IL105481A - Phenyl isoxazole sulfonamide derivatives and endothelin antagonist pharmaceutical compositions containing the same - Google Patents
Phenyl isoxazole sulfonamide derivatives and endothelin antagonist pharmaceutical compositions containing the sameInfo
- Publication number
- IL105481A IL105481A IL10548193A IL10548193A IL105481A IL 105481 A IL105481 A IL 105481A IL 10548193 A IL10548193 A IL 10548193A IL 10548193 A IL10548193 A IL 10548193A IL 105481 A IL105481 A IL 105481A
- Authority
- IL
- Israel
- Prior art keywords
- isoxazolyl
- dimethyl
- sulfonamide
- compound
- alkyl
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 3
- 239000002308 endothelin receptor antagonist Substances 0.000 title description 3
- IHWKKPLIRGORJX-UHFFFAOYSA-N n-phenyl-1,2-oxazole-3-sulfonamide Chemical class C1=CON=C1S(=O)(=O)NC1=CC=CC=C1 IHWKKPLIRGORJX-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 105
- -1 cycloalkenylalkyl Chemical group 0.000 claims abstract description 92
- 125000003118 aryl group Chemical group 0.000 claims abstract description 63
- 239000001257 hydrogen Substances 0.000 claims abstract description 58
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 58
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 51
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 43
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 42
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 39
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 37
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 35
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 33
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 33
- 125000000392 cycloalkenyl group Chemical group 0.000 claims abstract description 29
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 16
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims abstract description 16
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 16
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 11
- 125000001475 halogen functional group Chemical group 0.000 claims abstract 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract 6
- 229940124530 sulfonamide Drugs 0.000 claims description 29
- 229920006395 saturated elastomer Polymers 0.000 claims description 21
- 125000004450 alkenylene group Chemical group 0.000 claims description 20
- 125000002947 alkylene group Chemical group 0.000 claims description 19
- 239000004305 biphenyl Substances 0.000 claims description 14
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 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 9
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- SBXDENYROQKXBE-UHFFFAOYSA-N 2-phenylbenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1C1=CC=CC=C1 SBXDENYROQKXBE-UHFFFAOYSA-N 0.000 claims description 7
- 125000004429 atom Chemical group 0.000 claims description 7
- 235000010290 biphenyl Nutrition 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- GDARDKVQKGHHRI-UHFFFAOYSA-N 2-(2-aminophenyl)-n-(3,4-dimethyl-1,2-oxazol-5-yl)benzenesulfonamide Chemical compound CC1=NOC(NS(=O)(=O)C=2C(=CC=CC=2)C=2C(=CC=CC=2)N)=C1C GDARDKVQKGHHRI-UHFFFAOYSA-N 0.000 claims description 3
- FICDMFJBLNFMAR-UHFFFAOYSA-N 2-bromo-n-(3,4-dimethyl-1,2-oxazol-5-yl)benzenesulfonamide Chemical compound CC1=NOC(NS(=O)(=O)C=2C(=CC=CC=2)Br)=C1C FICDMFJBLNFMAR-UHFFFAOYSA-N 0.000 claims description 3
