CA2538410A1 - 2-pyridone derivatives as netrophil elastase inhibitors and their use - Google Patents
2-pyridone derivatives as netrophil elastase inhibitors and their use Download PDFInfo
- Publication number
- CA2538410A1 CA2538410A1 CA002538410A CA2538410A CA2538410A1 CA 2538410 A1 CA2538410 A1 CA 2538410A1 CA 002538410 A CA002538410 A CA 002538410A CA 2538410 A CA2538410 A CA 2538410A CA 2538410 A1 CA2538410 A1 CA 2538410A1
- Authority
- CA
- Canada
- Prior art keywords
- oxo
- alkyl
- phenyl
- methyl
- trifluoromethyl
- 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
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 title description 4
- 239000003602 elastase inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 204
- 238000000034 method Methods 0.000 claims abstract description 51
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- 230000008569 process Effects 0.000 claims abstract description 26
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 108010028275 Leukocyte Elastase Proteins 0.000 claims abstract description 5
- 102000016799 Leukocyte elastase Human genes 0.000 claims abstract description 5
- 230000003287 optical effect Effects 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 137
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 122
- 125000003545 alkoxy group Chemical group 0.000 claims description 62
- 229910052760 oxygen Inorganic materials 0.000 claims description 61
- 125000005842 heteroatom Chemical group 0.000 claims description 53
- -1 CO2R47 Chemical group 0.000 claims description 51
- 229910052717 sulfur Inorganic materials 0.000 claims description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 39
- 229920006395 saturated elastomer Polymers 0.000 claims description 36
- 125000001153 fluoro group Chemical group F* 0.000 claims description 32
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 31
- 125000001072 heteroaryl group Chemical group 0.000 claims description 30
- 229910052757 nitrogen Inorganic materials 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 23
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 18
- 125000000623 heterocyclic group Chemical group 0.000 claims description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
- 125000001589 carboacyl group Chemical group 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 16
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical group [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 12
- 229910002091 carbon monoxide Chemical group 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 8
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 8
- 208000027866 inflammatory disease Diseases 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 230000005764 inhibitory process Effects 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 238000011321 prophylaxis Methods 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000005647 linker group Chemical group 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 230000009286 beneficial effect Effects 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000002346 iodo group Chemical group I* 0.000 claims description 3
- 125000002950 monocyclic group Chemical group 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 claims description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 230000000269 nucleophilic effect Effects 0.000 claims description 2
- 125000002355 alkine group Chemical group 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 78
- 239000003112 inhibitor Substances 0.000 abstract description 12
- 238000002560 therapeutic procedure Methods 0.000 abstract description 4
- 238000000668 atmospheric pressure chemical ionisation mass spectrometry Methods 0.000 description 166
- 238000005160 1H NMR spectroscopy Methods 0.000 description 92
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 85
