BG104328A - Изохинолини като инхибитори на урокиназа - Google Patents
Изохинолини като инхибитори на урокиназа Download PDFInfo
- Publication number
- BG104328A BG104328A BG104328A BG10432800A BG104328A BG 104328 A BG104328 A BG 104328A BG 104328 A BG104328 A BG 104328A BG 10432800 A BG10432800 A BG 10432800A BG 104328 A BG104328 A BG 104328A
- Authority
- BG
- Bulgaria
- Prior art keywords
- optionally substituted
- alkylene
- compound
- halogen
- halogen atoms
- Prior art date
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- 239000002797 plasminogen activator inhibitor Substances 0.000 title abstract description 10
- 150000002537 isoquinolines Chemical class 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 157
- 150000003839 salts Chemical class 0.000 claims abstract description 64
- 239000000203 mixture Substances 0.000 claims description 72
- 125000000217 alkyl group Chemical group 0.000 claims description 67
- -1 arylAalkylene) Chemical group 0.000 claims description 64
- 125000005843 halogen group Chemical group 0.000 claims description 63
- 238000000034 method Methods 0.000 claims description 59
- 229910052736 halogen Inorganic materials 0.000 claims description 48
- 150000002367 halogens Chemical class 0.000 claims description 43
- 125000001424 substituent group Chemical group 0.000 claims description 37
- 125000003118 aryl group Chemical group 0.000 claims description 33
- 125000003545 alkoxy group Chemical group 0.000 claims description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- 229910052794 bromium Inorganic materials 0.000 claims description 27
- 229910052760 oxygen Inorganic materials 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 22
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 22
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 claims description 19
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 claims description 19
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 17
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 16
- 229960005356 urokinase Drugs 0.000 claims description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- OSILBMSORKFRTB-UHFFFAOYSA-N isoquinolin-1-amine Chemical compound C1=CC=C2C(N)=NC=CC2=C1 OSILBMSORKFRTB-UHFFFAOYSA-N 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 230000008569 process Effects 0.000 claims description 13
- 125000002947 alkylene group Chemical group 0.000 claims description 11
- 125000004429 atom Chemical group 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 229920006395 saturated elastomer Polymers 0.000 claims description 11
- 206010028980 Neoplasm Diseases 0.000 claims description 9
- 208000025865 Ulcer Diseases 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- 231100000397 ulcer Toxicity 0.000 claims description 9
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 8
- 230000033115 angiogenesis Effects 0.000 claims description 8
- 230000001684 chronic effect Effects 0.000 claims description 8
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 230000029663 wound healing Effects 0.000 claims description 8
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 230000009545 invasion Effects 0.000 claims description 7
- 210000001519 tissue Anatomy 0.000 claims description 7
- 230000017423 tissue regeneration Effects 0.000 claims description 7
- 210000004881 tumor cell Anatomy 0.000 claims description 7
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 6
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 6
