BRPI0907234B1 - Derivados de pirazolona-azo biciclo-substituído, seu uso, seu intermediário e seus processos de preparação, composição farmacêutica e deu uso - Google Patents
Derivados de pirazolona-azo biciclo-substituído, seu uso, seu intermediário e seus processos de preparação, composição farmacêutica e deu uso Download PDFInfo
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- BRPI0907234B1 BRPI0907234B1 BRPI0907234-9A BRPI0907234A BRPI0907234B1 BR PI0907234 B1 BRPI0907234 B1 BR PI0907234B1 BR PI0907234 A BRPI0907234 A BR PI0907234A BR PI0907234 B1 BRPI0907234 B1 BR PI0907234B1
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- Brazil
- Prior art keywords
- mixture
- methyl
- carboxylic acid
- dihydro
- mmol
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims description 166
- -1 aniline compound Chemical class 0.000 claims description 48
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- 239000001257 hydrogen Substances 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 150000001733 carboxylic acid esters Chemical group 0.000 claims description 15
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 150000001732 carboxylic acid derivatives Chemical group 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 206010043554 thrombocytopenia Diseases 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- MGQNMYSRDBFUIR-UHFFFAOYSA-N nitro cyanoformate Chemical compound [O-][N+](=O)OC(=O)C#N MGQNMYSRDBFUIR-UHFFFAOYSA-N 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 102000004127 Cytokines Human genes 0.000 claims description 5
- 108090000695 Cytokines Proteins 0.000 claims description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000000556 agonist Substances 0.000 claims description 5
- 238000005859 coupling reaction Methods 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 5
- 125000005047 dihydroimidazolyl group Chemical group N1(CNC=C1)* 0.000 claims description 4
- 102000019034 Chemokines Human genes 0.000 claims description 3
- 108010012236 Chemokines Proteins 0.000 claims description 3
- 102000007644 Colony-Stimulating Factors Human genes 0.000 claims description 3
- 108010071942 Colony-Stimulating Factors Proteins 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 150000001728 carbonyl compounds Chemical class 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 102000015696 Interleukins Human genes 0.000 claims description 2
- 108010093036 interleukin receptors Proteins 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims 1
- 238000010168 coupling process Methods 0.000 claims 1
- 102000003675 cytokine receptors Human genes 0.000 claims 1
- 108010057085 cytokine receptors Proteins 0.000 claims 1
- 125000003107 substituted aryl group Chemical group 0.000 claims 1
- 108010041111 Thrombopoietin Proteins 0.000 abstract description 37
- 102000036693 Thrombopoietin Human genes 0.000 abstract description 36
- 238000000034 method Methods 0.000 abstract description 10
- 150000004677 hydrates Chemical class 0.000 abstract description 5
- 239000012453 solvate Substances 0.000 abstract description 5
- 229940127323 Thrombopoietin Receptor Agonists Drugs 0.000 abstract description 2
- 229940124597 therapeutic agent Drugs 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 451
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 280
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 258
- 238000006243 chemical reaction Methods 0.000 description 173
- 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 146
- 239000011541 reaction mixture Substances 0.000 description 136
- 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
- 239000007787 solid Substances 0.000 description 132
- 239000002253 acid Chemical group 0.000 description 128
- 238000004949 mass spectrometry Methods 0.000 description 128
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 128
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 115
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 100
- 238000005160 1H NMR spectroscopy Methods 0.000 description 96
- 239000012065 filter cake Substances 0.000 description 94
- 238000001816 cooling Methods 0.000 description 85
- 239000005457 ice water Substances 0.000 description 83
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- 238000010898 silica gel chromatography Methods 0.000 description 64
- 235000010288 sodium nitrite Nutrition 0.000 description 64
- 239000000706 filtrate Substances 0.000 description 50
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 48
- 235000017557 sodium bicarbonate Nutrition 0.000 description 48
- 238000010992 reflux Methods 0.000 description 45
- 229920006395 saturated elastomer Polymers 0.000 description 43
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 35
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 35
- 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 35
