UA76760C2 - Піролопіримідини як інгібітори протеїнкінази - Google Patents
Піролопіримідини як інгібітори протеїнкінази Download PDFInfo
- Publication number
- UA76760C2 UA76760C2 UA2004010502A UA200410502A UA76760C2 UA 76760 C2 UA76760 C2 UA 76760C2 UA 2004010502 A UA2004010502 A UA 2004010502A UA 200410502 A UA200410502 A UA 200410502A UA 76760 C2 UA76760 C2 UA 76760C2
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- Prior art keywords
- alkyl
- compound according
- compound
- aryl
- substituted
- Prior art date
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- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title description 3
- 239000003909 protein kinase inhibitor Substances 0.000 title description 3
- DDWJFSYHYPDQEL-UHFFFAOYSA-N pyrimidine;1h-pyrrole Chemical class C=1C=CNC=1.C1=CN=CN=C1 DDWJFSYHYPDQEL-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 243
- 238000000034 method Methods 0.000 claims abstract description 64
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- 229940002612 prodrug Drugs 0.000 claims abstract description 16
- 239000012453 solvate Substances 0.000 claims abstract description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 71
- -1 cyclic acetal Chemical class 0.000 claims description 70
- 125000003118 aryl group Chemical group 0.000 claims description 38
- 125000001072 heteroaryl group Chemical group 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 25
- 125000001041 indolyl group Chemical group 0.000 claims description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 19
- 125000003342 alkenyl group Chemical group 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 14
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- 206010028980 Neoplasm Diseases 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 11
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 11
- 230000003197 catalytic effect Effects 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 239000003112 inhibitor Substances 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 206010003246 arthritis Diseases 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 4
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 4
- 230000001668 ameliorated effect Effects 0.000 claims description 4
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
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- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 201000004624 Dermatitis Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 3
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 3
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 3
- 201000010105 allergic rhinitis Diseases 0.000 claims description 3
- 208000010668 atopic eczema Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 2
- 206010010744 Conjunctivitis allergic Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 2
- 229910052770 Uranium Inorganic materials 0.000 claims description 2
- 208000002205 allergic conjunctivitis Diseases 0.000 claims description 2
- 208000024998 atopic conjunctivitis Diseases 0.000 claims description 2
- 230000002757 inflammatory effect Effects 0.000 claims description 2
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- 201000005202 lung cancer Diseases 0.000 claims description 2
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- 201000001275 rectum cancer Diseases 0.000 claims description 2
- 201000005404 rubella Diseases 0.000 claims description 2
- 208000017520 skin disease Diseases 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 201000002510 thyroid cancer Diseases 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims 2
- 206010010741 Conjunctivitis Diseases 0.000 claims 1
- 206010011686 Cutaneous vasculitis Diseases 0.000 claims 1