- 125000004419 alkynylene group Chemical group 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000004494 ethyl ester group Chemical group 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- HMZBPKJDXIHPEG-UHFFFAOYSA-N n-(3,4-dimethyl-1,2-oxazol-5-yl)-2-nitrobenzenesulfonamide Chemical compound CC1=NOC(NS(=O)(=O)C=2C(=CC=CC=2)[N+]([O-])=O)=C1C HMZBPKJDXIHPEG-UHFFFAOYSA-N 0.000 claims description 3
- XANLXADXCDHWKP-UHFFFAOYSA-N n-(3,4-dimethyl-1,2-oxazol-5-yl)-2-phenoxybenzenesulfonamide Chemical compound CC1=NOC(NS(=O)(=O)C=2C(=CC=CC=2)OC=2C=CC=CC=2)=C1C XANLXADXCDHWKP-UHFFFAOYSA-N 0.000 claims description 3
- SLBYWDJLJLBXGV-UHFFFAOYSA-N n-(3,4-dimethyl-1,2-oxazol-5-yl)-2-phenylbenzenesulfonamide Chemical compound CC1=NOC(NS(=O)(=O)C=2C(=CC=CC=2)C=2C=CC=CC=2)=C1C SLBYWDJLJLBXGV-UHFFFAOYSA-N 0.000 claims description 3
- ANCMRDKQGAORLD-UHFFFAOYSA-N n-[3-[(3,4-dimethyl-1,2-oxazol-5-yl)sulfamoyl]-4-methylphenyl]acetamide Chemical compound CC(=O)NC1=CC=C(C)C(S(=O)(=O)NC2=C(C(C)=NO2)C)=C1 ANCMRDKQGAORLD-UHFFFAOYSA-N 0.000 claims description 3
- XIOWPJCHSRNYQG-UHFFFAOYSA-N 2-(4-tert-butylphenyl)-n-(3,4-dimethyl-1,2-oxazol-5-yl)benzenesulfonamide Chemical compound CC1=NOC(NS(=O)(=O)C=2C(=CC=CC=2)C=2C=CC(=CC=2)C(C)(C)C)=C1C XIOWPJCHSRNYQG-UHFFFAOYSA-N 0.000 claims description 2
- FAJJTSBWHDOEGD-UHFFFAOYSA-N 2-(dimethylamino)-n-(3,4-dimethyl-1,2-oxazol-5-yl)benzenesulfonamide Chemical compound CN(C)C1=CC=CC=C1S(=O)(=O)NC1=C(C)C(C)=NO1 FAJJTSBWHDOEGD-UHFFFAOYSA-N 0.000 claims description 2
- WXBXZJWIPDOUMI-UHFFFAOYSA-N 2-amino-n-(3,4-dimethyl-1,2-oxazol-5-yl)benzenesulfonamide Chemical compound CC1=NOC(NS(=O)(=O)C=2C(=CC=CC=2)N)=C1C WXBXZJWIPDOUMI-UHFFFAOYSA-N 0.000 claims description 2
- RRELFOAIHGTXMK-UHFFFAOYSA-N 4-amino-2-fluoro-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C(=CC(N)=CC=2)F)=N1 RRELFOAIHGTXMK-UHFFFAOYSA-N 0.000 claims description 2
- UXGOVZWJTNZGPA-UHFFFAOYSA-N 5-amino-n-(3,4-dimethyl-1,2-oxazol-5-yl)-2-methylbenzenesulfonamide Chemical compound CC1=NOC(NS(=O)(=O)C=2C(=CC=C(N)C=2)C)=C1C UXGOVZWJTNZGPA-UHFFFAOYSA-N 0.000 claims description 2
- IRWKUXXPQOGSND-UHFFFAOYSA-N n-(3,4-dimethyl-1,2-oxazol-5-yl)-2-(4-methoxyphenyl)benzenesulfonamide Chemical compound C1=CC(OC)=CC=C1C1=CC=CC=C1S(=O)(=O)NC1=C(C)C(C)=NO1 IRWKUXXPQOGSND-UHFFFAOYSA-N 0.000 claims description 2
- DYLKKVMDOFKPBE-UHFFFAOYSA-N n-(3,4-dimethyl-1,2-oxazol-5-yl)-2-(4-propan-2-yloxyphenyl)benzenesulfonamide Chemical compound C1=CC(OC(C)C)=CC=C1C1=CC=CC=C1S(=O)(=O)NC1=C(C)C(C)=NO1 DYLKKVMDOFKPBE-UHFFFAOYSA-N 0.000 claims description 2
- PEIJQOZFRKLCAI-UHFFFAOYSA-N n-(3,4-dimethyl-1,2-oxazol-5-yl)-2-[2-hydroxy-4-(2-methylpropyl)phenyl]benzenesulfonamide Chemical compound OC1=CC(CC(C)C)=CC=C1C1=CC=CC=C1S(=O)(=O)NC1=C(C)C(C)=NO1 PEIJQOZFRKLCAI-UHFFFAOYSA-N 0.000 claims description 2
- RZRSCFPIKIODFH-UHFFFAOYSA-N n-(3,4-dimethyl-1,2-oxazol-5-yl)-2-fluorobenzenesulfonamide Chemical compound CC1=NOC(NS(=O)(=O)C=2C(=CC=CC=2)F)=C1C RZRSCFPIKIODFH-UHFFFAOYSA-N 0.000 claims description 2
- ZQUFTQSIAVTDPF-UHFFFAOYSA-N n-(3,4-dimethyl-1,2-oxazol-5-yl)-2-naphthalen-1-ylbenzenesulfonamide Chemical compound CC1=NOC(NS(=O)(=O)C=2C(=CC=CC=2)C=2C3=CC=CC=C3C=CC=2)=C1C ZQUFTQSIAVTDPF-UHFFFAOYSA-N 0.000 claims description 2
- APFKWATYQZKXFJ-UHFFFAOYSA-N n-[3-[2-[(3,4-dimethyl-1,2-oxazol-5-yl)sulfamoyl]phenyl]phenyl]acetamide Chemical compound CC(=O)NC1=CC=CC(C=2C(=CC=CC=2)S(=O)(=O)NC2=C(C(C)=NO2)C)=C1 APFKWATYQZKXFJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000005236 alkanoylamino group Chemical group 0.000 claims 4
- 125000003282 alkyl amino group Chemical group 0.000 claims 4
- 125000004663 dialkyl amino group Chemical group 0.000 claims 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 2