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 64
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
- 239000007787 solid Substances 0.000 description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 50
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 48
- 101150041968 CDC13 gene Proteins 0.000 description 47
- 239000000243 solution Substances 0.000 description 45
- 238000002953 preparative HPLC Methods 0.000 description 44
- 239000002904 solvent Substances 0.000 description 44
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 42
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 41
- 239000011541 reaction mixture Substances 0.000 description 40
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 37
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 33
- 235000019439 ethyl acetate Nutrition 0.000 description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 24
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 24
- 238000005481 NMR spectroscopy Methods 0.000 description 23
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- 238000003756 stirring Methods 0.000 description 21
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- 239000000460 chlorine Substances 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 229910052938 sodium sulfate Inorganic materials 0.000 description 16
- 235000011152 sodium sulphate Nutrition 0.000 description 16
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 14
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 14
- 239000000843 powder Substances 0.000 description 14
- VMNXLLDFGVEBLE-UHFFFAOYSA-N (4-methylsulfonylphenyl)methanamine Chemical compound CS(=O)(=O)C1=CC=C(CN)C=C1 VMNXLLDFGVEBLE-UHFFFAOYSA-N 0.000 description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- 101000851058 Homo sapiens Neutrophil elastase Proteins 0.000 description 12
- 102000052502 human ELANE Human genes 0.000 description 12
- USMWDGUFWSUYSK-UHFFFAOYSA-N 2-methyl-6-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3,5-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=C(C(O)=O)C(=O)N1C1=CC=CC(C(F)(F)F)=C1 USMWDGUFWSUYSK-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 238000001704 evaporation Methods 0.000 description 11
- 230000008020 evaporation Effects 0.000 description 11
- ANNOWMBWHHKGLN-UHFFFAOYSA-N pyridine-3,5-dicarboxamide Chemical compound NC(=O)C1=CN=CC(C(N)=O)=C1 ANNOWMBWHHKGLN-UHFFFAOYSA-N 0.000 description 11
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 10
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 229910052786 argon Inorganic materials 0.000 description 10
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 10
- 235000005152 nicotinamide Nutrition 0.000 description 10
- 239000011570 nicotinamide Substances 0.000 description 10
- DFPAKSUCGFBDDF-UHFFFAOYSA-N nicotinic acid amide Natural products NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- STWNGMSGPBZFMX-UHFFFAOYSA-N pyridine-3-carboxamide Chemical compound NC(=O)C1=CC=CN=C1.NC(=O)C1=CC=CN=C1 STWNGMSGPBZFMX-UHFFFAOYSA-N 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 239000012267 brine Substances 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 238000003818 flash chromatography Methods 0.000 description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 8
- 238000007792 addition Methods 0.000 description 8
- 239000011664 nicotinic acid Substances 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000000377 silicon dioxide Substances 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 206010014561 Emphysema Diseases 0.000 description 7
- 102000016387 Pancreatic elastase Human genes 0.000 description 7
- 108010067372 Pancreatic elastase Proteins 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 239000001828 Gelatine Substances 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 6