- 206010012468 Dermatitis herpetiformis Diseases 0.000 claims 1
- 206010048768 Dermatosis Diseases 0.000 claims 1
- 208000000453 Skin Neoplasms Diseases 0.000 claims 1
- 206010047124 Vasculitis necrotising Diseases 0.000 claims 1
- 230000000172 allergic effect Effects 0.000 claims 1
- 201000000849 skin cancer Diseases 0.000 claims 1
- 238000012876 topography Methods 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 29
- 150000001204 N-oxides Chemical class 0.000 abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 93
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 76
- 239000000243 solution Substances 0.000 description 49
- 230000003993 interaction Effects 0.000 description 47
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 36
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 34
- 230000000052 comparative effect Effects 0.000 description 32
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 238000010992 reflux Methods 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- 108091000080 Phosphotransferase Proteins 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- 102000020233 phosphotransferase Human genes 0.000 description 18
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 17
- 235000019341 magnesium sulphate Nutrition 0.000 description 17
- 125000004432 carbon atom Chemical group C* 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 15
- 230000008569 process Effects 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 239000002585 base Substances 0.000 description 14
- 239000000377 silicon dioxide Substances 0.000 description 14
- 238000003818 flash chromatography Methods 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
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- 239000011541 reaction mixture Substances 0.000 description 12
- 239000012312 sodium hydride Substances 0.000 description 12
- 229910000104 sodium hydride Inorganic materials 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 11
- 229910052740 iodine Inorganic materials 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- 102000001253 Protein Kinase Human genes 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
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- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 9
- 108060006633 protein kinase Proteins 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
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- 239000011630 iodine Substances 0.000 description 8
- 229910052763 palladium Inorganic materials 0.000 description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 7
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 7
- 230000029936 alkylation Effects 0.000 description 7
- 238000005804 alkylation reaction Methods 0.000 description 7
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
- 241000282414 Homo sapiens Species 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
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- 210000003630 histaminocyte Anatomy 0.000 description 6
- 150000004677 hydrates Chemical class 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
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- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 125000004076 pyridyl group Chemical group 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- ZXUCBXRTRRIBSO-UHFFFAOYSA-L tetrabutylazanium;sulfate Chemical compound [O-]S([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC ZXUCBXRTRRIBSO-UHFFFAOYSA-L 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
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- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
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- 125000002950 monocyclic group Chemical group 0.000 description 5
