CA2250664A1 - Substituted isoquinoline-3-carboxamides, their preparation and their use as pharmaceuticals - Google Patents
Substituted isoquinoline-3-carboxamides, their preparation and their use as pharmaceuticals Download PDFInfo
- Publication number
- CA2250664A1 CA2250664A1 CA002250664A CA2250664A CA2250664A1 CA 2250664 A1 CA2250664 A1 CA 2250664A1 CA 002250664 A CA002250664 A CA 002250664A CA 2250664 A CA2250664 A CA 2250664A CA 2250664 A1 CA2250664 A1 CA 2250664A1
- Authority
- CA
- Canada
- Prior art keywords
- hydrogen
- chlorine
- formula
- alkoxy
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 239000003814 drug Substances 0.000 title abstract description 8
- KKSZSACCVDIWIE-UHFFFAOYSA-N isoquinoline-3-carboxamide Chemical class C1=CC=C2C=NC(C(=O)N)=CC2=C1 KKSZSACCVDIWIE-UHFFFAOYSA-N 0.000 title abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 101
- 239000001257 hydrogen Substances 0.000 claims abstract description 101
- 239000000460 chlorine Chemical group 0.000 claims abstract description 71
- 229910052801 chlorine Chemical group 0.000 claims abstract description 71
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 69
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims abstract description 32
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 32
- 102000004079 Prolyl Hydroxylases Human genes 0.000 claims abstract description 28
- 108010043005 Prolyl Hydroxylases Proteins 0.000 claims abstract description 28
- 125000004428 fluoroalkoxy group Chemical group 0.000 claims abstract description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 21
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 21
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000011737 fluorine Chemical group 0.000 claims abstract description 16
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 14
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 113
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 56
- -1 (C1-C8)-alkoxy Substances 0.000 claims description 47
- 210000004185 liver Anatomy 0.000 claims description 27
- 230000005764 inhibitory process Effects 0.000 claims description 19
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 18
- 150000002431 hydrogen Chemical class 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 11
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 10
- 230000036570 collagen biosynthesis Effects 0.000 claims description 10
- 230000003176 fibrotic effect Effects 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 5
- OUQVKRKGTAUJQA-UHFFFAOYSA-N n-[(1-chloro-4-hydroxyisoquinolin-3-yl)carbonyl]glycine Chemical compound C1=CC=CC2=C(O)C(C(=O)NCC(=O)O)=NC(Cl)=C21 OUQVKRKGTAUJQA-UHFFFAOYSA-N 0.000 claims description 4
- UNZIXZKBJVFYAO-UHFFFAOYSA-N 2-[(1-chloro-4-hydroxy-7-propan-2-yloxyisoquinoline-3-carbonyl)amino]acetic acid Chemical compound OC1=C(C(=O)NCC(O)=O)N=C(Cl)C2=CC(OC(C)C)=CC=C21 UNZIXZKBJVFYAO-UHFFFAOYSA-N 0.000 claims description 3
- TWOHDFPODFCUOB-UHFFFAOYSA-N 2-[(4-hydroxy-7-propan-2-yloxyisoquinoline-3-carbonyl)amino]acetic acid Chemical compound OC1=C(C(=O)NCC(O)=O)N=CC2=CC(OC(C)C)=CC=C21 TWOHDFPODFCUOB-UHFFFAOYSA-N 0.000 claims description 3
- 210000004072 lung Anatomy 0.000 claims description 3