- 210000000988 bone and bone Anatomy 0.000 claims description 6
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 230000002500 effect on skin Effects 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
- VYCKDIRCVDCQAE-UHFFFAOYSA-N isoquinolin-3-amine Chemical class C1=CC=C2C=NC(N)=CC2=C1 VYCKDIRCVDCQAE-UHFFFAOYSA-N 0.000 claims description 6
- 230000001404 mediated effect Effects 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 230000008439 repair process Effects 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- KLIDCXVFHGNTTM-UHFFFAOYSA-N 2,6-dimethoxyphenol Chemical group COC1=CC=CC(OC)=C1O KLIDCXVFHGNTTM-UHFFFAOYSA-N 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 5
- 206010016654 Fibrosis Diseases 0.000 claims description 5
- 206010003246 arthritis Diseases 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 230000004069 differentiation Effects 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 230000004761 fibrosis Effects 0.000 claims description 5
- 239000012458 free base Substances 0.000 claims description 5
- 210000002865 immune cell Anatomy 0.000 claims description 5
- 238000002513 implantation Methods 0.000 claims description 5
- 230000008595 infiltration Effects 0.000 claims description 5
- 238000001764 infiltration Methods 0.000 claims description 5
- 210000000056 organ Anatomy 0.000 claims description 5
- 230000016087 ovulation Effects 0.000 claims description 5
- 125000002971 oxazolyl group Chemical group 0.000 claims description 5
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 5
- 230000021595 spermatogenesis Effects 0.000 claims description 5
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- 210000004291 uterus Anatomy 0.000 claims description 5
- FXVHAOFNNRNCRJ-UHFFFAOYSA-N 2-(4-chloro-7-sulfamoylisoquinolin-1-yl)guanidine Chemical compound C1=C(S(N)(=O)=O)C=C2C(NC(=N)N)=NC=C(Cl)C2=C1 FXVHAOFNNRNCRJ-UHFFFAOYSA-N 0.000 claims description 4
- NNEJXIJKGKRBBF-UHFFFAOYSA-N 2-[7-(phenylsulfamoyl)isoquinolin-1-yl]guanidine Chemical compound C1=C2C(NC(=N)N)=NC=CC2=CC=C1S(=O)(=O)NC1=CC=CC=C1 NNEJXIJKGKRBBF-UHFFFAOYSA-N 0.000 claims description 4
- 206010061218 Inflammation Diseases 0.000 claims description 4
- 206010029113 Neovascularisation Diseases 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 230000015556 catabolic process Effects 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 230000004054 inflammatory process Effects 0.000 claims description 4
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 4
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 4
- 125000001425 triazolyl group Chemical group 0.000 claims description 4
- WFWVGNODYCIFAT-UHFFFAOYSA-N 2-(4-chloro-7-phenylsulfanylisoquinolin-1-yl)guanidine Chemical compound C1=C2C(NC(=N)N)=NC=C(Cl)C2=CC=C1SC1=CC=CC=C1 WFWVGNODYCIFAT-UHFFFAOYSA-N 0.000 claims description 3
- NRVVFOKWKSWIIV-UHFFFAOYSA-N 2-(7-sulfamoylisoquinolin-1-yl)guanidine Chemical compound C1=C(S(N)(=O)=O)C=C2C(NC(=N)N)=NC=CC2=C1 NRVVFOKWKSWIIV-UHFFFAOYSA-N 0.000 claims description 3
- RFKKRFPXGHPURP-UHFFFAOYSA-N 2-[7-(benzenesulfonyl)-4-chloroisoquinolin-1-yl]guanidine Chemical compound C1=C2C(NC(=N)N)=NC=C(Cl)C2=CC=C1S(=O)(=O)C1=CC=CC=C1 RFKKRFPXGHPURP-UHFFFAOYSA-N 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- 230000000996 additive effect Effects 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 210000001161 mammalian embryo Anatomy 0.000 claims description 3
- 230000001394 metastastic effect Effects 0.000 claims description 3
