ES2533366T3 - Derivados azoicos de pirazolona biciclo-sustituidos, procedimiento de preparacion y utilización farmacéutica de los mismos - Google Patents
Derivados azoicos de pirazolona biciclo-sustituidos, procedimiento de preparacion y utilización farmacéutica de los mismos Download PDFInfo
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- ES2533366T3 ES2533366T3 ES09703490.4T ES09703490T ES2533366T3 ES 2533366 T3 ES2533366 T3 ES 2533366T3 ES 09703490 T ES09703490 T ES 09703490T ES 2533366 T3 ES2533366 T3 ES 2533366T3
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- Spain
- Prior art keywords
- mixture
- methyl
- mmol
- hydroxy
- dihydro
- Prior art date
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- 238000000034 method Methods 0.000 title description 11
- 238000002360 preparation method Methods 0.000 title description 11
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical class O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 207
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 39
- 239000001257 hydrogen Substances 0.000 claims abstract description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 16
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 15
- 150000002367 halogens Chemical class 0.000 claims abstract description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 14
- 150000001733 carboxylic acid esters Chemical class 0.000 claims abstract description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 10
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 239000012453 solvate Substances 0.000 claims abstract description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 5
- MGQNMYSRDBFUIR-UHFFFAOYSA-N nitro cyanoformate Chemical compound [O-][N+](=O)OC(=O)C#N MGQNMYSRDBFUIR-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 description 427
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 273
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 249
- 238000006243 chemical reaction Methods 0.000 description 169
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 154
- 238000004809 thin layer chromatography Methods 0.000 description 151
- 239000007858 starting material Substances 0.000 description 148
- 230000008034 disappearance Effects 0.000 description 138
- 239000011541 reaction mixture Substances 0.000 description 136
- -1 5'-Fluoro-2'-hydroxy-3 '- [N' - (1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene) -hydrazino] -biphenyl Chemical group 0.000 description 135
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 134
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 132
- 238000004949 mass spectrometry Methods 0.000 description 132
- 239000007787 solid Substances 0.000 description 132
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 126
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 123
- 239000002253 acid Substances 0.000 description 119
- 239000012065 filter cake Substances 0.000 description 113
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 83
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- 239000005457 ice water Substances 0.000 description 81
- 238000005160 1H NMR spectroscopy Methods 0.000 description 77
- 238000010898 silica gel chromatography Methods 0.000 description 64
- 235000010288 sodium nitrite Nutrition 0.000 description 63
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 54
- 238000010992 reflux Methods 0.000 description 45
- 229920006395 saturated elastomer Polymers 0.000 description 44