- WDEHYUGVPBGBKG-UHFFFAOYSA-N 1-chloro-4-hydroxy-n-(2-hydroxyethyl)-7-propan-2-yloxyisoquinoline-3-carboxamide Chemical compound OC1=C(C(=O)NCCO)N=C(Cl)C2=CC(OC(C)C)=CC=C21 WDEHYUGVPBGBKG-UHFFFAOYSA-N 0.000 claims description 2
- WAYDNPKLQYUNMN-UHFFFAOYSA-N 2-[(8-chloro-4-hydroxyisoquinoline-3-carbonyl)amino]acetic acid Chemical compound ClC1=CC=CC2=C(O)C(C(=O)NCC(=O)O)=NC=C21 WAYDNPKLQYUNMN-UHFFFAOYSA-N 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 210000003734 kidney Anatomy 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical class C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 7
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 18
- 125000000217 alkyl group Chemical group 0.000 abstract description 4
- 230000007863 steatosis Effects 0.000 abstract description 4
- 231100000240 steatosis hepatitis Toxicity 0.000 abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 abstract 3
- 125000005415 substituted alkoxy group Chemical group 0.000 abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 56
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 24
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 23
- 239000000203 mixture Substances 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- 229920001436 collagen Polymers 0.000 description 16
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- 102000008186 Collagen Human genes 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000003208 petroleum Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 230000010412 perfusion Effects 0.000 description 13
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- 241000700159 Rattus Species 0.000 description 11
- 238000001727 in vivo Methods 0.000 description 10
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 229960002429 proline Drugs 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- 229960002591 hydroxyproline Drugs 0.000 description 8
- 239000000651 prodrug Substances 0.000 description 8
- 229940002612 prodrug Drugs 0.000 description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 7
- 239000004471 Glycine Substances 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 210000000056 organ Anatomy 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000000354 decomposition reaction Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 229950005499 carbon tetrachloride Drugs 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 5
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
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- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 102000004266 Collagen Type IV Human genes 0.000 description 3
- 108010042086 Collagen Type IV Proteins 0.000 description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 3
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
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- GBCAVSYHPPARHX-UHFFFAOYSA-M n'-cyclohexyl-n-[2-(4-methylmorpholin-4-ium-4-yl)ethyl]methanediimine;4-methylbenzenesulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1.C1CCCCC1N=C=NCC[N+]1(C)CCOCC1 GBCAVSYHPPARHX-UHFFFAOYSA-M 0.000 description 3
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- NDMFETHQFUOIQX-UHFFFAOYSA-N 1-(3-chloropropyl)imidazolidin-2-one Chemical compound ClCCCN1CCNC1=O NDMFETHQFUOIQX-UHFFFAOYSA-N 0.000 description 2
- HCSZZFWDZRMHSW-UHFFFAOYSA-N 1-chloro-4-hydroxy-7-propan-2-yloxyisoquinoline-3-carboxylic acid Chemical compound OC1=C(C(O)=O)N=C(Cl)C2=CC(OC(C)C)=CC=C21 HCSZZFWDZRMHSW-UHFFFAOYSA-N 0.000 description 2