- 239000000243 solution Substances 0.000 description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
- 239000000284 extract Substances 0.000 description 31
- 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
- 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
- 239000003921 oil Substances 0.000 description 20
- 239000011877 solvent mixture Substances 0.000 description 20
- 229940126214 compound 3 Drugs 0.000 description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
- 230000002378 acidificating effect Effects 0.000 description 18
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 17
- 229910000029 sodium carbonate Inorganic materials 0.000 description 17
- 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 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 16
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 15
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- 238000002156 mixing Methods 0.000 description 15
- 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 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 238000012360 testing method Methods 0.000 description 13
- 229940125782 compound 2 Drugs 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 150000004702 methyl esters Chemical class 0.000 description 12
- 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 11
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- 108020003175 receptors Proteins 0.000 description 11
- 102000005962 receptors Human genes 0.000 description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 11
- 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
- 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 9
- 239000012298 atmosphere Substances 0.000 description 9
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical group [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 8
- 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 7
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 7
- 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 7
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 7
- 125000004494 ethyl ester group Chemical group 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-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
- 239000012230 colorless oil Substances 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 239000002904 solvent 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
- 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
- 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 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 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
- 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
- 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
- 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 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
- 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 4
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 4
- 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 4
- FVWMLPLQQVWWBZ-UHFFFAOYSA-N 4-(3-amino-2-hydroxyphenyl)-1h-pyrrole-2-carboxylic acid Chemical compound NC1=CC=CC(C=2C=C(NC=2)C(O)=O)=C1O FVWMLPLQQVWWBZ-UHFFFAOYSA-N 0.000 description 4
- DXKYHAPIBYYLJR-UHFFFAOYSA-N 4-ethoxycarbonyl-3,5-dimethyl-1h-pyrrole-2-carboxylic acid Chemical compound CCOC(=O)C1=C(C)NC(C(O)=O)=C1C DXKYHAPIBYYLJR-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
- SEQHEDQNODAFIU-UHFFFAOYSA-N 6-bromo-2,3-dihydroinden-1-one Chemical compound BrC1=CC=C2CCC(=O)C2=C1 SEQHEDQNODAFIU-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 4
- 210000001185 bone marrow Anatomy 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- OSQPUMRCKZAIOZ-UHFFFAOYSA-N carbon dioxide;ethanol Chemical compound CCO.O=C=O OSQPUMRCKZAIOZ-UHFFFAOYSA-N 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 4
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 210000003593 megakaryocyte Anatomy 0.000 description 4
- RFVWMXPMHIHIIB-UHFFFAOYSA-N methyl 5-(3-amino-2-hydroxyphenyl)furan-2-carboxylate Chemical compound O1C(C(=O)OC)=CC=C1C1=CC=CC(N)=C1O RFVWMXPMHIHIIB-UHFFFAOYSA-N 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
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 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
- 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 4
- 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 3
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- ZASHKTYXIFWHMP-UHFFFAOYSA-N tert-butyl n-(3,3-dimethyl-1,2-dihydroinden-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=C2CCC(C)(C)C2=C1 ZASHKTYXIFWHMP-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
- 125000001544 thienyl group Chemical group 0.000 description 1
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- 230000003582 thrombocytopenic effect Effects 0.000 description 1
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Classifications
-
- 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