- JNMBQUUVMUDBGI-UHFFFAOYSA-N 2-(3-aminophenyl)-n-(3,4-dimethyl-1,2-oxazol-5-yl)benzenesulfonamide Chemical compound CC1=NOC(NS(=O)(=O)C=2C(=CC=CC=2)C=2C=C(N)C=CC=2)=C1C JNMBQUUVMUDBGI-UHFFFAOYSA-N 0.000 claims 1
- RSFKORNHHZWOJK-UHFFFAOYSA-N 5-amino-n-(3,4-dimethyl-1,2-oxazol-5-yl)-2-[4-(2-methylpropyl)phenyl]benzenesulfonamide Chemical compound C1=CC(CC(C)C)=CC=C1C1=CC=C(N)C=C1S(=O)(=O)NC1=C(C)C(C)=NO1 RSFKORNHHZWOJK-UHFFFAOYSA-N 0.000 claims 1
- USQCUKQZXOWUDF-YWZLYKJASA-N 6-chloro-n-[(3s)-1-[(2s)-1-(4-methyl-5-oxo-1,4-diazepan-1-yl)-1-oxopropan-2-yl]-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide Chemical compound O=C([C@@H](N1C([C@@H](NS(=O)(=O)C=2C=C3C=CC(Cl)=CC3=CC=2)CC1)=O)C)N1CCN(C)C(=O)CC1 USQCUKQZXOWUDF-YWZLYKJASA-N 0.000 claims 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- ZYLOLYHYEVOCLC-UHFFFAOYSA-N n-(3,4-dimethyl-1,2-oxazol-5-yl)-2-(4-phenylmethoxyphenyl)benzenesulfonamide Chemical compound CC1=NOC(NS(=O)(=O)C=2C(=CC=CC=2)C=2C=CC(OCC=3C=CC=CC=3)=CC=2)=C1C ZYLOLYHYEVOCLC-UHFFFAOYSA-N 0.000 claims 1
- BBNRKSPDJHJZHA-UHFFFAOYSA-N n-(4,5-dimethyl-1,2-oxazol-3-yl)-2-[4-(2-methylpropyl)phenyl]benzenesulfonamide Chemical compound C1=CC(CC(C)C)=CC=C1C1=CC=CC=C1S(=O)(=O)NC1=NOC(C)=C1C BBNRKSPDJHJZHA-UHFFFAOYSA-N 0.000 claims 1
- 102000002045 Endothelin Human genes 0.000 abstract description 2
- 108050009340 Endothelin Proteins 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 329
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 185
- 229940126062 Compound A Drugs 0.000 description 116
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 116
- 239000000243 solution Substances 0.000 description 111
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 108
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 105
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 99
- 239000000203 mixture Substances 0.000 description 87
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 80
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 79
- 229910001868 water Inorganic materials 0.000 description 76
- 239000007787 solid Substances 0.000 description 71
- 239000000741 silica gel Substances 0.000 description 57
- 229910002027 silica gel Inorganic materials 0.000 description 57
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 47
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 47
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 47
- 238000004458 analytical method Methods 0.000 description 46
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 41
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 38
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 36
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 34
- 238000004587 chromatography analysis Methods 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 239000012267 brine Substances 0.000 description 27
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 27
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 26
- 238000010992 reflux Methods 0.000 description 26
- 238000003818 flash chromatography Methods 0.000 description 21
- 239000000377 silicon dioxide Substances 0.000 description 20
- 239000000284 extract Substances 0.000 description 19
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 19
- 235000019341 magnesium sulphate Nutrition 0.000 description 19
- 238000002425 crystallisation Methods 0.000 description 18
- 230000008025 crystallization Effects 0.000 description 18
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 18