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- LZCYTJFZWSPVRX-UHFFFAOYSA-N 2-(4-chloro-7-morpholin-4-ylsulfonylisoquinolin-1-yl)guanidine;hydrochloride Chemical compound Cl.C1=C2C(NC(=N)N)=NC=C(Cl)C2=CC=C1S(=O)(=O)N1CCOCC1 LZCYTJFZWSPVRX-UHFFFAOYSA-N 0.000 claims description 2
- HCACCYBLVLISIO-UHFFFAOYSA-N 2-[4-bromo-7-(3-methoxyphenyl)isoquinolin-1-yl]guanidine Chemical compound COC1=CC=CC(C=2C=C3C(NC(N)=N)=NC=C(Br)C3=CC=2)=C1 HCACCYBLVLISIO-UHFFFAOYSA-N 0.000 claims description 2
- QXVKRCPMWGQPQV-UHFFFAOYSA-N 2-[4-bromo-7-(4-methoxyphenyl)isoquinolin-1-yl]guanidine Chemical compound C1=CC(OC)=CC=C1C1=CC=C(C(Br)=CN=C2NC(N)=N)C2=C1 QXVKRCPMWGQPQV-UHFFFAOYSA-N 0.000 claims description 2
- RZXRBCPKMICCFA-UHFFFAOYSA-N 2-[4-chloro-7-(2,6-dimethoxyphenyl)isoquinolin-1-yl]guanidine Chemical compound COC1=CC=CC(OC)=C1C1=CC=C(C(Cl)=CN=C2NC(N)=N)C2=C1 RZXRBCPKMICCFA-UHFFFAOYSA-N 0.000 claims description 2
- XJVLWXLPNJUSJK-UHFFFAOYSA-N 2-[4-chloro-7-(3-methoxyphenyl)isoquinolin-1-yl]guanidine Chemical compound COC1=CC=CC(C=2C=C3C(NC(N)=N)=NC=C(Cl)C3=CC=2)=C1 XJVLWXLPNJUSJK-UHFFFAOYSA-N 0.000 claims description 2
- MOZIDBOJSUCARX-UHFFFAOYSA-N 2-[4-chloro-7-(4-methoxyphenyl)isoquinolin-1-yl]guanidine Chemical compound C1=CC(OC)=CC=C1C1=CC=C(C(Cl)=CN=C2NC(N)=N)C2=C1 MOZIDBOJSUCARX-UHFFFAOYSA-N 0.000 claims description 2
- QABOEPAYXSLSDJ-UHFFFAOYSA-N 2-[4-chloro-7-(cyclopentylsulfamoyl)isoquinolin-1-yl]guanidine Chemical compound C1=C2C(NC(=N)N)=NC=C(Cl)C2=CC=C1S(=O)(=O)NC1CCCC1 QABOEPAYXSLSDJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims description 2
- 125000004244 benzofuran-2-yl group Chemical group [H]C1=C(*)OC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- WWUZIQQURGPMPG-KRWOKUGFSA-N sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 claims description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 claims 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- RJODTPBPYVAHPU-UHFFFAOYSA-N 2-[4-chloro-7-(2-methoxyphenyl)isoquinolin-1-yl]guanidine Chemical compound COC1=CC=CC=C1C1=CC=C(C(Cl)=CN=C2NC(N)=N)C2=C1 RJODTPBPYVAHPU-UHFFFAOYSA-N 0.000 claims 1
- GKUKMDNHGBXAPN-UHFFFAOYSA-N 3H-1,2-oxazol-3-ide Chemical compound O1N=[C-]C=C1 GKUKMDNHGBXAPN-UHFFFAOYSA-N 0.000 claims 1
- 235000002918 Fraxinus excelsior Nutrition 0.000 claims 1
- 239000002956 ash Substances 0.000 claims 1
- 125000005605 benzo group Chemical group 0.000 claims 1
- 125000005879 dioxolanyl group Chemical group 0.000 claims 1
- 210000003754 fetus Anatomy 0.000 claims 1
- 150000002460 imidazoles Chemical class 0.000 claims 1
- 230000002757 inflammatory effect Effects 0.000 claims 1
- 230000035755 proliferation Effects 0.000 claims 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 claims 1
- 238000005481 NMR spectroscopy Methods 0.000 description 99
- 239000007787 solid Substances 0.000 description 79
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 70
- 239000000243 solution Substances 0.000 description 69
- PMDKYLLIOLFQPO-UHFFFAOYSA-N monocyclohexyl phthalate Chemical compound OC(=O)C1=CC=CC=C1C(=O)OC1CCCCC1 PMDKYLLIOLFQPO-UHFFFAOYSA-N 0.000 description 64
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 41
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 31
- 238000000921 elemental analysis Methods 0.000 description 31
- 235000019439 ethyl acetate Nutrition 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 239000002904 solvent Substances 0.000 description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 21
- 238000004440 column chromatography Methods 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 19