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- 239000000725 suspension Substances 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 5
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 5
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 5
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- 125000004432 carbon atom Chemical group C* 0.000 description 5
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- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 5
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- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 4
- FAFGMAGIYHHRKN-UHFFFAOYSA-N 2-diphenylphosphanylethyl(diphenyl)phosphane;palladium Chemical compound [Pd].C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1.C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 FAFGMAGIYHHRKN-UHFFFAOYSA-N 0.000 description 4
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- 239000007821 HATU Substances 0.000 description 4
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- HCGSLFVFFQYIJZ-UHFFFAOYSA-N 5-(hydrazinecarbonyl)-6-methyl-n-[(4-methylsulfonylphenyl)methyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]pyridine-3-carboxamide Chemical compound O=C1N(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(C(=O)NN)C=C1C(=O)NCC1=CC=C(S(C)(=O)=O)C=C1 HCGSLFVFFQYIJZ-UHFFFAOYSA-N 0.000 description 3
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- IDESUFGLLCLZEG-UHFFFAOYSA-N tert-butyl 2-[2-methyl-5-[(4-methylsulfonylphenyl)methylcarbamoyl]-6-oxo-1-[3-(trifluoromethyl)phenyl]pyridin-3-yl]oxyacetate Chemical compound O=C1N(C=2C=C(C=CC=2)C(F)(F)F)C(C)=C(OCC(=O)OC(C)(C)C)C=C1C(=O)NCC1=CC=C(S(C)(=O)=O)C=C1 IDESUFGLLCLZEG-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229940074410 trehalose Drugs 0.000 description 1
- WOZZOSDBXABUFO-UHFFFAOYSA-N tri(butan-2-yloxy)alumane Chemical compound [Al+3].CCC(C)[O-].CCC(C)[O-].CCC(C)[O-] WOZZOSDBXABUFO-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- QIWRFOJWQSSRJZ-UHFFFAOYSA-N tributyl(ethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C QIWRFOJWQSSRJZ-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- MTMBLPOPETZZRX-UHFFFAOYSA-N trimethyl(2-pyridin-3-ylethynyl)silane Chemical compound C[Si](C)(C)C#CC1=CC=CN=C1 MTMBLPOPETZZRX-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- 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]
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE0302487A SE0302487D0 (sv) | 2003-09-18 | 2003-09-18 | Novel compounds |
| SE0302487-4 | 2003-09-18 | ||
| PCT/SE2004/001336 WO2005026124A1 (en) | 2003-09-18 | 2004-09-15 | 2-pyridone derivatives as netrophil elastase inhibitors and their use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2538410A1 true CA2538410A1 (en) | 2005-03-24 |
Family
ID=29212489
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002538410A Abandoned CA2538410A1 (en) | 2003-09-18 | 2004-09-15 | 2-pyridone derivatives as netrophil elastase inhibitors and their use |
Country Status (25)
Families Citing this family (65)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW200500341A (en) * | 2002-11-12 | 2005-01-01 | Astrazeneca Ab | Novel compounds |
| SE0302486D0 (sv) | 2003-09-18 | 2003-09-18 | Astrazeneca Ab | Novel compounds |
| US7459562B2 (en) | 2004-04-23 | 2008-12-02 | Bristol-Myers Squibb Company | Monocyclic heterocycles as kinase inhibitors |
| TW200538453A (en) | 2004-04-26 | 2005-12-01 | Bristol Myers Squibb Co | Bicyclic heterocycles as kinase inhibitors |
| US7173031B2 (en) | 2004-06-28 | 2007-02-06 | Bristol-Myers Squibb Company | Pyrrolotriazine kinase inhibitors |
| US7439246B2 (en) | 2004-06-28 | 2008-10-21 | Bristol-Myers Squibb Company | Fused heterocyclic kinase inhibitors |
| US7432373B2 (en) | 2004-06-28 | 2008-10-07 | Bristol-Meyers Squibb Company | Processes and intermediates useful for preparing fused heterocyclic kinase inhibitors |
| TW200700392A (en) * | 2005-03-16 | 2007-01-01 | Astrazeneca Ab | Novel compounds |
