KR20120095481A - Ｈｃｎ 차단제로서의 아미노-헤테로아릴 유도체 - Google Patents
Ｈｃｎ 차단제로서의 아미노-헤테로아릴 유도체 Download PDFInfo
- Publication number
- KR20120095481A KR20120095481A KR1020127019218A KR20127019218A KR20120095481A KR 20120095481 A KR20120095481 A KR 20120095481A KR 1020127019218 A KR1020127019218 A KR 1020127019218A KR 20127019218 A KR20127019218 A KR 20127019218A KR 20120095481 A KR20120095481 A KR 20120095481A
- Authority
- KR
- South Korea
- Prior art keywords
- alkyl
- pyrimidin
- ethyl
- formula
- amine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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- 125000005214 aminoheteroaryl group Chemical group 0.000 title claims abstract description 29
- 208000002193 Pain Diseases 0.000 claims abstract description 22
- 230000036407 pain Effects 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 208000004296 neuralgia Diseases 0.000 claims abstract description 15
- 208000021722 neuropathic pain Diseases 0.000 claims abstract description 15
- 206010065390 Inflammatory pain Diseases 0.000 claims abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 155
- 125000000217 alkyl group Chemical group 0.000 claims description 88
- 125000005843 halogen group Chemical group 0.000 claims description 50
- 125000003545 alkoxy group Chemical group 0.000 claims description 41
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- 229920006395 saturated elastomer Polymers 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000004414 alkyl thio group Chemical group 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 10
- 230000002981 neuropathic effect Effects 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- IVWOENWZBVIUFI-MRVPVSSYSA-N 4-[(1r)-1-(3-methoxypyridin-2-yl)oxyethyl]pyrimidin-2-amine Chemical compound COC1=CC=CN=C1O[C@H](C)C1=CC=NC(N)=N1 IVWOENWZBVIUFI-MRVPVSSYSA-N 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- ICFLLTCXXSTBNA-SSDOTTSWSA-N 4-[(1r)-1-[3-(trifluoromethyl)pyridin-2-yl]oxyethyl]pyrimidin-2-amine Chemical compound O([C@H](C)C=1N=C(N)N=CC=1)C1=NC=CC=C1C(F)(F)F ICFLLTCXXSTBNA-SSDOTTSWSA-N 0.000 claims description 4
- CWQVTZBWZFEUCZ-ZCFIWIBFSA-N 4-[(1r)-1-[4-(trifluoromethyl)pyrimidin-2-yl]oxyethyl]pyrimidin-2-amine Chemical compound O([C@H](C)C=1N=C(N)N=CC=1)C1=NC=CC(C(F)(F)F)=N1 CWQVTZBWZFEUCZ-ZCFIWIBFSA-N 0.000 claims description 4
- BRDFFIWBTPFAGW-UHFFFAOYSA-N 4-[1-[3-(trifluoromethyl)pyridin-2-yl]sulfanylethyl]pyrimidin-2-amine Chemical compound C=1C=NC(N)=NC=1C(C)SC1=NC=CC=C1C(F)(F)F BRDFFIWBTPFAGW-UHFFFAOYSA-N 0.000 claims description 4
- 230000001404 mediated effect Effects 0.000 claims description 4
- OCGVPGIOKVTCBH-SSDOTTSWSA-N 4-[(1r)-1-(2,5-difluorophenoxy)ethyl]pyrimidin-2-amine Chemical compound O([C@H](C)C=1N=C(N)N=CC=1)C1=CC(F)=CC=C1F OCGVPGIOKVTCBH-SSDOTTSWSA-N 0.000 claims description 3
- RPQVMJSHJBPMOL-SSDOTTSWSA-N 4-[(1r)-1-(2-chloro-5-fluorophenoxy)ethyl]pyrimidin-2-amine Chemical compound O([C@H](C)C=1N=C(N)N=CC=1)C1=CC(F)=CC=C1Cl RPQVMJSHJBPMOL-SSDOTTSWSA-N 0.000 claims description 3
- YIIPERPMWRNKSL-MRVPVSSYSA-N 4-[(1r)-1-(3-fluorophenoxy)ethyl]pyrimidin-2-amine Chemical compound O([C@H](C)C=1N=C(N)N=CC=1)C1=CC=CC(F)=C1 YIIPERPMWRNKSL-MRVPVSSYSA-N 0.000 claims description 3
- FWRGXFQZCMCDER-UHFFFAOYSA-N 4-[1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]sulfanylethyl]pyrimidin-2-amine Chemical compound C=1C=NC(N)=NC=1C(C)SC1=NC=C(C(F)(F)F)C=C1Cl FWRGXFQZCMCDER-UHFFFAOYSA-N 0.000 claims description 3
- FHTLKGVVDAFGRW-UHFFFAOYSA-N 4-[1-[[3-(trifluoromethyl)pyridin-2-yl]amino]ethyl]pyrimidin-2-amine Chemical compound C=1C=NC(N)=NC=1C(C)NC1=NC=CC=C1C(F)(F)F FHTLKGVVDAFGRW-UHFFFAOYSA-N 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- YYEYMXDRGTXIIZ-SSDOTTSWSA-N 4-[(1r)-1-(2,4-difluorophenoxy)ethyl]pyrimidin-2-amine Chemical compound O([C@H](C)C=1N=C(N)N=CC=1)C1=CC=C(F)C=C1F YYEYMXDRGTXIIZ-SSDOTTSWSA-N 0.000 claims description 2
