2)C(C)(C)C)=C1 LFVLVWOACUGFQP-UHFFFAOYSA-N 0.000 description 1
- OAQQQIAMSJGIAV-UHFFFAOYSA-N methyl 3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]-4-methoxybenzoate Chemical compound COC(=O)C1=CC=C(OC)C(OCC=2SC=C(N=2)C(C)(C)C)=C1 OAQQQIAMSJGIAV-UHFFFAOYSA-N 0.000 description 1
- CEUUKGAVLJGIPA-UHFFFAOYSA-N methyl 3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]-4-methylbenzoate Chemical compound COC(=O)C1=CC=C(C)C(OCC=2SC=C(N=2)C(C)(C)C)=C1 CEUUKGAVLJGIPA-UHFFFAOYSA-N 0.000 description 1
- WHORZHOBEUBBII-UHFFFAOYSA-N methyl 3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]-4-nitrobenzoate Chemical compound COC(=O)C1=CC=C([N+]([O-])=O)C(OCC=2SC=C(N=2)C(C)(C)C)=C1 WHORZHOBEUBBII-UHFFFAOYSA-N 0.000 description 1
- IKMPCBYPLJRWGC-UHFFFAOYSA-N methyl 3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]-5-chlorobenzoate Chemical compound COC(=O)C1=CC(Cl)=CC(OCC=2SC=C(N=2)C(C)(C)C)=C1 IKMPCBYPLJRWGC-UHFFFAOYSA-N 0.000 description 1
- SKCDOCWPHWYLGI-UHFFFAOYSA-N methyl 3-[(4-tert-butyl-5-methyl-1,3-thiazol-2-yl)methoxy]benzoate Chemical compound COC(=O)C1=CC=CC(OCC=2SC(C)=C(N=2)C(C)(C)C)=C1 SKCDOCWPHWYLGI-UHFFFAOYSA-N 0.000 description 1
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- XRRQNRZGFDVPTE-UHFFFAOYSA-N methyl 6-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]pyridine-2-carboxylate Chemical compound COC(=O)C1=CC=CC(OCC=2SC=C(N=2)C(C)(C)C)=N1 XRRQNRZGFDVPTE-UHFFFAOYSA-N 0.000 description 1
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- WYEOBDWVHSYRHS-UHFFFAOYSA-N n-[5-[3-(benzenesulfonyl)propyl]-2-hydroxyphenyl]-3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]benzamide Chemical compound CC(C)(C)C1=CSC(COC=2C=C(C=CC=2)C(=O)NC=2C(=CC=C(CCCS(=O)(=O)C=3C=CC=CC=3)C=2)O)=N1 WYEOBDWVHSYRHS-UHFFFAOYSA-N 0.000 description 1
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- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- YLLIGHVCTUPGEH-UHFFFAOYSA-M potassium;ethanol;hydroxide Chemical compound [OH-].[K+].CCO YLLIGHVCTUPGEH-UHFFFAOYSA-M 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
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- 150000003431 steroids Chemical class 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
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- 208000024891 symptom Diseases 0.000 description 1
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- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 238000005732 thioetherification reaction Methods 0.000 description 1
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- 239000012929 tonicity agent Substances 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
-
- 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
- A61P17/00—Drugs for dermatological disorders
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or 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 to ring carbon atoms
- C07D263/36—One oxygen atom
- C07D263/38—One oxygen atom attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/24—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/26—Radicals substituted by sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/30—Radicals substituted by 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
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or 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 to ring carbon atoms
- C07D277/36—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pulmonology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Immunology (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Photoreceptors In Electrophotography (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP24948894 | 1994-10-14 | ||