- 239000000741 silica gel Substances 0.000 description 19
- 229910002027 silica gel Inorganic materials 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 17
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- 239000012267 brine Substances 0.000 description 17
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- 238000004458 analytical method Methods 0.000 description 16
- YOSQVMGMENUCDX-UHFFFAOYSA-N 4'-methyl-α-pyrrolidinohexiophenone Chemical compound C=1C=C(C)C=CC=1C(=O)C(CCCC)N1CCCC1 YOSQVMGMENUCDX-UHFFFAOYSA-N 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 15
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- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 13
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000002253 acid Substances 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
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- 239000000843 powder Substances 0.000 description 10
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- 238000010992 reflux Methods 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
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- 238000003786 synthesis reaction Methods 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
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- 229960004198 guanidine Drugs 0.000 description 6
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- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 239000011159 matrix material Substances 0.000 description 6
- UEWAZISAXQEMSD-UHFFFAOYSA-N 4,7-dibromo-1-chloroisoquinoline Chemical compound C1=C(Br)C=C2C(Cl)=NC=C(Br)C2=C1 UEWAZISAXQEMSD-UHFFFAOYSA-N 0.000 description 5
- 206010052428 Wound Diseases 0.000 description 5
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- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 5
- 229960002576 amiloride Drugs 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- FMIYJSROVCVYDT-UHFFFAOYSA-N 1,4-dichloro-7-phenylsulfanylisoquinoline Chemical compound C=1C=C2C(Cl)=CN=C(Cl)C2=CC=1SC1=CC=CC=C1 FMIYJSROVCVYDT-UHFFFAOYSA-N 0.000 description 4
- MBXFJGWNDTUZLK-UHFFFAOYSA-N 2-isoquinolin-1-ylguanidine Chemical class C1=CC=C2C(NC(=N)N)=NC=CC2=C1 MBXFJGWNDTUZLK-UHFFFAOYSA-N 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
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- SKJPLKCXYSBRPG-UHFFFAOYSA-N tert-butyl N-isoquinolin-3-yl-N-[N-[(2-methylpropan-2-yl)oxycarbonyl]carbamimidoyl]carbamate Chemical compound CC(C)(C)OC(=O)NC(=N)N(C1=CC2=CC=CC=C2C=N1)C(=O)OC(C)(C)C SKJPLKCXYSBRPG-UHFFFAOYSA-N 0.000 description 1
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- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
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- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
-
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- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- 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
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- 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
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/48—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
- C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
- C07D217/26—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
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Reproductive Health (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Pain & Pain Management (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Immunology (AREA)