- OCGVPGIOKVTCBH-ZETCQYMHSA-N 4-[(1s)-1-(2,5-difluorophenoxy)ethyl]pyrimidin-2-amine Chemical compound O([C@@H](C)C=1N=C(N)N=CC=1)C1=CC(F)=CC=C1F OCGVPGIOKVTCBH-ZETCQYMHSA-N 0.000 claims description 2
- YIIPERPMWRNKSL-QMMMGPOBSA-N 4-[(1s)-1-(3-fluorophenoxy)ethyl]pyrimidin-2-amine Chemical compound O([C@@H](C)C=1N=C(N)N=CC=1)C1=CC=CC(F)=C1 YIIPERPMWRNKSL-QMMMGPOBSA-N 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 2
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- -1 4-chlorophenoxy Chemical group 0.000 description 77
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 51
- 239000000243 solution Substances 0.000 description 48
- 239000000203 mixture Substances 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 31
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- 239000003153 chemical reaction reagent Substances 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 27
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 27
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 26
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 26
- 229940093499 ethyl acetate Drugs 0.000 description 23
- 235000019439 ethyl acetate Nutrition 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- GRCYXPAUEDBQEP-SCSAIBSYSA-N (1r)-1-(2-aminopyrimidin-4-yl)ethanol Chemical compound C[C@@H](O)C1=CC=NC(N)=N1 GRCYXPAUEDBQEP-SCSAIBSYSA-N 0.000 description 21
- 239000007787 solid Substances 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- GRCYXPAUEDBQEP-UHFFFAOYSA-N 1-(2-aminopyrimidin-4-yl)ethanol Chemical compound CC(O)C1=CC=NC(N)=N1 GRCYXPAUEDBQEP-UHFFFAOYSA-N 0.000 description 13
- 108091006146 Channels Proteins 0.000 description 13
- 229910052751 metal Inorganic materials 0.000 description 13
- 239000002184 metal Substances 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 239000000377 silicon dioxide Substances 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 235000011152 sodium sulphate Nutrition 0.000 description 10
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 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 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- GNHWZRZIPQSPAM-UHFFFAOYSA-N 4-(1,1-dimethoxyethyl)pyrimidin-2-amine Chemical compound COC(C)(OC)C1=CC=NC(N)=N1 GNHWZRZIPQSPAM-UHFFFAOYSA-N 0.000 description 7
- 239000007868 Raney catalyst Substances 0.000 description 7
- 229910000564 Raney nickel Inorganic materials 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 125000002524 organometallic group Chemical group 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- UWJBSSXERIXLCT-ZCFIWIBFSA-N (1r)-1-(2-aminopyrimidin-4-yl)propan-1-ol Chemical compound CC[C@@H](O)C1=CC=NC(N)=N1 UWJBSSXERIXLCT-ZCFIWIBFSA-N 0.000 description 6
- JGPUNUZKILMJDR-UHFFFAOYSA-N 1-[2-(methylamino)pyrimidin-4-yl]ethanol Chemical compound CNC1=NC=CC(C(C)O)=N1 JGPUNUZKILMJDR-UHFFFAOYSA-N 0.000 description 6
- IGYXYGDEYHNFFT-UHFFFAOYSA-N 2-chloro-4-fluorophenol Chemical compound OC1=CC=C(F)C=C1Cl IGYXYGDEYHNFFT-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 125000001309 chloro group Chemical group Cl* 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- GRCYXPAUEDBQEP-BYPYZUCNSA-N (1s)-1-(2-aminopyrimidin-4-yl)ethanol Chemical compound C[C@H](O)C1=CC=NC(N)=N1 GRCYXPAUEDBQEP-BYPYZUCNSA-N 0.000 description 5
- XDKSEDDZHXZRKQ-UHFFFAOYSA-N 1-(2-aminopyrimidin-4-yl)ethanone Chemical compound CC(=O)C1=CC=NC(N)=N1 XDKSEDDZHXZRKQ-UHFFFAOYSA-N 0.000 description 5