| AU2006244072B2 (en) | 2005-05-10 | 2012-09-20 | Intermune, Inc. | Pyridone derivatives for modulating stress-activated protein kinase system |
| EP1924553A1 (en) | 2005-08-08 | 2008-05-28 | Argenta Discovery Limited | Bicyclo[2.2.]hept-7-ylamine derivatives and their uses |
| GB0516313D0 (en) | 2005-08-08 | 2005-09-14 | Argenta Discovery Ltd | Azole derivatives and their uses |
| WO2007036028A1 (en) * | 2005-09-29 | 2007-04-05 | University Of Alberta | Compositions for and methods of granzyme b inhibition |
| GB0605469D0 (en) * | 2006-03-17 | 2006-04-26 | Argenta Discovery Ltd | Multimers of heterocyclic compounds and their use |
| TW200808763A (en) | 2006-05-08 | 2008-02-16 | Astrazeneca Ab | Novel compounds I |
| TW200808771A (en) * | 2006-05-08 | 2008-02-16 | Astrazeneca Ab | Novel compounds II |
| EP2535330A3 (en) | 2006-10-23 | 2012-12-26 | Takeda Pharmaceutical Company Limited | Iminopyridine derivative and use thereof |
| US7851489B2 (en) | 2006-11-08 | 2010-12-14 | Bristol-Myers Squibb Company | Pyridinone compounds |
| AR069206A1 (es) * | 2007-11-06 | 2010-01-06 | Astrazeneca Ab | Derivados de 2-pirazinona, proceso para preparalos, composiciones farmaceuticas que los comprenden, proceso de preparacion de las mismas y usos en el tratamiento de trastornos osteoarticularesy del aparato respiratorio, entre otros. |
| PL2327693T3 (pl) | 2007-12-14 | 2012-11-30 | Pulmagen Therapeutics Asthma Ltd | Indole i ich zastosowanie terapeutyczne |
| BRPI0906444B8 (pt) | 2008-01-23 | 2021-05-25 | Bristol Myers Squibb Co | compostos de 4-piridinona, composição farmacêutica que os compreende, bem como uso dos mesmos |
| US8481569B2 (en) | 2008-04-23 | 2013-07-09 | Takeda Pharmaceutical Company Limited | Iminopyridine derivatives and use thereof |
| EP2296653B1 (en) | 2008-06-03 | 2016-01-27 | Intermune, Inc. | Compounds and methods for treating inflammatory and fibrotic disorders |
| GB0902648D0 (en) | 2009-02-17 | 2009-04-01 | Argenta Discovery Ltd | Pharmaceutical compounds and compositions |
| PE20120655A1 (es) | 2009-02-17 | 2012-06-07 | Chiesi Farma Spa | Derivados de triazolopiridina como inhibidores de proteinas cinasas activadas por mitogeno p38 (map) |
| TW201036957A (en) | 2009-02-20 | 2010-10-16 | Astrazeneca Ab | Novel salt 628 |
| KR20120099639A (ko) * | 2009-10-02 | 2012-09-11 | 아스트라제네카 아베 | 호중구 엘라스타제의 억제제로서 사용되는 2-피리돈 화합물 |
| GB0918924D0 (en) | 2009-10-28 | 2009-12-16 | Vantia Ltd | Azaindole derivatives |
| GB0918922D0 (en) | 2009-10-28 | 2009-12-16 | Vantia Ltd | Aminopyridine derivatives |
| GB0918923D0 (en) | 2009-10-28 | 2009-12-16 | Vantia Ltd | Aminothiazole derivatives |
| MX2012006524A (es) * | 2009-12-08 | 2012-07-17 | Boehringer Ingelheim Int | Proceso para la sintesis de compuestos intermedios de utilidad para preparar compuestos sustituidos de indazol y azaindol. |
| GB201009731D0 (en) | 2010-06-10 | 2010-07-21 | Pulmagen Therapeutics Inflamma | Kinase inhibitors |
| US9040516B2 (en) | 2011-08-01 | 2015-05-26 | Sumitomo Dainippon Pharma Co., Ltd. | Uracil derivative and use thereof for medical purposes |
| RU2623734C9 (ru) | 2011-12-09 | 2017-09-18 | КЬЕЗИ ФАРМАЧЕУТИЧИ С.п.А. | Ингибиторы киназы |
| KR101994381B1 (ko) | 2011-12-09 | 2019-06-28 | 키에시 파르마슈티시 엣스. 피. 에이. | 키나아제 억제제 |
| EP2788345B1 (en) | 2011-12-09 | 2020-06-10 | Chiesi Farmaceutici S.p.A. | Derivatives of 4-hydroxy-1,2,3,4-tetrahydronaphtalen-1-yl urea and their use in the treatment of, inter alia, diseases of the respiratory tract |
| US20140057920A1 (en) | 2012-08-23 | 2014-02-27 | Boehringer Ingelheim International Gmbh | Substituted 4-pyridones and their use as inhibitors of neutrophil elastase activity |
| US9102624B2 (en) | 2012-08-23 | 2015-08-11 | Boehringer Ingelheim International Gmbh | Substituted 4-pyridones and their use as inhibitors of neutrophil elastase activity |