- 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 42
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 40
- 235000017557 sodium bicarbonate Nutrition 0.000 description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- 238000001816 cooling Methods 0.000 description 38
- 108010041111 Thrombopoietin Proteins 0.000 description 37
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 37
- 102000036693 Thrombopoietin Human genes 0.000 description 36
- 239000000243 solution Substances 0.000 description 35
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 33
- 239000000284 extract Substances 0.000 description 31
- 239000000706 filtrate Substances 0.000 description 31
- 206010033799 Paralysis Diseases 0.000 description 30
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 23
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
- 239000002274 desiccant Substances 0.000 description 21
- 239000010410 layer Substances 0.000 description 21
- 238000005481 NMR spectroscopy Methods 0.000 description 20
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 20
- 239000003921 oil Substances 0.000 description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
- HLSKTUANRGHHGI-UHFFFAOYSA-N 2-(2,3-dihydro-1h-inden-5-yl)-5-methyl-4h-pyrazol-3-one Chemical compound O=C1CC(C)=NN1C1=CC=C(CCC2)C2=C1 HLSKTUANRGHHGI-UHFFFAOYSA-N 0.000 description 18
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 229910000029 sodium carbonate Inorganic materials 0.000 description 16
- 238000012360 testing method Methods 0.000 description 16
- AJNGYKJVXWONGA-UHFFFAOYSA-N 5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-4h-pyrazol-3-one Chemical compound O=C1CC(C)=NN1C1=CC=C(CCCC2)C2=C1 AJNGYKJVXWONGA-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000002156 mixing Methods 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 14
- 239000011877 solvent mixture Substances 0.000 description 14
- 239000012043 crude product Substances 0.000 description 12
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
- 150000004702 methyl esters Chemical class 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- JKHCSEPRRUKNJR-UHFFFAOYSA-N 2-(2-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound C1=CC=C([N+]([O-])=O)C(OC)=C1B1OC(C)(C)C(C)(C)O1 JKHCSEPRRUKNJR-UHFFFAOYSA-N 0.000 description 10
- QWDNBBMMGCAVTN-UHFFFAOYSA-N 3-(3-amino-2-hydroxy-5-methylphenyl)benzoic acid;hydrochloride Chemical compound Cl.CC1=CC(N)=C(O)C(C=2C=C(C=CC=2)C(O)=O)=C1 QWDNBBMMGCAVTN-UHFFFAOYSA-N 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 10
- 125000001072 heteroaryl group Chemical group 0.000 description 10
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 10
- DVNVHYZCRZPUIM-UHFFFAOYSA-N 2-(3,3-dimethyl-1,2-dihydroinden-5-yl)-5-methyl-4h-pyrazol-3-one Chemical compound O=C1CC(C)=NN1C1=CC=C(CCC2(C)C)C2=C1 DVNVHYZCRZPUIM-UHFFFAOYSA-N 0.000 description 9
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 9
- 125000003118 aryl group Chemical group 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- LIIUUBUEBVCYDA-UHFFFAOYSA-N 3-(3-amino-2-hydroxyphenyl)benzoic acid;hydrobromide Chemical compound Br.NC1=CC=CC(C=2C=C(C=CC=2)C(O)=O)=C1O LIIUUBUEBVCYDA-UHFFFAOYSA-N 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 8
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 7