- Endocrinology (AREA)
- Dermatology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9721964.6A GB9721964D0 (en) | 1997-10-16 | 1997-10-16 | Isoquinolines |
| PCT/EP1998/006353 WO1999020608A1 (fr) | 1997-10-16 | 1998-10-05 | Isoquinolines en tant qu'inhibiteurs de l'urokinase |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| BG104328A true BG104328A (bg) | 2000-12-29 |
Family
ID=10820680
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BG104328A BG104328A (bg) | 1997-10-16 | 2000-04-11 | Изохинолини като инхибитори на урокиназа |
Country Status (41)
| Country | Link |
|---|---|
| US (1) | US6248738B1 (fr) |
| EP (1) | EP1023268B1 (fr) |
| JP (1) | JP3600794B2 (fr) |
| KR (1) | KR20010031163A (fr) |
| CN (1) | CN1275979A (fr) |
| AP (1) | AP959A (fr) |
| AR (1) | AR015964A1 (fr) |
| AT (1) | ATE240943T1 (fr) |
| AU (1) | AU727315B2 (fr) |
| BG (1) | BG104328A (fr) |
| BR (1) | BR9812922A (fr) |
| CA (1) | CA2306782C (fr) |
| CO (1) | CO4990959A1 (fr) |
| DE (1) | DE69814894T2 (fr) |
| DK (1) | DK1023268T3 (fr) |
| DZ (1) | DZ2624A1 (fr) |
| EA (1) | EA002632B1 (fr) |
| ES (1) | ES2197514T3 (fr) |
| GB (1) | GB9721964D0 (fr) |
| GT (1) | GT199800159A (fr) |
| HN (1) | HN1998000158A (fr) |
| HR (1) | HRP20000217A2 (fr) |
| HU (1) | HUP0004491A3 (fr) |
| ID (1) | ID23913A (fr) |
| IL (1) | IL135122A0 (fr) |
| IS (1) | IS5412A (fr) |
| MA (1) | MA26552A1 (fr) |
| NO (1) | NO20001924L (fr) |
| NZ (1) | NZ503390A (fr) |
| OA (1) | OA11348A (fr) |
| PA (1) | PA8461601A1 (fr) |
| PE (1) | PE121299A1 (fr) |
| PL (1) | PL340035A1 (fr) |
| PT (1) | PT1023268E (fr) |
| SK (1) | SK4872000A3 (fr) |
| TN (1) | TNSN98185A1 (fr) |
| TR (1) | TR200001010T2 (fr) |
| UY (2) | UY25211A1 (fr) |
| WO (1) | WO1999020608A1 (fr) |
| YU (1) | YU21100A (fr) |
| ZA (1) | ZA989412B (fr) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000005214A2 (fr) * | 1998-07-24 | 2000-02-03 | Pfizer Inc. | Isoquinoleines utilisees en tant qu'inhibiteurs de l'urokinase |
| DE19940389A1 (de) * | 1999-08-25 | 2001-03-01 | Wilex Biotechnology Gmbh | Selektive Inhibitoren des Urokinase-Plasminogen Aktivators |
| ES2172376B1 (es) * | 2000-01-28 | 2003-11-16 | Servier Lab | Nuevos derivados de isoquinoleinas, su procedimiento de preparacion y las composiciones farmaceuticas que los contienen. |
| DE10013715A1 (de) | 2000-03-20 | 2001-09-27 | Wilex Biotechnology Gmbh | Hochselektive Inhibitoren des Urokinase-Plasminogenaktivators |
| GB0026490D0 (en) * | 2000-10-30 | 2000-12-13 | Pfizer Ltd | Process |
| ATE415162T1 (de) * | 2001-06-11 | 2008-12-15 | Vertex Pharma | Isochinolin-inhibitoren von p38 |
| EP1549632A4 (fr) | 2002-05-28 | 2005-11-09 | Dimensional Pharm Inc | Nouvelles amidines de thiophene, compositions de ces amidines et procede pour traiter des maladies et des etats medies par le complement |
| DE60329318D1 (de) * | 2002-11-20 | 2009-10-29 | Japan Tobacco Inc | 4-oxochinolinverbindungen und deren verwendung als hiv-integrase-inhibitoren |
| GB0326964D0 (en) * | 2003-11-19 | 2003-12-24 | Glaxo Group Ltd | Chemical compounds |
| MY134672A (en) * | 2004-05-20 | 2007-12-31 | Japan Tobacco Inc | Stable crystal of 4-oxoquinoline compound |
| WO2005113509A1 (fr) * | 2004-05-20 | 2005-12-01 | Japan Tobacco Inc. | Nouveau composé 4-oxoquinoline et utilisation de celui-ci comme inhibiteur d'intégrase de vih |
| US7872136B2 (en) | 2005-02-25 | 2011-01-18 | Kowa Co., Ltd. | Process for production of 4-fluoroisoquinoline-5-sulfonyl halide or salt thereof |