- PZURRDUNVQLWGD-UHFFFAOYSA-N 2-(isoquinoline-3-carbonylamino)acetic acid Chemical class C1=CC=C2C=NC(C(=O)NCC(=O)O)=CC2=C1 PZURRDUNVQLWGD-UHFFFAOYSA-N 0.000 description 2
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- SWCWDNMHZACKBG-UHFFFAOYSA-N 4-hydroxy-1-oxo-2h-isoquinoline-3-carboxylic acid Chemical class C1=CC=CC2=C(O)C(C(=O)O)=NC(O)=C21 SWCWDNMHZACKBG-UHFFFAOYSA-N 0.000 description 2
- XTAHQCRCBHEGRP-UHFFFAOYSA-N 4-methylbenzenesulfonic acid;pentyl 2-aminoacetate Chemical compound CCCCCOC(=O)CN.CC1=CC=C(S(O)(=O)=O)C=C1 XTAHQCRCBHEGRP-UHFFFAOYSA-N 0.000 description 2
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- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
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- KPZGRMZPZLOPBS-UHFFFAOYSA-N 1,3-dichloro-2,2-bis(chloromethyl)propane Chemical compound ClCC(CCl)(CCl)CCl KPZGRMZPZLOPBS-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- QKJMMOXAZPSGCV-UHFFFAOYSA-N 1,6,7-trichloro-4-hydroxyisoquinoline-3-carboxylic acid Chemical compound C1=C(Cl)C(Cl)=CC2=C(O)C(C(=O)O)=NC(Cl)=C21 QKJMMOXAZPSGCV-UHFFFAOYSA-N 0.000 description 1
- XZLVYXBBRWFZAO-UHFFFAOYSA-N 1-chloro-4-hydroxy-6-methoxyisoquinoline-3-carboxylic acid Chemical compound ClC1=NC(C(O)=O)=C(O)C2=CC(OC)=CC=C21 XZLVYXBBRWFZAO-UHFFFAOYSA-N 0.000 description 1
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- UVTPTBQGLUKEIM-UHFFFAOYSA-N ethyl 2-[(1-chloro-4-hydroxy-6-phenylmethoxyisoquinoline-3-carbonyl)amino]acetate Chemical compound C=1C2=C(O)C(C(=O)NCC(=O)OCC)=NC(Cl)=C2C=CC=1OCC1=CC=CC=C1 UVTPTBQGLUKEIM-UHFFFAOYSA-N 0.000 description 1
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- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
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- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
- XAAKCCMYRKZRAK-UHFFFAOYSA-N isoquinoline-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=NC=CC2=C1 XAAKCCMYRKZRAK-UHFFFAOYSA-N 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
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- 210000005228 liver tissue Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
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- NZSBEZMTLFUYJD-UHFFFAOYSA-N methyl 1,6,7-trichloro-4-hydroxyisoquinoline-3-carboxylate Chemical compound C1=C(Cl)C(Cl)=CC2=C(O)C(C(=O)OC)=NC(Cl)=C21 NZSBEZMTLFUYJD-UHFFFAOYSA-N 0.000 description 1
- JCLXQWPJRSUMFT-UHFFFAOYSA-N methyl 1-chloro-4-hydroxyisoquinoline-3-carboxylate Chemical compound C1=CC=CC2=C(O)C(C(=O)OC)=NC(Cl)=C21 JCLXQWPJRSUMFT-UHFFFAOYSA-N 0.000 description 1
- BPSBCFXSFAXTIV-UHFFFAOYSA-N methyl 2-[(1-chloro-4-hydroxyisoquinoline-3-carbonyl)amino]acetate Chemical compound C1=CC=CC2=C(O)C(C(=O)NCC(=O)OC)=NC(Cl)=C21 BPSBCFXSFAXTIV-UHFFFAOYSA-N 0.000 description 1
- SNAIQLNIIAIHIC-UHFFFAOYSA-N methyl 2-[(8-chloro-4-hydroxyisoquinoline-3-carbonyl)amino]acetate Chemical compound ClC1=CC=CC2=C(O)C(C(=O)NCC(=O)OC)=NC=C21 SNAIQLNIIAIHIC-UHFFFAOYSA-N 0.000 description 1
- JOURGLFWVLLAPY-UHFFFAOYSA-N methyl 4-hydroxy-1-oxo-2h-isoquinoline-3-carboxylate Chemical compound C1=CC=C2C(O)=C(C(=O)OC)NC(=O)C2=C1 JOURGLFWVLLAPY-UHFFFAOYSA-N 0.000 description 1