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- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
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- CBTVGIZVANVGBH-UHFFFAOYSA-N aminomethyl propanol Chemical compound CC(C)(N)CO CBTVGIZVANVGBH-UHFFFAOYSA-N 0.000 description 4
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- YMQRPXBBBOXHNZ-UHFFFAOYSA-N 2-chloro-1-morpholin-4-ylethanone Chemical compound ClCC(=O)N1CCOCC1 YMQRPXBBBOXHNZ-UHFFFAOYSA-N 0.000 description 3
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
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- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
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- AAWZDTNXLSGCEK-LNVDRNJUSA-N (3r,5r)-1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid Chemical class O[C@@H]1CC(O)(C(O)=O)C[C@@H](O)C1O AAWZDTNXLSGCEK-LNVDRNJUSA-N 0.000 description 2
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- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
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- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
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- 125000003373 pyrazinyl group Chemical group 0.000 description 1
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- ABMYEXAYWZJVOV-UHFFFAOYSA-N pyridin-3-ylboronic acid Chemical compound OB(O)C1=CC=CN=C1 ABMYEXAYWZJVOV-UHFFFAOYSA-N 0.000 description 1
- 125000005400 pyridylcarbonyl group Chemical group N1=C(C=CC=C1)C(=O)* 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
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- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-N sodium;hydron;carbonate Chemical compound [Na+].OC(O)=O UIIMBOGNXHQVGW-UHFFFAOYSA-N 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 230000020347 spindle assembly Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
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- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical class NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
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- 201000004595 synovitis Diseases 0.000 description 1
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- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
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- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
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- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 description 1
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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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
-
- 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
- A61P17/06—Antipsoriatics
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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
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/14—Decongestants or antiallergics
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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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- 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
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- 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
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0115393.1A GB0115393D0 (en) | 2001-06-23 | 2001-06-23 | Chemical compounds |
| US30167801P | 2001-06-28 | 2001-06-28 | |
| PCT/GB2002/002835 WO2003000695A1 (fr) | 2001-06-23 | 2002-06-21 | Pyrrolopyrimidines utilisees en tant qu'inhibiteurs des proteines kinases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| UA76760C2 true UA76760C2 (uk) | 2006-09-15 |
Family
ID=9917225
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| UA2004010502A UA76760C2 (uk) | 2001-06-23 | 2002-06-21 | Піролопіримідини як інгібітори протеїнкінази |