| DE602006009257D1 (de) | 2005-06-24 | 2009-10-29 | Wilex Ag | Verwendung von urokinase-inhibitoren zur behandlunklerose (als) |
| BRPI0708685B8 (pt) * | 2006-03-06 | 2021-05-25 | Japan Tobacco Inc | composto de 4-oxoquinolina, seu uso e método para produção dos mesmos |
| TWI795381B (zh) * | 2016-12-21 | 2023-03-11 | 比利時商健生藥品公司 | 作為malt1抑制劑之吡唑衍生物 |
| CN106831575B (zh) * | 2017-02-13 | 2019-04-16 | 北京六合宁远科技有限公司 | 一种1-氨基异喹啉-6-甲醇的制备方法 |
| CN113877483B (zh) * | 2021-07-20 | 2023-11-24 | 烟台宁远药业有限公司 | 医药中间体卤代异喹啉类硼酸的低温连续合成装置与方法 |
| CN115286573B (zh) * | 2022-08-04 | 2024-12-10 | 常州工程职业技术学院 | 一种1-烷氧基异喹啉化合物的绿色合成方法 |
-
1997
- 1997-10-16 GB GBGB9721964.6A patent/GB9721964D0/en not_active Ceased
-
1998
- 1998-10-05 NZ NZ503390A patent/NZ503390A/en unknown
- 1998-10-05 DE DE69814894T patent/DE69814894T2/de not_active Expired - Fee Related
- 1998-10-05 HR HR20000217A patent/HRP20000217A2/hr not_active Application Discontinuation
- 1998-10-05 JP JP2000516950A patent/JP3600794B2/ja not_active Expired - Fee Related
- 1998-10-05 ES ES98954357T patent/ES2197514T3/es not_active Expired - Lifetime
- 1998-10-05 PT PT98954357T patent/PT1023268E/pt unknown
- 1998-10-05 ID IDW20000691A patent/ID23913A/id unknown
- 1998-10-05 US US09/424,497 patent/US6248738B1/en not_active Expired - Fee Related
- 1998-10-05 WO PCT/EP1998/006353 patent/WO1999020608A1/fr not_active Ceased
- 1998-10-05 TR TR2000/01010T patent/TR200001010T2/xx unknown
- 1998-10-05 CA CA002306782A patent/CA2306782C/fr not_active Expired - Fee Related
- 1998-10-05 CN CN98810108A patent/CN1275979A/zh active Pending
- 1998-10-05 DK DK98954357T patent/DK1023268T3/da active
- 1998-10-05 HU HU0004491A patent/HUP0004491A3/hu unknown
- 1998-10-05 PL PL98340035A patent/PL340035A1/xx unknown
- 1998-10-05 AU AU11508/99A patent/AU727315B2/en not_active Ceased
- 1998-10-05 IL IL13512298A patent/IL135122A0/xx unknown
- 1998-10-05 KR KR1020007004083A patent/KR20010031163A/ko not_active Abandoned
- 1998-10-05 BR BR9812922-8A patent/BR9812922A/pt not_active Application Discontinuation
- 1998-10-05 EP EP98954357A patent/EP1023268B1/fr not_active Expired - Lifetime
- 1998-10-05 SK SK487-2000A patent/SK4872000A3/sk unknown
- 1998-10-05 EA EA200000320A patent/EA002632B1/ru not_active IP Right Cessation
- 1998-10-05 YU YU21100A patent/YU21100A/sh unknown
- 1998-10-05 AT AT98954357T patent/ATE240943T1/de not_active IP Right Cessation
- 1998-10-08 HN HN1998000158A patent/HN1998000158A/es unknown
- 1998-10-09 GT GT199800159A patent/GT199800159A/es unknown
- 1998-10-12 PA PA19988461601A patent/PA8461601A1/es unknown
- 1998-10-14 MA MA25298A patent/MA26552A1/fr unknown
- 1998-10-14 DZ DZ980234A patent/DZ2624A1/fr active
- 1998-10-14 TN TNTNSN98185A patent/TNSN98185A1/fr unknown
- 1998-10-14 AR ARP980105113A patent/AR015964A1/es not_active Application Discontinuation
- 1998-10-15 ZA ZA9809412A patent/ZA989412B/xx unknown
- 1998-10-15 PE PE1998000973A patent/PE121299A1/es not_active Application Discontinuation
- 1998-10-15 UY UY25211A patent/UY25211A1/es unknown
- 1998-10-16 CO CO98060365A patent/CO4990959A1/es unknown
- 1998-10-19 AP APAP/P/1998/001366A patent/AP959A/en active
- 1998-12-08 UY UY25291A patent/UY25291A1/es not_active IP Right Cessation
-
2000
- 2000-03-21 IS IS5412A patent/IS5412A/is unknown
- 2000-04-07 OA OA1200000102A patent/OA11348A/en unknown
- 2000-04-11 BG BG104328A patent/BG104328A/bg unknown
- 2000-04-13 NO NO20001924A patent/NO20001924L/no unknown
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