- FASZWOLPNJDCCV-UHFFFAOYSA-N 1-(2-aminopyrimidin-4-yl)propan-2-one Chemical compound CC(=O)CC1=CC=NC(N)=N1 FASZWOLPNJDCCV-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 208000004454 Hyperalgesia Diseases 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- QMPSUPWBJMOGPS-UHFFFAOYSA-N [Ru].CC(C)C1=CC=C(C)C=C1 Chemical compound [Ru].CC(C)C1=CC=C(C)C=C1 QMPSUPWBJMOGPS-UHFFFAOYSA-N 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 210000003594 spinal ganglia Anatomy 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 5
- UWJBSSXERIXLCT-LURJTMIESA-N (1s)-1-(2-aminopyrimidin-4-yl)propan-1-ol Chemical compound CC[C@H](O)C1=CC=NC(N)=N1 UWJBSSXERIXLCT-LURJTMIESA-N 0.000 description 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 4
- GCMMYIYEKSCNRT-UHFFFAOYSA-N 1-(2-aminopyridin-4-yl)ethanol Chemical compound CC(O)C1=CC=NC(N)=C1 GCMMYIYEKSCNRT-UHFFFAOYSA-N 0.000 description 4
- SJTBRFHBXDZMPS-UHFFFAOYSA-N 3-fluorophenol Chemical compound OC1=CC=CC(F)=C1 SJTBRFHBXDZMPS-UHFFFAOYSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- 101001009074 Homo sapiens Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 Proteins 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 125000001118 alkylidene group Chemical group 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 150000004678 hydrides Chemical class 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 150000002466 imines Chemical class 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 238000001356 surgical procedure Methods 0.000 description 4
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 3
- WXWFPQXHEKFXJZ-UHFFFAOYSA-N 1-(4-amino-6-methylsulfanyl-1,3,5-triazin-2-yl)ethanol Chemical compound CSC1=NC(N)=NC(C(C)O)=N1 WXWFPQXHEKFXJZ-UHFFFAOYSA-N 0.000 description 3
- OVRSIQWVIJSERH-UHFFFAOYSA-N 1-(dimethylamino)-4,4-dimethoxypent-1-en-3-one Chemical compound COC(C)(OC)C(=O)C=CN(C)C OVRSIQWVIJSERH-UHFFFAOYSA-N 0.000 description 3
- LQJNIKQNMJEMOZ-UHFFFAOYSA-N 1-[2-(methylamino)pyrimidin-4-yl]ethanone Chemical compound CNC1=NC=CC(C(C)=O)=N1 LQJNIKQNMJEMOZ-UHFFFAOYSA-N 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- JSTJKIRLQHXBFE-SECBINFHSA-N 2-bromo-6-[(1r)-1-(3-fluorophenoxy)ethyl]pyridine Chemical compound O([C@H](C)C=1N=C(Br)C=CC=1)C1=CC=CC(F)=C1 JSTJKIRLQHXBFE-SECBINFHSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 0 CC(C)(*I)C(N=CC)=C Chemical compound CC(C)(*I)C(N=CC)=C 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000006254 arylation reaction Methods 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 210000005036 nerve Anatomy 0.000 description 3
- 210000002569 neuron Anatomy 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 210000000278 spinal cord Anatomy 0.000 description 3
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- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000008736 traumatic injury Effects 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- PTMFUWGXPRYYMC-UHFFFAOYSA-N triethylazanium;formate Chemical compound OC=O.CCN(CC)CC PTMFUWGXPRYYMC-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 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
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 231100000691 up-and-down procedure Toxicity 0.000 description 1
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Addiction (AREA)
- Virology (AREA)
- Pain & Pain Management (AREA)
- AIDS & HIV (AREA)
- Communicable Diseases (AREA)
- Tropical Medicine & Parasitology (AREA)
- Psychiatry (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US28918209P | 2009-12-22 | 2009-12-22 | |
| US61/289,182 | 2009-12-22 | ||
| EP09180321.3 | 2009-12-22 | ||