Country Status (22)
| Country | Link |
|---|---|
| EP (1) | EP1404676A1 (fr) |
| JP (1) | JP4344607B2 (fr) |
| CN (1) | CN1294135C (fr) |
| AU (1) | AU2002314325B8 (fr) |
| BR (1) | BR0210652A (fr) |
| CA (1) | CA2451932C (fr) |
| CZ (1) | CZ20033443A3 (fr) |
| EA (1) | EA007415B1 (fr) |
| EC (1) | ECSP034922A (fr) |
| EE (1) | EE05432B1 (fr) |
| GB (1) | GB0115393D0 (fr) |
| HU (1) | HUP0400300A3 (fr) |
| ME (1) | MEP19308A (fr) |
| NZ (1) | NZ529766A (fr) |
| OA (1) | OA12632A (fr) |
| PL (1) | PL374096A1 (fr) |
| RS (1) | RS51698B (fr) |
| SK (1) | SK15882003A3 (fr) |
| TN (1) | TNSN03144A1 (fr) |
| TR (1) | TR200302242T2 (fr) |
| UA (1) | UA76760C2 (fr) |
| WO (1) | WO2003000695A1 (fr) |
Families Citing this family (57)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0202679D0 (en) * | 2002-02-05 | 2002-03-20 | Glaxo Group Ltd | Novel compounds |
| US7517886B2 (en) | 2002-07-29 | 2009-04-14 | Rigel Pharmaceuticals, Inc. | Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds |
| EP1687309A1 (fr) | 2003-11-17 | 2006-08-09 | Pfizer Products Inc. | Composés de pyrrolopyrimidine utiles dans le traitement du cancer |
| BRPI0416909A (pt) * | 2003-11-25 | 2007-01-16 | Pfizer Prod Inc | método de tratamento de aterosclerose |
| US20050250829A1 (en) * | 2004-04-23 | 2005-11-10 | Takeda San Diego, Inc. | Kinase inhibitors |
| FR2876103B1 (fr) * | 2004-10-01 | 2008-02-22 | Aventis Pharma Sa | Nouveaux derives bis-azaindoles, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de kinases |
| US7713973B2 (en) | 2004-10-15 | 2010-05-11 | Takeda Pharmaceutical Company Limited | Kinase inhibitors |
| FR2878849B1 (fr) | 2004-12-06 | 2008-09-12 | Aventis Pharma Sa | Indoles substitues, compositions les contenant, procede de fabrication et utilisation |
| CA2607901C (fr) | 2005-06-13 | 2016-08-16 | Rigel Pharmaceuticals, Inc. | Methodes et compositions pour le traitement de maladies osseuses degeneratives comprenant un compose inhibiteur syk 2,4-pyrimidinediamine |
| US8119655B2 (en) | 2005-10-07 | 2012-02-21 | Takeda Pharmaceutical Company Limited | Kinase inhibitors |
| MY162590A (en) | 2005-12-13 | 2017-06-30 | Incyte Holdings Corp | Heteroaryl substituted pyrrolo[2,3-b] pyridines and pyrrolo[2,3-b] pyrimidines as janus kinase inhibitors |
| JP2010505962A (ja) | 2006-10-09 | 2010-02-25 | 武田薬品工業株式会社 | キナーゼ阻害剤 |
| EP3495369B1 (fr) | 2007-06-13 | 2021-10-27 | Incyte Holdings Corporation | Utilisation des sels de l'inhibiteur de janus kinase (r)-3-(4-(7h-pyrrolo [2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropanenitrile |
| NZ586642A (en) | 2008-01-11 | 2012-04-27 | Natco Pharma Ltd | Novel pyrazolo [3, 4 -d] pyrimidine derivatives as anti -cancer agents |
| PE20140407A1 (es) | 2008-06-10 | 2014-04-25 | Abbott Lab | Nuevos compuestos triciclicos |
| MX2011012262A (es) | 2009-05-22 | 2012-01-25 | Incyte Corp | 3-[4-(7h-pirrolo[2,3-d]pirimidin-4-il)-1h-pirazol-1-il] octano-o heptano-nitrilo como inhibidores de cinasas janus (jak). |
| EA025520B1 (ru) | 2009-05-22 | 2017-01-30 | Инсайт Холдингс Корпорейшн | N-(ГЕТЕРО)АРИЛПИРРОЛИДИНОВЫЕ ПРОИЗВОДНЫЕ ПИРАЗОЛ-4-ИЛ-ПИРРОЛО[2,3-d]ПИРИМИДИНОВ И ПИРРОЛ-3-ИЛ-ПИРРОЛО[2,3-d]ПИРИМИДИНОВ В КАЧЕСТВЕ ИНГИБИТОРОВ ЯНУС-КИНАЗЫ |
| WO2011018894A1 (fr) * | 2009-08-10 | 2011-02-17 | Raqualia Pharma Inc. | Dérivés de pyrrolopyrimidine comme modulateurs des canaux potassium |
| TW201113285A (en) | 2009-09-01 | 2011-04-16 | Incyte Corp | Heterocyclic derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors |
| US9029359B2 (en) | 2009-09-04 | 2015-05-12 | Biogen Idec Ma, Inc. | Heteroaryl Btk inhibitors |
| TW201802091A (zh) * | 2009-12-01 | 2018-01-16 | 艾伯維有限公司 | 新穎三環化合物 |