-
- 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)
| Application Number | Priority Date | Filing Date | Title |
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| CN200810000346.6 | 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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| BRPI0907234A2 BRPI0907234A2 (pt) | 2020-08-04 |
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| EP (1) | EP2236500B1 (https=) |
| JP (1) | JP5441269B2 (https=) |
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| CA (1) | CA2711535C (https=) |
| ES (1) | ES2533366T3 (https=) |
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| UA (1) | UA101172C2 (https=) |
| WO (1) | WO2009092276A1 (https=) |
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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 |
| JP5704073B2 (ja) * | 2009-10-23 | 2015-04-22 | 日産化学工業株式会社 | 縮環へテロ環化合物及びトロンボポエチンレセプター活性化剤 |
| 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 |
| US9849077B2 (en) | 2014-03-10 | 2017-12-26 | 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 |
| 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 |
| TW201726129A (zh) * | 2016-01-22 | 2017-08-01 | 江蘇恆瑞醫藥股份有限公司 | 一種含有雙環取代吡唑酮偶氮類衍生物或其鹽的藥物組成物及其製備方法 |
| TWI762556B (zh) * | 2017-01-19 | 2022-05-01 | 大陸商江蘇恆瑞醫藥股份有限公司 | 一種雙環取代吡唑酮偶氮類衍生物的製備方法及其中間體 |
| 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 |
| CN113226463A (zh) * | 2019-01-08 | 2021-08-06 | 江苏恒瑞医药股份有限公司 | 双环取代吡唑酮偶氮类衍生物的给药方案 |
| 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 |
| US20250144077A1 (en) * | 2022-01-25 | 2025-05-08 | Jiangsu Hengrui Pharmaceuticals Co., Ltd. | Dosage regimen for thrombopoietin receptor agonist |
| 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 |
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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 |
| TR199701526T1 (xx) | 1995-06-07 | 1998-03-21 | Glaxo Group Limited | Bir trombopoietin resept�r�ne ba�lanan peptitler ve bile�ikler. |
| US5869451A (en) | 1995-06-07 | 1999-02-09 | Glaxo Group Limited | Peptides and compounds that bind to a receptor |
| 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 |
| AU9265698A (en) | 1997-09-02 | 1999-03-22 | Boehringer Mannheim Gmbh | Mpl-receptor ligands, process for their preparation, medicaments containing themand their use for the treatment and prevention of thrombocytopaenia and anaemia |
| JP2002529502A (ja) | 1998-11-17 | 2002-09-10 | スミスクライン・ビーチャム・コーポレイション | 血小板減少症の治療法 |
| WO2000039773A1 (de) | 1998-12-14 | 2000-07-06 | Mannesmann 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 |
| EP1213965B1 (en) | 1999-09-10 | 2006-01-18 | Smithkline Beecham Corporation | Thrombopoietin mimetics |
| WO2001034585A1 (en) | 1999-11-05 | 2001-05-17 | Smithkline Beecham Corporation | Semicarbazone derivatives and their use as thrombopoietin mimetics |
| AU2079901A (en) | 1999-12-06 | 2001-06-12 | Smithkline Beecham Corporation | Thrombopoietin mimetics |
| 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 |
| TWI280128B (en) * | 2002-05-22 | 2007-05-01 | Smithkline Beecham Corp | 3'-[(2Z)-[1-(3,4- dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid bis-(monoethanolamine) |
| EP2387998A1 (en) * | 2003-04-29 | 2011-11-23 | Glaxosmithkline LLC | Methods for treating degenerative diseases/injuries |
| DE602004019685D1 (de) | 2003-12-26 | 2009-04-09 | Allergan Inc | DISUBSTITUIERTE CHALCOGENOXIME MIT ANTAGONISTISCHER WIRKUNG AM RAR(Gamma)-RETINOIDREZEPTOR |
| JP4518819B2 (ja) * | 2004-03-17 | 2010-08-04 | 富士フイルム株式会社 | アゾ化合物 |
| AU2005314788B2 (en) * | 2004-12-14 | 2011-09-22 | Nissan Chemical Industries, Ltd. | Amide compound and thrombopoietin receptor activator |
| JP2009511603A (ja) * | 2005-10-13 | 2009-03-19 | スミスクライン・ビーチャム・コーポレイション | 貯蔵中の血小板の有効性を維持する方法 |
| CA2630234A1 (en) * | 2005-11-23 | 2007-05-31 | Ligand Pharmaceuticals Inc. | Thrombopoietin activity modulating compounds and methods |
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| PT2236500E (pt) | 2015-04-07 |
| RU2010127786A (ru) | 2012-02-20 |
| KR101556808B1 (ko) | 2015-10-01 |
| CA2711535C (en) | 2015-12-15 |
| BRPI0907234A2 (pt) | 2020-08-04 |
| KR20100120141A (ko) | 2010-11-12 |
| ES2533366T3 (es) | 2015-04-09 |
| CN101679286A (zh) | 2010-03-24 |
| US20100316601A1 (en) | 2010-12-16 |
| RU2488582C2 (ru) | 2013-07-27 |
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| HK1134818A1 (en) | 2010-05-14 |
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| EP2236500A1 (en) | 2010-10-06 |
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| CN101481352A (zh) | 2009-07-15 |
| EP2236500A4 (en) | 2012-08-22 |
| CN101679286B (zh) | 2011-06-08 |
| UA101172C2 (ru) | 2013-03-11 |
| US20130123507A1 (en) | 2013-05-16 |
| AU2009207966B2 (en) | 2013-03-21 |
| US8367710B2 (en) | 2013-02-05 |
| ZA201004794B (en) | 2011-09-28 |
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