- JUTDHLQZZORZJS-UHFFFAOYSA-N 5-methyl-2-(3-methyl-2,3-dihydro-1h-inden-5-yl)-4h-pyrazol-3-one Chemical compound C1=C2C(C)CCC2=CC=C1N1N=C(C)CC1=O JUTDHLQZZORZJS-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- 239000012298 atmosphere Substances 0.000 description 7
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 7
- ZKFZFBOAGWUBQI-UHFFFAOYSA-N 3-(3-amino-5-fluoro-2-hydroxyphenyl)benzoic acid Chemical compound NC1=CC(F)=CC(C=2C=C(C=CC=2)C(O)=O)=C1O ZKFZFBOAGWUBQI-UHFFFAOYSA-N 0.000 description 6
- CEAZQXRZBQTIIW-UHFFFAOYSA-N 5-(3-amino-2-hydroxyphenyl)furan-2-carboxylic acid;hydrobromide Chemical compound Br.NC1=CC=CC(C=2OC(=CC=2)C(O)=O)=C1O CEAZQXRZBQTIIW-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000012300 argon atmosphere Substances 0.000 description 6
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- 239000012230 colorless oil Substances 0.000 description 6
- 125000004494 ethyl ester group Chemical group 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 210000003593 megakaryocyte Anatomy 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 description 6
- YAYBLVOBUIXMQY-UHFFFAOYSA-N 1-bromo-2-methoxy-3-nitrobenzene Chemical compound COC1=C(Br)C=CC=C1[N+]([O-])=O YAYBLVOBUIXMQY-UHFFFAOYSA-N 0.000 description 5
- LAADWVXCBDSARD-UHFFFAOYSA-N 2-(2,2-dimethyl-1,3-dihydroinden-5-yl)-5-methyl-4h-pyrazol-3-one Chemical compound O=C1CC(C)=NN1C1=CC=C(CC(C)(C)C2)C2=C1 LAADWVXCBDSARD-UHFFFAOYSA-N 0.000 description 5
- SWSCKLXUQFVPPN-UHFFFAOYSA-N 2-amino-6-[3-(2H-tetrazol-5-yl)phenyl]phenol Chemical compound NC1=CC=CC(C=2C=C(C=CC=2)C=2NN=NN=2)=C1O SWSCKLXUQFVPPN-UHFFFAOYSA-N 0.000 description 5
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 5
- SSJHCVPKVRRXNR-UHFFFAOYSA-N 5-methyl-2-(1,1,3,3-tetramethyl-2h-inden-5-yl)-4h-pyrazol-3-one Chemical compound O=C1CC(C)=NN1C1=CC=C2C(C)(C)CC(C)(C)C2=C1 SSJHCVPKVRRXNR-UHFFFAOYSA-N 0.000 description 5
- SEQHEDQNODAFIU-UHFFFAOYSA-N 6-bromo-2,3-dihydroinden-1-one Chemical compound BrC1=CC=C2CCC(=O)C2=C1 SEQHEDQNODAFIU-UHFFFAOYSA-N 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000006285 cell suspension Substances 0.000 description 5
- 125000004093 cyano group Chemical group *C#N 0.000 description 5
- BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 150000003254 radicals Chemical group 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 206010043554 thrombocytopenia Diseases 0.000 description 5
- CMLYAHYWAINDLT-UHFFFAOYSA-N 1-bromo-2-methoxy-5-methyl-3-nitrobenzene Chemical compound COC1=C(Br)C=C(C)C=C1[N+]([O-])=O CMLYAHYWAINDLT-UHFFFAOYSA-N 0.000 description 4
- KBOGEGUAFGNMNM-UHFFFAOYSA-N 2-(2,3-dihydro-1-benzofuran-5-yl)-5-methyl-4h-pyrazol-3-one Chemical compound O=C1CC(C)=NN1C1=CC=C(OCC2)C2=C1 KBOGEGUAFGNMNM-UHFFFAOYSA-N 0.000 description 4
- CLSFJNMZEMHJON-UHFFFAOYSA-N 2-(3-ethyl-2,3-dihydro-1h-inden-5-yl)-5-methyl-4h-pyrazol-3-one Chemical compound C1=C2C(CC)CCC2=CC=C1N1N=C(C)CC1=O CLSFJNMZEMHJON-UHFFFAOYSA-N 0.000 description 4
- IQUPABOKLQSFBK-UHFFFAOYSA-N 2-nitrophenol Chemical compound OC1=CC=CC=C1[N+]([O-])=O IQUPABOKLQSFBK-UHFFFAOYSA-N 0.000 description 4
- BCUGMTSFLCYGEC-UHFFFAOYSA-N 5-(2-methoxy-3-nitrophenyl)furan-2-carboxylic acid Chemical compound C1=CC=C([N+]([O-])=O)C(OC)=C1C1=CC=C(C(O)=O)O1 BCUGMTSFLCYGEC-UHFFFAOYSA-N 0.000 description 4
- UCTQSSOHKXIBKJ-UHFFFAOYSA-N 5-(3-amino-2-hydroxy-5-methylphenyl)thiophene-2-carboxylic acid;hydrobromide Chemical compound Br.CC1=CC(N)=C(O)C(C=2SC(=CC=2)C(O)=O)=C1 UCTQSSOHKXIBKJ-UHFFFAOYSA-N 0.000 description 4