| SI3354652T1 (sl) | 2010-03-10 | 2020-08-31 | Incyte Holdings Corporation | Derivati piperidin-4-il azetidina kot inhibitorji JAK1 |
| SG10201910912TA (en) | 2010-05-21 | 2020-01-30 | Incyte Corp | Topical Formulation for a JAK Inhibitor |
| US9034884B2 (en) | 2010-11-19 | 2015-05-19 | Incyte Corporation | Heterocyclic-substituted pyrrolopyridines and pyrrolopyrimidines as JAK inhibitors |
| BR112013012502A2 (pt) | 2010-11-19 | 2019-03-06 | Incyte Corporation | pirrolopiridina ciclobutil substituída e derivados de pirrolopirimidina derivativos como inibidores de jak |
| CN102093364B (zh) * | 2011-01-07 | 2015-01-28 | 北京赛林泰医药技术有限公司 | 作为FAK/Pyk2抑制剂的2,4-二氨基-6,7-二氢-5H-吡咯并[2,3]嘧啶衍生物 |
| CN103476776B (zh) * | 2011-01-07 | 2016-09-28 | 北京赛林泰医药技术有限公司 | 作为FAK/Pyk2抑制剂的2,4-二氨基-6,7-二氢-5H-吡咯并[2,3]嘧啶衍生物 |
| MY165963A (en) | 2011-06-20 | 2018-05-18 | Incyte Holdings Corp | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as jak inhibitors |
| TW201313721A (zh) | 2011-08-18 | 2013-04-01 | Incyte Corp | 作為ｊａｋ抑制劑之環己基氮雜環丁烷衍生物 |
| UA111854C2 (uk) | 2011-09-07 | 2016-06-24 | Інсайт Холдінгс Корпорейшн | Способи і проміжні сполуки для отримання інгібіторів jak |
| JP6182593B2 (ja) | 2012-04-20 | 2017-08-16 | アドヴィーナス セラピューティクス リミテッド | 置換ヘテロ二環化合物、組成物及び医薬並びにそれらの用途 |
| US9193733B2 (en) | 2012-05-18 | 2015-11-24 | Incyte Holdings Corporation | Piperidinylcyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors |
| DK2877467T3 (en) | 2012-07-26 | 2017-02-13 | Glaxo Group Ltd | 2- (AZAINDOL-2-YL) BENZIMIDAZOLES AS PAD4 INHIBITORS |
| JP6318156B2 (ja) * | 2012-09-06 | 2018-04-25 | プレキシコン インコーポレーテッドＰｌｅｘｘｉｋｏｎ Ｉｎｃ． | キナーゼをモジュレートするための化合物および方法、ならびにその指標 |
| SG11201503695XA (en) | 2012-11-15 | 2015-06-29 | Incyte Corp | Sustained-release dosage forms of ruxolitinib |
| EA030705B1 (ru) | 2013-03-06 | 2018-09-28 | Инсайт Холдингс Корпорейшн | Способы и промежуточные соединения при получении ингибитора jak |
| AU2014244263A1 (en) | 2013-03-13 | 2015-08-13 | Abbvie Inc. | CDK9 kinase inhibitors |
| BR112015021549A2 (pt) | 2013-03-13 | 2017-07-18 | Abbvie Inc | inibidores de piridina cinase cdk9 |
| WO2014151444A1 (fr) | 2013-03-14 | 2014-09-25 | Abbvie Inc. | Inhibiteurs de pyrrolo[2,3-b]pyridine cdk9 kinase |
| AU2014231567A1 (en) | 2013-03-14 | 2015-10-01 | Abbvie Inc. | Pyrrolo[2,3-b]pyridine CDK9 kinase inhibitors |
| JP2016512560A (ja) * | 2013-03-14 | 2016-04-28 | アッヴィ・インコーポレイテッド | ピロロピリミジン系ｃｄｋ９キナーゼ阻害薬 |
| ES2792549T3 (es) | 2013-08-07 | 2020-11-11 | Incyte Corp | Formas de dosificación de liberación sostenida para un inhibidor de JAK1 |
| CN104804001B9 (zh) * | 2014-01-24 | 2022-02-08 | 江苏柯菲平医药股份有限公司 | 4-取代吡咯并[2,3-d]嘧啶化合物及其用途 |
| WO2015184305A1 (fr) | 2014-05-30 | 2015-12-03 | Incyte Corporation | Traitement de la leucémie neutrophile chronique (cnl) et de la leucémie myéloïde chronique atypique (acml) par des inhibiteurs de jak1 |
| SG10201913986YA (en) | 2015-10-16 | 2020-03-30 | Abbvie Inc | PROCESSES FOR THE PREPARATION OF (3S,4R)-3-ETHYL-4-(3H-IMIDAZO[1,2-a]PYRROLO[2,3-e]-PYRAZIN-8-YL)-N-(2,2,2-TRIFLUOROETHYL)PYRROLIDINE-1-CARBOXAMIDE AND SOLID STATE FORMS THEREOF |
| US11365198B2 (en) | 2015-10-16 | 2022-06-21 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
| US11773106B2 (en) | 2015-10-16 | 2023-10-03 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
| US11524964B2 (en) | 2015-10-16 | 2022-12-13 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
| US10550126B2 (en) | 2015-10-16 | 2020-02-04 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-A]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
| US11512092B2 (en) | 2015-10-16 | 2022-11-29 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
| US11564922B2 (en) | 2017-03-09 | 2023-01-31 | Abbvie Inc. | Methods of treating crohn's disease and ulcerative colitis |