- 229960000583 acetic acid Drugs 0.000 description 17
- 229910052786 argon Inorganic materials 0.000 description 17
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- 238000011282 treatment Methods 0.000 description 15
- 239000000725 suspension Substances 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- 239000005457 ice water Substances 0.000 description 12
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 12
- PYNDWPFZDQONDV-UHFFFAOYSA-N 3,4-dimethyl-1,2-oxazol-5-amine Chemical compound CC1=NOC(N)=C1C PYNDWPFZDQONDV-UHFFFAOYSA-N 0.000 description 11
- 239000012362 glacial acetic acid Substances 0.000 description 10
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 239000012259 ether extract Substances 0.000 description 9
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 239000013078 crystal Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000006286 aqueous extract Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 5
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
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- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229960002490 fosinopril Drugs 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
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- 230000002140 halogenating effect Effects 0.000 description 1
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- DMDGGSIALPNSEE-UHFFFAOYSA-N hydroflumethiazide Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O DMDGGSIALPNSEE-UHFFFAOYSA-N 0.000 description 1
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- 238000006138 lithiation reaction Methods 0.000 description 1
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- CWRJTQCWQJJTPF-UHFFFAOYSA-N n-(3,4-dimethyl-1,2-oxazol-5-yl)-2-propan-2-ylbenzenesulfonamide Chemical compound CC(C)C1=CC=CC=C1S(=O)(=O)NC1=C(C)C(C)=NO1 CWRJTQCWQJJTPF-UHFFFAOYSA-N 0.000 description 1
- KPYOOYQKINTMAO-UHFFFAOYSA-N n-(3,4-dimethyl-1,2-oxazol-5-yl)-5-methoxy-n-(2-methoxyethoxymethyl)-2-[4-(2-methylpropyl)phenyl]benzenesulfonamide Chemical compound C=1C(OC)=CC=C(C=2C=CC(CC(C)C)=CC=2)C=1S(=O)(=O)N(COCCOC)C=1ON=C(C)C=1C KPYOOYQKINTMAO-UHFFFAOYSA-N 0.000 description 1
- ZGKRVIAYOJYUBP-UHFFFAOYSA-N n-(3,4-dimethyl-1,2-oxazol-5-yl)-n-(2-methoxyethoxymethyl)-2-(2-nitrophenyl)benzenesulfonamide Chemical compound C=1C=CC=C(C=2C(=CC=CC=2)[N+]([O-])=O)C=1S(=O)(=O)N(COCCOC)C=1ON=C(C)C=1C ZGKRVIAYOJYUBP-UHFFFAOYSA-N 0.000 description 1
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- HOONKCULFMAHHT-UHFFFAOYSA-N n-(3,4-dimethyl-1,2-oxazol-5-yl)-n-(2-methoxyethoxymethyl)-2-naphthalen-1-ylbenzenesulfonamide Chemical compound C=1C=CC=C(C=2C3=CC=CC=C3C=CC=2)C=1S(=O)(=O)N(COCCOC)C=1ON=C(C)C=1C HOONKCULFMAHHT-UHFFFAOYSA-N 0.000 description 1
- XXHOHJTVFUJJMT-UHFFFAOYSA-N n-(3-bromophenyl)acetamide Chemical compound CC(=O)NC1=CC=CC(Br)=C1 XXHOHJTVFUJJMT-UHFFFAOYSA-N 0.000 description 1
- NRDNRKCJYHXRNQ-UHFFFAOYSA-N n-(3-methyl-4-nitro-1,2-oxazol-5-yl)-2-[4-(2-methylpropyl)phenyl]benzenesulfonamide Chemical compound C1=CC(CC(C)C)=CC=C1C1=CC=CC=C1S(=O)(=O)NC1=C([N+]([O-])=O)C(C)=NO1 NRDNRKCJYHXRNQ-UHFFFAOYSA-N 0.000 description 1
- NDZFZLQOTKAJTH-UHFFFAOYSA-N n-(4-benzyl-3-methyl-1,2-oxazol-5-yl)-2-[4-(2-methylpropyl)phenyl]benzenesulfonamide Chemical compound C1=CC(CC(C)C)=CC=C1C1=CC=CC=C1S(=O)(=O)NC1=C(CC=2C=CC=CC=2)C(C)=NO1 NDZFZLQOTKAJTH-UHFFFAOYSA-N 0.000 description 1
- HUMMCEUVDBVXTQ-UHFFFAOYSA-N naphthalen-1-ylboronic acid Chemical compound C1=CC=C2C(B(O)O)=CC=CC2=C1 HUMMCEUVDBVXTQ-UHFFFAOYSA-N 0.000 description 1