- YPMPBMCHAWUZCJ-UHFFFAOYSA-N 5-(3-amino-2-hydroxyphenyl)thiophene-2-carboxylic acid;hydrobromide Chemical compound Br.NC1=CC=CC(C=2SC(=CC=2)C(O)=O)=C1O YPMPBMCHAWUZCJ-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 4
- OSQPUMRCKZAIOZ-UHFFFAOYSA-N carbon dioxide;ethanol Chemical compound CCO.O=C=O OSQPUMRCKZAIOZ-UHFFFAOYSA-N 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000004677 hydrates Chemical class 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000013612 plasmid Substances 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 239000004317 sodium nitrate Substances 0.000 description 4
- 235000010344 sodium nitrate Nutrition 0.000 description 4
- 238000012453 sprague-dawley rat model Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 4
- RMUJVOPHLHFICQ-UHFFFAOYSA-N 1-bromo-5-fluoro-2-methoxy-3-nitrobenzene Chemical compound COC1=C(Br)C=C(F)C=C1[N+]([O-])=O RMUJVOPHLHFICQ-UHFFFAOYSA-N 0.000 description 3
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- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 1
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- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
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- 125000003373 pyrazinyl group Chemical group 0.000 description 1
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- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
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- 239000012312 sodium hydride Substances 0.000 description 1
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- SBHSXURZUDRJBS-UHFFFAOYSA-N tert-butyl n-(3,3-dimethylinden-5-yl)-n-[(2-methylpropan-2-yl)oxycarbonylamino]carbamate Chemical compound CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)C1=CC=C2C=CC(C)(C)C2=C1 SBHSXURZUDRJBS-UHFFFAOYSA-N 0.000 description 1
- QYZUVRASNWIITO-UHFFFAOYSA-N tert-butyl n-(3-ethyl-2,3-dihydro-1h-inden-5-yl)-n-[(2-methylpropan-2-yl)oxycarbonylamino]carbamate Chemical compound C1=C(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C=C2C(CC)CCC2=C1 QYZUVRASNWIITO-UHFFFAOYSA-N 0.000 description 1
- NNBGENCRTWJCDM-UHFFFAOYSA-N tert-butyl n-(3-methyl-1h-inden-5-yl)-n-[(2-methylpropan-2-yl)oxycarbonylamino]carbamate Chemical compound C1=C(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C=C2C(C)=CCC2=C1 NNBGENCRTWJCDM-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
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- 239000003643 water by type Substances 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D231/08—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen or sulfur atoms directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with 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
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
- C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with 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
- C07D231/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
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| CN200810000346 | 2008-01-10 | ||
| CNA2008100003466A CN101481352A (zh) | 2008-01-10 | 2008-01-10 | 双环取代吡唑酮偶氮类衍生物、其制备方法及其在医药上的应用 |
| PCT/CN2009/000001 WO2009092276A1 (zh) | 2008-01-10 | 2009-01-04 | 双环取代吡唑酮偶氮类衍生物、其制备方法及其在医药上的应用 |
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| WO (1) | WO2009092276A1 (enExample) |
| ZA (1) | ZA201004794B (enExample) |
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| SE0302486D0 (sv) * | 2003-09-18 | 2003-09-18 | Astrazeneca Ab | Novel compounds |