- WMQGVBYZDZCNKC-UHFFFAOYSA-N methyl 6,7-dichloro-4-hydroxy-1-oxo-2h-isoquinoline-3-carboxylate Chemical compound ClC1=C(Cl)C=C2C(O)=C(C(=O)OC)NC(=O)C2=C1 WMQGVBYZDZCNKC-UHFFFAOYSA-N 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- VMESOKCXSYNAKD-UHFFFAOYSA-N n,n-dimethylhydroxylamine Chemical compound CN(C)O VMESOKCXSYNAKD-UHFFFAOYSA-N 0.000 description 1
- KWDCBYBOHQWCKS-UHFFFAOYSA-N n-(2-aminoacetyl)-3-hydroxyquinoline-2-carboxamide Chemical class C1=CC=C2C=C(O)C(C(=O)NC(=O)CN)=NC2=C1 KWDCBYBOHQWCKS-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
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- 125000001190 organyl group Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- NWNGDHADXSESGZ-UHFFFAOYSA-N pentyl 2-[(1-chloro-4-hydroxy-6-methoxyisoquinoline-3-carbonyl)amino]acetate Chemical compound C1=CC(OC)=CC2=C(O)C(C(=O)NCC(=O)OCCCCC)=NC(Cl)=C21 NWNGDHADXSESGZ-UHFFFAOYSA-N 0.000 description 1
- WJQFJVWTEGGZQC-UHFFFAOYSA-N pentyl 2-[(1-chloro-4-hydroxy-6-propan-2-yloxyisoquinoline-3-carbonyl)amino]acetate Chemical compound C1=CC(OC(C)C)=CC2=C(O)C(C(=O)NCC(=O)OCCCCC)=NC(Cl)=C21 WJQFJVWTEGGZQC-UHFFFAOYSA-N 0.000 description 1
- SDEMTXKOSYZTHN-UHFFFAOYSA-N pentyl 2-[(1-chloro-4-hydroxy-7-methoxyisoquinoline-3-carbonyl)amino]acetate Chemical compound C1=C(OC)C=CC2=C(O)C(C(=O)NCC(=O)OCCCCC)=NC(Cl)=C21 SDEMTXKOSYZTHN-UHFFFAOYSA-N 0.000 description 1
- HKTWQRFIHHMWGI-UHFFFAOYSA-N pentyl 2-[(1-chloro-4-hydroxy-7-phenylmethoxyisoquinoline-3-carbonyl)amino]acetate Chemical compound C1=CC2=C(O)C(C(=O)NCC(=O)OCCCCC)=NC(Cl)=C2C=C1OCC1=CC=CC=C1 HKTWQRFIHHMWGI-UHFFFAOYSA-N 0.000 description 1
- OYFQFSFYDOUOGM-UHFFFAOYSA-N pentyl 2-[(1-chloro-4-hydroxy-7-propan-2-yloxyisoquinoline-3-carbonyl)amino]acetate Chemical compound C1=C(OC(C)C)C=CC2=C(O)C(C(=O)NCC(=O)OCCCCC)=NC(Cl)=C21 OYFQFSFYDOUOGM-UHFFFAOYSA-N 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
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- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- LGRFSURHDFAFJT-UHFFFAOYSA-N phthalic anhydride Chemical class C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 210000003240 portal vein Anatomy 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
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- 239000013049 sediment Substances 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 210000004500 stellate cell Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
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- 239000008158 vegetable oil Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
-
- 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
- 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
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious 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
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Urology & Nephrology (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Cardiology (AREA)
- Obesity (AREA)
- Gastroenterology & Hepatology (AREA)
- Pulmonology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Toxicology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19746287A DE19746287A1 (de) | 1997-10-20 | 1997-10-20 | Substituierte Isochinolin-2-Carbonsäureamide, ihre Herstellung und ihre Verwendung als Arzneimittel |
| DE19746287.1 | 1997-10-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2250664A1 true CA2250664A1 (en) | 1999-04-20 |
Family