| WO2018165581A1 (fr) | 2017-03-09 | 2018-09-13 | Abbvie Inc. | Procédés de traitement de la maladie de crohn et de la rectocolite hémorragique |
| US10596161B2 (en) | 2017-12-08 | 2020-03-24 | Incyte Corporation | Low dose combination therapy for treatment of myeloproliferative neoplasms |
| PL3746429T3 (pl) | 2018-01-30 | 2022-06-20 | Incyte Corporation | Procesy do otrzymywania (1-(3-fluoro-2-(trifluorometylo)izonikotynoilo)piperydyn-4-onu) |
| WO2019191684A1 (fr) | 2018-03-30 | 2019-10-03 | Incyte Corporation | Traitement de l'hidradénite suppurée à l'aide d'inhibiteurs de jak |
| EP3860998B1 (fr) | 2018-10-05 | 2023-12-27 | Annapurna Bio Inc. | Composés et compositions destinés au traitement d'états pathologiques associés à une activité du récepteur de l'apj |
| US11833155B2 (en) | 2020-06-03 | 2023-12-05 | Incyte Corporation | Combination therapy for treatment of myeloproliferative neoplasms |
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| AU1441497A (en) * | 1996-01-23 | 1997-08-20 | Novartis Ag | Pyrrolopyrimidines and processes for their preparation |
| BR9713552A (pt) * | 1996-11-27 | 2000-01-25 | Pfizer | Derivados de pirimidina bicìclicos condensados |
| ID26698A (id) * | 1998-06-19 | 2001-02-01 | Pfizer Prod Inc | SENYAWA-SENYAWA PIROLO [2,3-d] PIRIMIDINA |
| PA8474101A1 (es) * | 1998-06-19 | 2000-09-29 | Pfizer Prod Inc | Compuestos de pirrolo [2,3-d] pirimidina |
| CZ2001959A3 (cs) * | 1998-09-18 | 2001-12-12 | Basf Aktiengesellschaft | 4-Aminopyrrolopyrimidiny jako inhibitory kinasy |
| DK1235830T3 (da) * | 1999-12-10 | 2004-03-29 | Pfizer Prod Inc | Pyrrolo[2,3-d]pyrimidin-forbindelser som proteinkinaseinhibitorer |
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- 2002-06-21 TR TR2003/02242T patent/TR200302242T2/xx unknown
- 2002-06-21 PL PL02374096A patent/PL374096A1/xx not_active Application Discontinuation
- 2002-06-21 EA EA200400073A patent/EA007415B1/ru not_active IP Right Cessation
- 2002-06-21 UA UA2004010502A patent/UA76760C2/uk unknown
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- 2002-06-21 TN TNPCT/GB2002/002835A patent/TNSN03144A1/en unknown
- 2002-06-21 EP EP02740895A patent/EP1404676A1/fr not_active Withdrawn
- 2002-06-21 OA OA1200300335A patent/OA12632A/en unknown
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- 2002-06-21 SK SK1588-2003A patent/SK15882003A3/sk not_active Application Discontinuation
- 2002-06-21 WO PCT/GB2002/002835 patent/WO2003000695A1/fr active Application Filing
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- 2002-06-21 CZ CZ20033443A patent/CZ20033443A3/cs unknown
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| Publication number | Publication date |
|---|---|
| CN1518552A (zh) | 2004-08-04 |
| ECSP034922A (es) | 2004-04-28 |
| JP2005508300A (ja) | 2005-03-31 |
| WO2003000695A1 (fr) | 2003-01-03 |
| RS99203A (en) | 2006-12-15 |
| TR200302242T2 (tr) | 2004-12-21 |
| EA007415B1 (ru) | 2006-10-27 |
| NZ529766A (en) | 2008-11-28 |
| MEP19308A (en) | 2010-06-10 |
| JP4344607B2 (ja) | 2009-10-14 |
| CN1294135C (zh) | 2007-01-10 |
| SK15882003A3 (sk) | 2004-07-07 |
| HUP0400300A3 (en) | 2010-12-28 |
| HUP0400300A2 (en) | 2007-08-28 |
| AU2002314325B8 (en) | 2009-01-29 |
| AU2002314325B2 (en) | 2009-01-08 |
| RS51698B (en) | 2011-10-31 |
| EE200400003A (et) | 2004-02-16 |
| EP1404676A1 (fr) | 2004-04-07 |
| CA2451932A1 (fr) | 2003-01-03 |
| CA2451932C (fr) | 2009-12-29 |
| BR0210652A (pt) | 2004-08-10 |
| EA200400073A1 (ru) | 2004-08-26 |
| PL374096A1 (en) | 2005-09-19 |
| GB0115393D0 (en) | 2001-08-15 |
| TNSN03144A1 (en) | 2005-12-23 |
| EE05432B1 (et) | 2011-06-15 |
| CZ20033443A3 (en) | 2004-03-17 |
| WO2003000695A8 (fr) | 2004-03-11 |
| OA12632A (en) | 2006-06-14 |
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