| CN101921232A (zh) | 2009-06-11 | 2010-12-22 | 上海恒瑞医药有限公司 | 双环取代吡唑酮偶氮类衍生物的盐,其制备方法及其在医药上的应用 |
| EP2492262B1 (en) * | 2009-10-23 | 2016-04-20 | Nissan Chemical Industries, Ltd. | Fused heterocyclic compound and thrombopoietin receptor activator |
| CN103360317B (zh) * | 2012-04-11 | 2016-12-14 | 齐鲁制药有限公司 | 双环取代吡唑酮偶氮类衍生物、其制备方法及用途 |
| CN103724206A (zh) * | 2014-01-17 | 2014-04-16 | 青岛农业大学 | 化合物2-溴-4-氟-6-硝基苯酚的制备方法和农用生物活性 |
| WO2015111085A2 (en) * | 2014-01-27 | 2015-07-30 | Cadila Healthcare Limited | Processes for the preparation of eltrombopag and pharmaceutically acceptable salts, solvates and intermediates thereof |
| EP3116469B1 (en) | 2014-03-10 | 2018-10-03 | Mary Kay, Inc. | Skin lightening compositions |
| CN104592033A (zh) * | 2014-12-30 | 2015-05-06 | 杭州和泽医药科技有限公司 | 一种艾曲波帕关键中间体的合成方法 |
| EP3375442A4 (en) * | 2016-01-22 | 2018-12-26 | Jiangsu Hengrui Medicine Co., Ltd. | Pharmaceutical composition comprising bicyclo-substituted pyrazolon azo derivative or salt thereof and preparation method thereof |
| CN106994120B (zh) * | 2016-01-22 | 2021-05-14 | 江苏恒瑞医药股份有限公司 | 一种含有双环取代吡唑酮偶氮类衍生物或其盐的药物组合物及其制备方法 |
| WO2018133818A1 (zh) * | 2017-01-19 | 2018-07-26 | 江苏恒瑞医药股份有限公司 | 一种双环取代吡唑酮偶氮类衍生物的制备方法及其中间体 |
| CN110028497B (zh) * | 2018-01-11 | 2020-11-17 | 江苏恒瑞医药股份有限公司 | 一种血小板生成素模拟物的乙醇胺盐的结晶形式及制备方法 |
| US20220071961A1 (en) * | 2019-01-08 | 2022-03-10 | Jiangsu Hengrui Medicine Co., Ltd. | Dosing Regimen of Bicyclic Substituted Pyrazolone Azo Derivative |
| CN112062699B (zh) * | 2020-11-13 | 2021-02-26 | 苏州开元民生科技股份有限公司 | 一种邻氨基苯硫酚的制备方法 |
| WO2022228551A1 (zh) * | 2021-04-30 | 2022-11-03 | 江苏恒瑞医药股份有限公司 | 一种血小板生成素受体激动剂的给药方案 |
| WO2023143364A1 (zh) * | 2022-01-25 | 2023-08-03 | 江苏恒瑞医药股份有限公司 | 一种血小板生成素受体激动剂的给药方案 |
| WO2025140275A1 (zh) * | 2023-12-25 | 2025-07-03 | 江苏恒瑞医药股份有限公司 | 取代吡唑啉偶氮衍生物的磷酸酯化合物或其可药用盐 |
| CN120383561A (zh) * | 2025-03-26 | 2025-07-29 | 浙江本立科技股份有限公司 | 一种三氯甲基喹啉和2-取代乙酸联产喹啉酰氯和2-取代乙酰氯的方法 |
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| GB775216A (en) * | 1954-02-23 | 1957-05-22 | Sandoz Ltd | Improvements in or relating to monoazo dyestuffs of the benzene-azo-pyrazolone series and their chromium-complex compounds |
| GB806709A (en) * | 1955-04-22 | 1958-12-31 | Bayer Ag | Monoazo dyestuffs of the benzene-azo-pyrazolone series and metal complexes thereof |
| US5869451A (en) | 1995-06-07 | 1999-02-09 | Glaxo Group Limited | Peptides and compounds that bind to a receptor |
| CN1966520B (zh) | 1995-06-07 | 2012-07-11 | 葛兰素集团有限公司 | 结合血小板生成素受体的肽和化合物 |
| JPH111477A (ja) | 1997-06-12 | 1999-01-06 | Hokuriku Seiyaku Co Ltd | １，４−ベンゾジアゼピン誘導体及びその用途 |
| WO1999011262A1 (en) | 1997-09-02 | 1999-03-11 | Roche Diagnostics Gmbh | Mpl-receptor ligands, process for their preparation, medicaments containing them and their use for the treatment and prevention of thrombocytopaenia and anaemia |
| EP1133291B1 (en) | 1998-11-17 | 2006-01-11 | Smithkline Beecham Corporation | Cyclic polyamines for treating thrombocytopenia |
| EP1141909B1 (de) | 1998-12-14 | 2002-09-04 | Vodafone AG | Verfahren zur übertragung von verkehrsinformationen |
| GC0000177A (en) | 1998-12-17 | 2006-03-29 | Smithkline Beecham | Thrombopoietin mimetics |
| KR20020069183A (ko) | 1999-07-26 | 2002-08-29 | 시오노기세이야쿠가부시키가이샤 | 트롬보포이에틴 작동성을 나타내는 의약 조성물 |
| AU770564B2 (en) | 1999-09-10 | 2004-02-26 | Smithkline Beecham Corporation | Thrombopoietin mimetics |
| JP2003513965A (ja) | 1999-11-05 | 2003-04-15 | スミスクライン・ビーチャム・コーポレイション | セミカルバゾン誘導体およびそれらのトロンボポエチン模倣物としての使用 |