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- 229960005483 polythiazide Drugs 0.000 description 1
- 229920000046 polythiazide Polymers 0.000 description 1
- 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
- 239000004036 potassium channel stimulating agent Substances 0.000 description 1
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- JSDRRTOADPPCHY-HSQYWUDLSA-N quinapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 JSDRRTOADPPCHY-HSQYWUDLSA-N 0.000 description 1
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- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 1
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- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
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- LMJSLTNSBFUCMU-UHFFFAOYSA-N trichlormethiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC(C(Cl)Cl)NS2(=O)=O LMJSLTNSBFUCMU-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
- C07D261/14—Nitrogen atoms
- C07D261/16—Benzene-sulfonamido isoxazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- 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
-
- 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
-
- 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
- A61P9/08—Vasodilators for multiple indications
-
- 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
-
- 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
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
- C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Immunology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
- Peptides Or Proteins (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US87900092A | 1992-05-06 | 1992-05-06 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL105481A0 IL105481A0 (en) | 1993-08-18 |
| IL105481A true IL105481A (en) | 1996-12-05 |
Family
ID=25373236
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL10548193A IL105481A (en) | 1992-05-06 | 1993-04-21 | Phenyl isoxazole sulfonamide derivatives and endothelin antagonist pharmaceutical compositions containing the same |
Country Status (22)
| Country | Link |
|---|---|
| EP (1) | EP0569193B1 (enExample) |
| JP (1) | JP3286391B2 (enExample) |
| KR (1) | KR100277454B1 (enExample) |
| CN (1) | CN1066441C (enExample) |
| AT (1) | ATE149155T1 (enExample) |
| AU (1) | AU659545B2 (enExample) |
| CA (1) | CA2095174A1 (enExample) |
| CY (1) | CY2016A (enExample) |
| DE (1) | DE69308229T2 (enExample) |
| DK (1) | DK0569193T3 (enExample) |
| ES (1) | ES2100459T3 (enExample) |
| FI (1) | FI112655B (enExample) |
| GR (1) | GR3023421T3 (enExample) |
| HK (1) | HK98197A (enExample) |
| HU (1) | HU218938B (enExample) |
| IL (1) | IL105481A (enExample) |
| MX (1) | MX9302618A (enExample) |
| NO (1) | NO303065B1 (enExample) |
| NZ (1) | NZ247440A (enExample) |
| PL (1) | PL178165B1 (enExample) |
| RU (1) | RU2133742C1 (enExample) |
| ZA (1) | ZA932914B (enExample) |
Families Citing this family (78)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6124343A (en) * | 1919-01-27 | 2000-09-26 | Rhone-Poulenc Rorer Limited | Substituted phenyl compounds with a substituent having a thienyl ring |
| WO1988005799A1 (fr) * | 1987-02-09 | 1988-08-11 | Mitsui Petrochemical Industries, Ltd. | Materiau de moulage en feuilles et stratifie pour moulages contenant une couche composee dudit materiau |
| US5514691A (en) * | 1993-05-20 | 1996-05-07 | Immunopharmaceutics, Inc. | N-(4-halo-isoxazolyl)-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 |
| 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 |