JP25112194 | 1994-10-18 | ||
PCT/JP1995/002085 WO1996011916A1 (fr) | 1994-10-14 | 1995-10-12 | Derive d'azole |
Publications (3)
Publication Number | Publication Date |
---|---|
NO971685D0 NO971685D0 (no) | 1997-04-11 |
NO971685L NO971685L (no) | 1997-06-13 |
NO309268B1 true NO309268B1 (no) | 2001-01-08 |
Family
ID=26539322
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO971685A NO309268B1 (no) | 1994-10-14 | 1997-04-11 | Azolderivat, farmasöytisk preparat inneholdende dette, og mellomprodukter for dets fremstilling |
Country Status (16)
Country | Link |
---|---|
US (1) | US5981559A (zh) |
EP (1) | EP0786457B1 (zh) |
JP (1) | JP3061862B2 (zh) |
KR (1) | KR100386392B1 (zh) |
CN (1) | CN1107059C (zh) |
AT (1) | ATE218132T1 (zh) |
AU (1) | AU699476B2 (zh) |
CA (1) | CA2202623A1 (zh) |
DE (1) | DE69526862T2 (zh) |
FI (1) | FI971510A0 (zh) |
HU (1) | HUT77609A (zh) |
MX (1) | MX9702670A (zh) |
NO (1) | NO309268B1 (zh) |
RU (1) | RU2161612C2 (zh) |
TW (1) | TW381088B (zh) |
WO (1) | WO1996011916A1 (zh) |
Families Citing this family (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6376671B1 (en) | 1997-06-17 | 2002-04-23 | Kaken Pharmaceutical Co., Ltd. | 2-sulfamoylbenzoic acid derivatives |
WO1998057935A1 (fr) * | 1997-06-17 | 1998-12-23 | Kaken Pharmaceutical Co., Ltd. | Derives d'acide 2-sulfamoylbenzoique |
JP2004137284A (ja) * | 1997-06-17 | 2004-05-13 | Kaken Pharmaceut Co Ltd | 2−スルファモイル安息香酸誘導体 |
EP1227084B1 (en) * | 1999-10-28 | 2005-12-14 | Trine Pharmaceuticals, Inc. | Drug discharge pump inhibitors |
US7176243B2 (en) * | 2000-06-02 | 2007-02-13 | The General Hospital Corporation | CaR receptor as a mediator of migratory cell chemotaxis and/or chemokinesis |
JPWO2002087589A1 (ja) * | 2001-04-26 | 2004-08-12 | 第一製薬株式会社 | 薬剤排出ポンプ阻害薬 |
US7056917B2 (en) * | 2001-04-26 | 2006-06-06 | Daiichi Pharmaceutical Co., Ltd. | Drug efflux pump inhibitor |
US20060019269A1 (en) * | 2002-10-17 | 2006-01-26 | Decode Genetics, Inc. | Susceptibility gene for myocardial infarction, stroke, and PAOD, methods of treatment |
CA2502357A1 (en) * | 2002-10-17 | 2004-04-29 | Decode Genetics Ehf. | Susceptibility gene for myocardial infarction; methods of treatment |
US7507531B2 (en) * | 2002-10-17 | 2009-03-24 | Decode Genetics Chf. | Use of 5-lipoxygenase activating protein (FLAP) gene to assess susceptibility for myocardial infarction |
US7851486B2 (en) * | 2002-10-17 | 2010-12-14 | Decode Genetics Ehf. | Susceptibility gene for myocardial infarction, stroke, and PAOD; methods of treatment |
US20080293750A1 (en) * | 2002-10-17 | 2008-11-27 | Anna Helgadottir | Susceptibility Gene for Myocardial Infarction, Stroke, Paod and Methods of Treatment |
US20050272051A1 (en) * | 2003-09-17 | 2005-12-08 | Decode Genetics Ehf. | Methods of preventing or treating recurrence of myocardial infarction |
US8158362B2 (en) * | 2005-03-30 | 2012-04-17 | Decode Genetics Ehf. | Methods of diagnosing susceptibility to myocardial infarction and screening for an LTA4H haplotype |
US20100216863A1 (en) * | 2004-01-30 | 2010-08-26 | Decode Genetics Ehf. | Susceptibility Gene for Myocardial Infarction, Stroke, and PAOD; Methods of Treatment |
EP2308469A1 (en) * | 2005-05-18 | 2011-04-13 | Pulmatrix, Inc. | Formulations for alteration of biophysical properties of mucosal lining |
US8394841B2 (en) | 2007-02-22 | 2013-03-12 | Irm Llc | Compounds and methods for modulating G protein-coupled receptors |