| US20140057926A1 (en) | 2012-08-23 | 2014-02-27 | Boehringer Ingelheim International Gmbh | Substituted 4-pyridones and their use as inhibitors of neutrophil elastase activity |
| AR092742A1 (es) | 2012-10-02 | 2015-04-29 | Intermune Inc | Piridinonas antifibroticas |
| WO2014195402A1 (en) | 2013-06-06 | 2014-12-11 | Chiesi Farmaceutici S.P.A. | Kinase inhibitors |
| US9221807B2 (en) * | 2014-02-21 | 2015-12-29 | Boehringer Ingelheim International Gmbh | Substituted pyridones and pyrazinones and their use as inhibitors of neutrophil elastase activity |
| CN110452216B (zh) | 2014-04-02 | 2022-08-26 | 英特穆恩公司 | 抗纤维化吡啶酮类 |
| US10428026B2 (en) | 2015-09-02 | 2019-10-01 | Glaxosmithkline Intellectual Property (No.2) Limited | Pyridinone dicarboxamide for use as bromodomain inhibitors |
| TW201720828A (zh) | 2015-11-23 | 2017-06-16 | 赫孚孟拉羅股份公司 | 治療性化合物及組合物以及其使用方法 |
| EP3394060A1 (en) | 2015-12-23 | 2018-10-31 | Chiesi Farmaceutici S.p.A. | 1-(3-tert-butyl-2h-pyrazol-5-yl or 5-tert-butyl-isoxaol-3-yl)-3-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalenyl) urea derivatives and their use as p38 mapk inhibitors |
| TW201730189A (zh) | 2015-12-23 | 2017-09-01 | 吉斯藥品公司 | 激酶抑制劑 |
| AR107163A1 (es) | 2015-12-23 | 2018-03-28 | Chiesi Farm Spa | Inhibidores de quinasa |
| EP3452464B1 (en) | 2016-05-05 | 2021-12-15 | F. Hoffmann-La Roche AG | Pyrazole derivatives, compositions and therapeutic use thereof |
| EP3510030B1 (en) | 2016-09-06 | 2023-03-22 | F. Hoffmann-La Roche AG | 8-(azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridinyl compounds, compositions and methods of use thereof |
| JP6900491B2 (ja) | 2016-12-29 | 2021-07-07 | エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ | ピラゾロピリミジン化合物及びその使用方法 |
| CN110494434B (zh) | 2017-03-14 | 2022-05-24 | 豪夫迈·罗氏有限公司 | 吡唑并氯苯基化合物、其组合物及其使用方法 |
| CA3061236A1 (en) | 2017-05-22 | 2018-11-29 | F. Hoffmann-La Roche Ag | Therapeutic compounds and compositions, and methods of use thereof |
| US20180334465A1 (en) | 2017-05-22 | 2018-11-22 | Genentech, Inc. | Therapeutic compounds and compositions, and methods of use thereof |
| US10364245B2 (en) | 2017-06-07 | 2019-07-30 | Chiesi Farmaceutici S.P.A. | Kinase inhibitors |
| JP7339263B2 (ja) | 2018-01-15 | 2023-09-05 | エフ． ホフマン－ラ ロシュ アーゲー | Ｊａｋ阻害剤としてのピラゾロピリミジン化合物 |
| CN111683976B (zh) | 2018-02-05 | 2022-11-18 | 生物辐射实验室股份有限公司 | 具有阴离子交换-疏水混合模式配体的色谱树脂 |
| CN110192948B (zh) * | 2019-05-28 | 2022-01-04 | 河南省超亚医药器械有限公司 | 一种小儿腹部热敷贴 |
| CN110192947B (zh) * | 2019-05-28 | 2022-01-04 | 河南省超亚医药器械有限公司 | 一种小儿肺部热敷贴 |
| PE20220577A1 (es) | 2019-06-18 | 2022-04-20 | Hoffmann La Roche | Inhibidores de jak cinasas basados en pirazolopirimidina sulfona y usos de los mismos |
| WO2020257143A1 (en) | 2019-06-18 | 2020-12-24 | Genentech, Inc. | Pyrazolopyrimidine aryl ether inhibitors of jak kinases and uses thereof |
| TW202115069A (zh) | 2019-06-18 | 2021-04-16 | 瑞士商赫孚孟拉羅股份公司 | Ｊａｋ激酶之經四唑取代之吡唑并嘧啶抑制劑及其用途 |
| CN114650819A (zh) | 2019-09-17 | 2022-06-21 | 美莱奥生物制药第四有限公司 | 用于治疗移植物排斥、闭塞性细支气管炎综合征和移植物抗宿主病的阿维来司他 |
| US20230218596A1 (en) | 2020-04-16 | 2023-07-13 | Mereo Biopharma 4 Limited | Methods involving neutrophil elastase inhibitor alvelestat for treating coronavirus infection |
| KR20240090272A (ko) | 2021-10-20 | 2024-06-21 | 메레오 바이오파마 4 리미티드 | 섬유화 치료에 사용하기 위한 호중구 엘라스테이스 억제제 |
| CN114057630B (zh) * | 2021-12-23 | 2023-06-02 | 郑州大学 | 吡非尼酮衍生物及其合成方法和应用 |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9207145D0 (en) * | 1991-04-18 | 1992-05-13 | Ici Plc | Heterocyclic amides |
| US5521179A (en) * | 1991-04-18 | 1996-05-28 | Zeneca Limited | Heterocyclic amides |
| FR2687674B1 (fr) * | 1992-02-07 | 1995-05-19 | Roussel Uclaf | Nouveaux derives de la pyridone, leur procede de preparation, les nouveaux intermediaires obtenus, leur application a titre de medicaments et les compositions pharmaceutiques les renfermant. |