| DE60031714T2 (de) | 1999-12-06 | 2007-09-06 | Smithkline Beecham Corp. | Thrombopoietin-mimetika |
| TWI284639B (en) | 2000-01-24 | 2007-08-01 | Shionogi & Co | A compound having thrombopoietin receptor agonistic effect |
| CY2010012I2 (el) * | 2000-05-25 | 2020-05-29 | Novartis Ag | Μιμητικα θρομβοποιητινης |
| MY142390A (en) * | 2002-05-22 | 2010-11-30 | Glaxosmithkline Llc | 3' - [(2z)-[1-(3,4-dimethylphenyl)-1,5- dihydro-3- methyl-5-0xo-4h-pyrazol-4- ylidene]hydrazino]-2' -hydroxy -[1,1' -biphenyl]-3-carboxylic acid bis-(monoethanolamine) |
| EP1622609A4 (en) * | 2003-04-29 | 2008-09-03 | Smithkline Beecham Corp | METHODS OF TREATING DEGENERATIVE DISEASES / LESIONS |
| EP1701934B1 (en) | 2003-12-26 | 2009-02-25 | Allergan, Inc. | DISUBSTITUTED CHALCONE OXIMES HAVING RAR(Gamma)-RETINOID RECEPTOR ANTAGONIST ACTIVITY |
| JP4518819B2 (ja) * | 2004-03-17 | 2010-08-04 | 富士フイルム株式会社 | アゾ化合物 |
| KR101215207B1 (ko) | 2004-12-14 | 2012-12-26 | 닛산 가가쿠 고교 가부시키 가이샤 | 아미드 화합물 및 트롬보포이에틴 리셉터 활성화제 |
| WO2007044982A2 (en) * | 2005-10-13 | 2007-04-19 | Smithkline Beecham Corporation | Methods for the preservation of platelet efficacy during storage |
| CA2630234A1 (en) * | 2005-11-23 | 2007-05-31 | Ligand Pharmaceuticals Inc. | Thrombopoietin activity modulating compounds and methods |
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2009
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- 2009-01-04 WO PCT/CN2009/000001 patent/WO2009092276A1/zh not_active Ceased
- 2009-01-04 MX MX2010007553A patent/MX2010007553A/es active IP Right Grant
- 2009-01-04 KR KR1020107017630A patent/KR101556808B1/ko active Active
- 2009-01-04 JP JP2010541680A patent/JP5441269B2/ja active Active
- 2009-01-04 US US12/812,119 patent/US8367710B2/en active Active
- 2009-01-04 UA UAA201008616A patent/UA101172C2/ru unknown
- 2009-01-04 ES ES09703490.4T patent/ES2533366T3/es active Active
- 2009-01-04 PT PT97034904T patent/PT2236500E/pt unknown
- 2009-01-04 CN CN2009800001980A patent/CN101679286B/zh active Active
- 2009-01-04 RU RU2010127786/04A patent/RU2488582C2/ru active
- 2009-01-04 BR BRPI0907234-9A patent/BRPI0907234B1/pt active IP Right Grant
- 2009-01-04 AU AU2009207966A patent/AU2009207966B2/en active Active
- 2009-01-04 EP EP09703490.4A patent/EP2236500B1/en active Active
-
2010
- 2010-07-07 ZA ZA2010/04794A patent/ZA201004794B/en unknown
-
2013
- 2013-01-16 US US13/742,633 patent/US20130123507A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| KR20100120141A (ko) | 2010-11-12 |
| EP2236500A1 (en) | 2010-10-06 |
| AU2009207966A1 (en) | 2009-07-30 |
| US8367710B2 (en) | 2013-02-05 |
| CA2711535C (en) | 2015-12-15 |
| US20100316601A1 (en) | 2010-12-16 |
| KR101556808B1 (ko) | 2015-10-01 |
| ZA201004794B (en) | 2011-09-28 |
| AU2009207966B2 (en) | 2013-03-21 |
| BRPI0907234B1 (pt) | 2021-08-10 |
| BRPI0907234A2 (pt) | 2020-08-04 |
| CA2711535A1 (en) | 2009-07-30 |
| EP2236500B1 (en) | 2014-12-24 |
| US20130123507A1 (en) | 2013-05-16 |
| RU2488582C2 (ru) | 2013-07-27 |
| MX2010007553A (es) | 2010-10-04 |
| RU2010127786A (ru) | 2012-02-20 |
| CN101679286A (zh) | 2010-03-24 |
| JP2011509263A (ja) | 2011-03-24 |
| JP5441269B2 (ja) | 2014-03-12 |
| CN101481352A (zh) | 2009-07-15 |
| EP2236500A4 (en) | 2012-08-22 |
| CN101679286B (zh) | 2011-06-08 |
| WO2009092276A1 (zh) | 2009-07-30 |
| UA101172C2 (ru) | 2013-03-11 |
| HK1134818A1 (en) | 2010-05-14 |
| PT2236500E (pt) | 2015-04-07 |
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