| 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 |
| US5736509A (en) * | 1990-12-14 | 1998-04-07 | Texas Biotechnology Corporation | Cyclic peptide surface feature mimics of endothelin |
| US5767310A (en) * | 1993-03-19 | 1998-06-16 | Merck & Co., Inc. | Phenoxyphenylacetic acid derivatives |
| CA2121724A1 (en) | 1993-04-21 | 1994-10-22 | Toshifumi Watanabe | Methods and compositions for the prophylactic and/or therapeutic treatment of organ hypofunction |
| 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 |
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| TW224462B (enExample) * | 1992-02-24 | 1994-06-01 | Squibb & Sons Inc |
-
1993
- 1993-04-20 NZ NZ247440A patent/NZ247440A/en unknown
- 1993-04-21 IL IL10548193A patent/IL105481A/en not_active IP Right Cessation
- 1993-04-26 ZA ZA932914A patent/ZA932914B/xx unknown
- 1993-04-28 JP JP10235493A patent/JP3286391B2/ja not_active Expired - Fee Related
- 1993-04-29 ES ES93303373T patent/ES2100459T3/es not_active Expired - Lifetime
- 1993-04-29 DE DE69308229T patent/DE69308229T2/de not_active Expired - Fee Related
- 1993-04-29 AT AT93303373T patent/ATE149155T1/de not_active IP Right Cessation
- 1993-04-29 DK DK93303373.0T patent/DK0569193T3/da active
- 1993-04-29 EP EP93303373A patent/EP0569193B1/en not_active Expired - Lifetime
- 1993-04-29 CA CA002095174A patent/CA2095174A1/en not_active Abandoned
- 1993-05-04 MX MX9302618A patent/MX9302618A/es not_active IP Right Cessation
- 1993-05-04 KR KR1019930007628A patent/KR100277454B1/ko not_active Expired - Fee Related
- 1993-05-05 NO NO931638A patent/NO303065B1/no not_active IP Right Cessation
- 1993-05-05 AU AU38382/93A patent/AU659545B2/en not_active Ceased
- 1993-05-05 PL PL93298828A patent/PL178165B1/pl unknown
- 1993-05-05 RU RU93004992A patent/RU2133742C1/ru not_active IP Right Cessation
- 1993-05-05 HU HU9301305A patent/HU218938B/hu not_active IP Right Cessation
- 1993-05-06 CN CN93107073A patent/CN1066441C/zh not_active Expired - Fee Related
- 1993-05-06 FI FI932052A patent/FI112655B/fi not_active IP Right Cessation
-
1997
- 1997-05-15 GR GR970401070T patent/GR3023421T3/el unknown
- 1997-06-26 HK HK98197A patent/HK98197A/en not_active IP Right Cessation
-
1998
- 1998-02-20 CY CY201698A patent/CY2016A/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| KR930023337A (ko) | 1993-12-18 |
| FI932052A0 (fi) | 1993-05-06 |
| JPH0649046A (ja) | 1994-02-22 |
| PL298828A1 (en) | 1993-12-27 |
| KR100277454B1 (ko) | 2001-01-15 |
| NO931638D0 (no) | 1993-05-05 |
| RU2133742C1 (ru) | 1999-07-27 |
| HU218938B (hu) | 2001-01-29 |
| MX9302618A (es) | 1994-05-31 |
| CY2016A (en) | 1998-02-20 |
| HUT65751A (en) | 1994-07-28 |
| JP3286391B2 (ja) | 2002-05-27 |
| CN1066441C (zh) | 2001-05-30 |
| FI932052L (fi) | 1993-11-07 |
| FI112655B (fi) | 2003-12-31 |
| ES2100459T3 (es) | 1997-06-16 |
| IL105481A0 (en) | 1993-08-18 |
| PL178165B1 (pl) | 2000-03-31 |
| AU659545B2 (en) | 1995-05-18 |
| EP0569193A1 (en) | 1993-11-10 |
| NO303065B1 (no) | 1998-05-25 |
| AU3838293A (en) | 1993-11-11 |
| NO931638L (no) | 1993-11-08 |
| GR3023421T3 (en) | 1997-08-29 |
| NZ247440A (en) | 1995-04-27 |
| ATE149155T1 (de) | 1997-03-15 |
| CA2095174A1 (en) | 1993-11-07 |
| CN1084515A (zh) | 1994-03-30 |
| HU9301305D0 (en) | 1993-09-28 |
| DE69308229D1 (de) | 1997-04-03 |
| HK98197A (en) | 1997-08-08 |
| ZA932914B (en) | 1993-11-12 |
| EP0569193B1 (en) | 1997-02-26 |
| DE69308229T2 (de) | 1997-07-17 |
| DK0569193T3 (enExample) | 1997-03-17 |
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