ID=7846053
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002250664A Abandoned CA2250664A1 (en) | 1997-10-20 | 1998-10-19 | Substituted isoquinoline-3-carboxamides, their preparation and their use as pharmaceuticals |
| CA2251647A Expired - Lifetime CA2251647C (en) | 1997-10-20 | 1998-10-20 | Substituted isoquinoline-3-carboxamides, their preparation and their use as pharmaceuticals |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2251647A Expired - Lifetime CA2251647C (en) | 1997-10-20 | 1998-10-20 | Substituted isoquinoline-3-carboxamides, their preparation and their use as pharmaceuticals |
Country Status (24)
| Country | Link |
|---|---|
| US (1) | US6093730A (https=) |
| EP (2) | EP0911340B1 (https=) |
| JP (2) | JP3782591B2 (https=) |
| KR (1) | KR100618922B1 (https=) |
| CN (1) | CN1117079C (https=) |
| AR (1) | AR013696A1 (https=) |
| AT (2) | ATE432940T1 (https=) |
| AU (1) | AU755714B2 (https=) |
| BR (1) | BR9804504B1 (https=) |
| CA (2) | CA2250664A1 (https=) |
| CZ (1) | CZ337298A3 (https=) |
| DE (3) | DE19746287A1 (https=) |
| DK (2) | DK1538160T3 (https=) |
| ES (2) | ES2245471T3 (https=) |
| HU (1) | HUP9802422A3 (https=) |
| ID (1) | ID21115A (https=) |
| IL (1) | IL126638A0 (https=) |
| NO (1) | NO312365B1 (https=) |
| NZ (1) | NZ332363A (https=) |
| PL (1) | PL192354B1 (https=) |
| PT (1) | PT911340E (https=) |
| SG (1) | SG87776A1 (https=) |
| TR (1) | TR199802106A2 (https=) |
| ZA (1) | ZA989505B (https=) |
Families Citing this family (58)
| Publication number | Priority date | Publication date | Assignee | Title |
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| AU2001275014A1 (en) * | 2000-05-30 | 2001-12-11 | Neurogen Corporation | Imidazoloisoquinolines |
| US6762318B2 (en) * | 2001-12-03 | 2004-07-13 | Novo Nordisk A/S | Glucagon antagonists |
| CN102552263A (zh) * | 2001-12-06 | 2012-07-11 | 法布罗根股份有限公司 | 提高内源性红细胞生成素(epo)的方法 |
| US8318703B2 (en) | 2001-12-06 | 2012-11-27 | Fibrogen, Inc. | Methods for improving kidney function |
| EP2295060B1 (en) | 2001-12-06 | 2018-10-31 | Fibrogen, Inc. | Treatment or prevention of ischemic or hypoxic conditions |
| US8124582B2 (en) * | 2002-12-06 | 2012-02-28 | Fibrogen, Inc. | Treatment of diabetes |
| US7618940B2 (en) | 2002-12-06 | 2009-11-17 | Fibrogen, Inc. | Fat regulation |
| WO2005007192A2 (en) * | 2003-06-06 | 2005-01-27 | Fibrogen, Inc. | Cytoprotection through the use of hif hydroxylase inhibitors |
| US8614204B2 (en) * | 2003-06-06 | 2013-12-24 | Fibrogen, Inc. | Enhanced erythropoiesis and iron metabolism |
| CA2528232C (en) | 2003-06-06 | 2010-05-25 | Fibrogen, Inc. | Novel nitrogen-containing heteroaryl compounds and their use in increasing endogenous erythropoietin |
| US20060276477A1 (en) * | 2005-06-06 | 2006-12-07 | Fibrogen, Inc. | Treatment method for anemia |
| AU2006259352A1 (en) | 2005-06-15 | 2006-12-28 | Fibrogen, Inc. | Use of HIF 1alfa modulators for treatment of cancer |
| JP5202327B2 (ja) * | 2005-12-09 | 2013-06-05 | アムジエン・インコーポレーテツド | プロリルヒドロキシラーゼ阻害活性を示すキノロンベースの化合物、およびこの組成物、およびこの使用 |
| EP2476669A1 (en) | 2006-01-27 | 2012-07-18 | Fibrogen, Inc. | Cyanoisoquinoline compounds and methods of use thereof |
| US7745461B1 (en) | 2006-02-27 | 2010-06-29 | Alcon Research, Ltd. | Method of treating dry eye disorders |