| DK1142887T3 (da) * | 1993-11-19 | 2004-06-21 | Parke Davis & Co | 5,6-Dihydropyronderivater som proteaseinhibitorer og antivirale midler |
| RU2067579C1 (ru) * | 1994-10-07 | 1996-10-10 | Пермский фармацевтический институт | 3-(2'-нафтоилметилен)-пиперазинон-2 и 1-n-фенил-3-фенацилиденпиперазинон-2, проявляющие противовоспалительную активность |
| TWI287004B (en) * | 2000-12-28 | 2007-09-21 | Shionogi & Co | A pyridone derivative having an affinity effect for cannabinoid 2 type receptor |
| GB0129260D0 (en) * | 2001-12-06 | 2002-01-23 | Eisai London Res Lab Ltd | Pharmaceutical compositions and their uses |
| CA2470813A1 (en) * | 2001-12-20 | 2003-07-03 | Bayer Healthcare Ag | 1,4-dihydro-1,4-diphenylpyridine derivatives |
| GB2383326A (en) * | 2001-12-20 | 2003-06-25 | Bayer Ag | Antiinflammatory dihydropyridines |
| TW200500341A (en) * | 2002-11-12 | 2005-01-01 | Astrazeneca Ab | Novel compounds |
| SE0302486D0 (sv) * | 2003-09-18 | 2003-09-18 | Astrazeneca Ab | Novel compounds |
-
2003
- 2003-09-18 SE SE0302487A patent/SE0302487D0/xx unknown
-
2004
- 2004-09-13 TW TW093127678A patent/TW200526579A/zh unknown
- 2004-09-15 RU RU2006112427/04A patent/RU2348617C2/ru not_active IP Right Cessation
- 2004-09-15 UY UY28513A patent/UY28513A1/es unknown
- 2004-09-15 MX MXPA06002723A patent/MXPA06002723A/es unknown
- 2004-09-15 US US10/572,640 patent/US20070043036A1/en not_active Abandoned
- 2004-09-15 WO PCT/SE2004/001336 patent/WO2005026124A1/en not_active Ceased
- 2004-09-15 JP JP2006526856A patent/JP2007505902A/ja active Pending
- 2004-09-15 ES ES04775439T patent/ES2319300T3/es not_active Expired - Lifetime
- 2004-09-15 AT AT04775439T patent/ATE420861T1/de not_active IP Right Cessation
- 2004-09-15 EP EP04775439A patent/EP1663974B1/en not_active Expired - Lifetime
- 2004-09-15 KR KR1020067005458A patent/KR20060096995A/ko not_active Withdrawn
- 2004-09-15 UA UAA200602252A patent/UA84878C2/ru unknown
- 2004-09-15 AU AU2004272485A patent/AU2004272485B2/en not_active Ceased
- 2004-09-15 CN CNB2004800275174A patent/CN100439339C/zh not_active Expired - Fee Related
- 2004-09-15 BR BRPI0414570-4A patent/BRPI0414570A/pt not_active IP Right Cessation
- 2004-09-15 CA CA002538410A patent/CA2538410A1/en not_active Abandoned
- 2004-09-15 DE DE602004019110T patent/DE602004019110D1/de not_active Expired - Fee Related
- 2004-09-17 AR ARP040103354A patent/AR046083A1/es not_active Application Discontinuation
- 2004-09-18 SA SA4250300A patent/SA04250300B1/ar unknown
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2006
- 2006-02-27 IL IL173986A patent/IL173986A0/en unknown
- 2006-03-15 CO CO06026211A patent/CO5670357A2/es not_active Application Discontinuation
- 2006-03-17 ZA ZA200602262A patent/ZA200602262B/xx unknown
- 2006-03-31 IS IS8394A patent/IS8394A/is unknown
- 2006-04-18 NO NO20061700A patent/NO20061700L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200602262B (en) | 2007-07-25 |
| CN100439339C (zh) | 2008-12-03 |
| AU2004272485A1 (en) | 2005-03-24 |
| KR20060096995A (ko) | 2006-09-13 |
| UA84878C2 (ru) | 2008-12-10 |
| CO5670357A2 (es) | 2006-08-31 |
| RU2006112427A (ru) | 2007-11-10 |
| US20070043036A1 (en) | 2007-02-22 |
| BRPI0414570A (pt) | 2006-11-07 |
| UY28513A1 (es) | 2005-04-29 |
| AR046083A1 (es) | 2005-11-23 |
| RU2348617C2 (ru) | 2009-03-10 |
| SA04250300B1 (ar) | 2008-09-07 |
| DE602004019110D1 (de) | 2009-03-05 |
| JP2007505902A (ja) | 2007-03-15 |
| MXPA06002723A (es) | 2006-06-06 |
| NO20061700L (no) | 2006-04-18 |
| IL173986A0 (en) | 2006-07-05 |
| ATE420861T1 (de) | 2009-01-15 |
| SE0302487D0 (sv) | 2003-09-18 |
| WO2005026124A1 (en) | 2005-03-24 |
| EP1663974B1 (en) | 2009-01-14 |
| IS8394A (is) | 2006-03-31 |
| ES2319300T3 (es) | 2009-05-06 |
| HK1089167A1 (en) | 2006-11-24 |
| EP1663974A1 (en) | 2006-06-07 |
| CN1856467A (zh) | 2006-11-01 |
| TW200526579A (en) | 2005-08-16 |
| AU2004272485B2 (en) | 2008-03-13 |
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