US8758824B2 (en) | 2010-08-30 | 2014-06-24 | Pulmatrix, Inc. | Respirably dry powder comprising calcium lactate, sodium chloride and leucine |
JP5877201B2 (ja) | 2010-08-30 | 2016-03-02 | パルマトリックス,インコーポレイテッド | 肺疾患を治療するための乾燥粉末製剤および方法 |
CA2812414C (en) | 2010-09-29 | 2020-09-22 | Pulmatrix, Inc. | Monovalent metal cation dry powders for inhalation |
DK2621488T3 (en) | 2010-09-29 | 2019-03-04 | Pulmatrix Operating Co Inc | CATIONIC DRY POWDER |
CN107596518B (zh) | 2012-02-29 | 2021-04-23 | 普马特里克斯营业公司 | 可吸入干粉剂 |
CN105324106A (zh) | 2013-04-01 | 2016-02-10 | 普马特里克斯营业公司 | 噻托铵干粉 |
CN111278845A (zh) | 2017-07-04 | 2020-06-12 | 尹图赛利有限公司 | 包含可裂解接头的化合物及其用途 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS532613A (en) * | 1976-06-24 | 1978-01-11 | Shinkou Burain Kk | Crepe forming method for paper |
JPS63258854A (ja) * | 1987-04-16 | 1988-10-26 | Mitsubishi Kasei Corp | カルボキシスチレン誘導体およびそれを有効成分とする薬剤 |
NZ229761A (en) * | 1988-07-12 | 1991-10-25 | Ici Pharma | Substituted thiazole derivatives for use as inhibitors of enzyme 5-lipoxygenase; pharmaceutical compositions and preparatory processes |
JPH0832688B2 (ja) * | 1990-10-16 | 1996-03-29 | テルモ株式会社 | フェノキシ酢酸誘導体及びこれを含有する医薬製剤 |
JPH0532613A (ja) * | 1991-07-29 | 1993-02-09 | Terumo Corp | フエノキシ酢酸誘導体およびこれを含有する医薬製剤 |
US5273986A (en) * | 1992-07-02 | 1993-12-28 | Hoffmann-La Roche Inc. | Cycloalkylthiazoles |
-
1995
- 1995-10-12 US US08/809,466 patent/US5981559A/en not_active Expired - Fee Related
- 1995-10-12 WO PCT/JP1995/002085 patent/WO1996011916A1/ja active IP Right Grant
- 1995-10-12 HU HU9702271A patent/HUT77609A/hu unknown
- 1995-10-12 EP EP95934280A patent/EP0786457B1/en not_active Expired - Lifetime
- 1995-10-12 TW TW084110701A patent/TW381088B/zh not_active IP Right Cessation
- 1995-10-12 KR KR1019970701880A patent/KR100386392B1/ko not_active IP Right Cessation
- 1995-10-12 AU AU36730/95A patent/AU699476B2/en not_active Ceased
- 1995-10-12 MX MX9702670A patent/MX9702670A/es not_active IP Right Cessation
- 1995-10-12 CN CN95195649A patent/CN1107059C/zh not_active Expired - Fee Related
- 1995-10-12 JP JP8513092A patent/JP3061862B2/ja not_active Expired - Lifetime
- 1995-10-12 AT AT95934280T patent/ATE218132T1/de not_active IP Right Cessation
- 1995-10-12 CA CA002202623A patent/CA2202623A1/en not_active Abandoned
- 1995-10-12 RU RU97107457/04A patent/RU2161612C2/ru active
- 1995-10-12 DE DE69526862T patent/DE69526862T2/de not_active Expired - Fee Related
-
1997
- 1997-04-11 NO NO971685A patent/NO309268B1/no not_active IP Right Cessation
- 1997-04-11 FI FI971510A patent/FI971510A0/fi unknown
Also Published As
Publication number | Publication date |
---|---|
FI971510A (fi) | 1997-04-11 |
KR970706265A (ko) | 1997-11-03 |
DE69526862D1 (de) | 2002-07-04 |
AU699476B2 (en) | 1998-12-03 |
HUT77609A (hu) | 1998-06-29 |
DE69526862T2 (de) | 2003-01-02 |
RU2161612C2 (ru) | 2001-01-10 |
AU3673095A (en) | 1996-05-06 |
WO1996011916A1 (fr) | 1996-04-25 |
TW381088B (en) | 2000-02-01 |
CN1160397A (zh) | 1997-09-24 |
FI971510A0 (fi) | 1997-04-11 |
MX9702670A (es) | 1997-07-31 |
JP3061862B2 (ja) | 2000-07-10 |
CN1107059C (zh) | 2003-04-30 |
NO971685L (no) | 1997-06-13 |
US5981559A (en) | 1999-11-09 |
EP0786457B1 (en) | 2002-05-29 |
CA2202623A1 (en) | 1996-04-25 |
NO971685D0 (no) | 1997-04-11 |
ATE218132T1 (de) | 2002-06-15 |
EP0786457A1 (en) | 1997-07-30 |
EP0786457A4 (en) | 1997-12-29 |
KR100386392B1 (ko) | 2003-10-11 |
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