| WO2007101204A1 (en) * | 2006-02-27 | 2007-09-07 | Alcon Research, Ltd. | Method of treating glaucoma |
| WO2007114612A1 (en) * | 2006-03-30 | 2007-10-11 | Lg Electronics Inc. | A method and apparatus for decoding/encoding a video signal |
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| DE4015255A1 (de) * | 1990-05-12 | 1991-11-14 | Hoechst Ag | Oxalyl-aminosaeurederivate, verfahren zu ihrer herstellung und ihrer verwendung als arzneimittel zur inhibierung der prolyl-hydroxylase |
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| EP0650961B1 (de) * | 1993-11-02 | 1997-03-05 | Hoechst Aktiengesellschaft | Substituierte heterocyclische Carbonsäureamide, ihre Herstellung und ihre Verwendung als Arzneimittel |
| NZ270267A (en) * | 1993-12-30 | 1997-03-24 | Hoechst Ag | 3-hydroxypyridin-2yl (and -quinolin-2-yl) carboxamide derivatives and pharmaceutical compositions |
| SE9400810D0 (sv) * | 1994-03-10 | 1994-03-10 | Pharmacia Ab | New use of Quinoline-3-carboxamide compounds |
| IL135495A (en) * | 1995-09-28 | 2002-12-01 | Hoechst Ag | Intermediate compounds for the preparation of quinoline-converted amines - 2 - carboxylic acid |
-
1997
- 1997-10-20 DE DE19746287A patent/DE19746287A1/de not_active Withdrawn
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1998
- 1998-10-16 NZ NZ332363A patent/NZ332363A/xx unknown
- 1998-10-16 EP EP98119591A patent/EP0911340B1/de not_active Expired - Lifetime
- 1998-10-16 AT AT05004047T patent/ATE432940T1/de active
- 1998-10-16 ID IDP981374A patent/ID21115A/id unknown
- 1998-10-16 PT PT98119591T patent/PT911340E/pt unknown
- 1998-10-16 ES ES98119591T patent/ES2245471T3/es not_active Expired - Lifetime
- 1998-10-16 DK DK05004047T patent/DK1538160T3/da active
- 1998-10-16 DE DE59814365T patent/DE59814365D1/de not_active Expired - Lifetime
- 1998-10-16 ES ES05004047T patent/ES2328156T3/es not_active Expired - Lifetime
- 1998-10-16 AT AT98119591T patent/ATE299148T1/de active
- 1998-10-16 DK DK98119591T patent/DK0911340T3/da active
- 1998-10-16 EP EP05004047A patent/EP1538160B1/de not_active Expired - Lifetime
- 1998-10-16 AR ARP980105164A patent/AR013696A1/es unknown
- 1998-10-16 DE DE59812907T patent/DE59812907D1/de not_active Expired - Lifetime
- 1998-10-18 IL IL12663898A patent/IL126638A0/xx unknown
- 1998-10-19 CA CA002250664A patent/CA2250664A1/en not_active Abandoned
- 1998-10-19 ZA ZA989505A patent/ZA989505B/xx unknown
- 1998-10-19 KR KR1019980043578A patent/KR100618922B1/ko not_active Expired - Lifetime
- 1998-10-19 JP JP29701198A patent/JP3782591B2/ja not_active Expired - Lifetime
- 1998-10-19 CZ CZ983372A patent/CZ337298A3/cs unknown
- 1998-10-19 BR BRPI9804504-0A patent/BR9804504B1/pt not_active IP Right Cessation
- 1998-10-19 AU AU89413/98A patent/AU755714B2/en not_active Expired
- 1998-10-19 TR TR1998/02106A patent/TR199802106A2/xx unknown
- 1998-10-19 US US09/174,558 patent/US6093730A/en not_active Expired - Lifetime
- 1998-10-19 HU HU9802422A patent/HUP9802422A3/hu unknown
- 1998-10-19 NO NO19984877A patent/NO312365B1/no not_active IP Right Cessation
- 1998-10-20 SG SG9804225A patent/SG87776A1/en unknown
- 1998-10-20 PL PL329274A patent/PL192354B1/pl unknown
- 1998-10-20 CA CA2251647A patent/CA2251647C/en not_active Expired - Lifetime
- 1998-10-20 CN CN98121000A patent/CN1117079C/zh not_active Expired - Lifetime
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