| EP09180321 | 2009-12-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20120095481A true KR20120095481A (ko) | 2012-08-28 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020127019218A Withdrawn KR20120095481A (ko) | 2009-12-22 | 2010-12-20 | Ｈｃｎ 차단제로서의 아미노-헤테로아릴 유도체 |
Country Status (12)
| Country | Link |
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| US (1) | US8952001B2 (OSRAM) |
| EP (1) | EP2516397B1 (OSRAM) |
| JP (1) | JP5728024B2 (OSRAM) |
| KR (1) | KR20120095481A (OSRAM) |
| CN (1) | CN102884048B (OSRAM) |
| AR (1) | AR079543A1 (OSRAM) |
| AU (1) | AU2010335231C1 (OSRAM) |
| BR (1) | BR112012015170A8 (OSRAM) |
| CA (1) | CA2783209C (OSRAM) |
| MX (1) | MX2012007426A (OSRAM) |
| RU (1) | RU2549546C2 (OSRAM) |
| WO (1) | WO2011076723A1 (OSRAM) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2012157336A1 (ja) * | 2011-05-19 | 2012-11-22 | 株式会社東芝 | モリブデン造粒粉の製造方法およびモリブデン造粒粉 |
| AU2012300567B2 (en) | 2011-09-02 | 2016-03-10 | Purdue Pharma L.P. | Pyrimidines as sodium channel blockers |
| WO2013072758A1 (en) | 2011-11-15 | 2013-05-23 | Purdue Pharma L.P. | Pyrimidine diol amides as sodium channel blockers |
| MX2014014308A (es) * | 2012-05-30 | 2015-02-12 | Hoffmann La Roche | Pirrolidino heterociclos. |
| CN106588803A (zh) * | 2016-11-16 | 2017-04-26 | 西南科技大学 | 一种制备5‑乙酰基异噁唑的新方法 |
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| US4606757A (en) * | 1982-12-23 | 1986-08-19 | The Dow Chemical Company | Diphenoxymethylpyridines having herbicidal properties |
| KR100197583B1 (ko) | 1997-02-04 | 1999-06-15 | 이민화 | 환자용모니터를 구비한 초음파진단장치 |
| WO2001090142A2 (en) | 2000-05-24 | 2001-11-29 | Akzo Nobel N.V. | FULL LENGTH HUMAN HCN1 Ih CHANNEL SUBUNIT AND VARIANTS |
| CA2443636C (en) * | 2001-04-10 | 2009-11-17 | Nippon Shinyaku Co., Ltd. | Remedial agent for chronic articular rheumatism |
| US6980419B2 (en) | 2003-03-12 | 2005-12-27 | Zonare Medical Systems, Inc. | Portable ultrasound unit and docking station |
| US20090182228A1 (en) | 2004-09-17 | 2009-07-16 | Koninklijke Philips Electronics, N.V. | Wireless ultrasound system display |
| US20070135437A1 (en) * | 2005-03-04 | 2007-06-14 | Alsgen, Inc. | Modulation of neurodegenerative diseases |
| LT2848610T (lt) * | 2006-11-15 | 2017-11-10 | Ym Biosciences Australia Pty Ltd | Kinazės aktyvumo inhibitoriai |
| WO2009077608A1 (en) * | 2007-12-19 | 2009-06-25 | Palau Pharma, S. A. | 2 -aminopyrimidine derivatives as histamine h4 antagonists |
| JP5523352B2 (ja) * | 2008-02-28 | 2014-06-18 | バーテックス ファーマシューティカルズ インコーポレイテッド | Ｃｆｔｒ修飾因子としてのへテロアリール誘導体 |
| TW201022233A (en) | 2008-11-04 | 2010-06-16 | Organon Nv | (Pyrrolidin-2-yl)phenyl derivatives |
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2010
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- 2010-12-20 BR BR112012015170A patent/BR112012015170A8/pt not_active Application Discontinuation
- 2010-12-20 RU RU2012131279/04A patent/RU2549546C2/ru not_active IP Right Cessation
- 2010-12-20 EP EP10795690.6A patent/EP2516397B1/en not_active Not-in-force
- 2010-12-20 WO PCT/EP2010/070213 patent/WO2011076723A1/en not_active Ceased
- 2010-12-20 KR KR1020127019218A patent/KR20120095481A/ko not_active Withdrawn
- 2010-12-20 MX MX2012007426A patent/MX2012007426A/es active IP Right Grant
- 2010-12-20 CN CN201080064520.9A patent/CN102884048B/zh not_active Expired - Fee Related
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- 2010-12-20 AR ARP100104763A patent/AR079543A1/es unknown
- 2010-12-20 JP JP2012545268A patent/JP5728024B2/ja not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP5728024B2 (ja) | 2015-06-03 |
| RU2549546C2 (ru) | 2015-04-27 |
| US20120264728A1 (en) | 2012-10-18 |
| MX2012007426A (es) | 2012-07-23 |
| RU2012131279A (ru) | 2014-01-27 |
| CN102884048B (zh) | 2014-07-23 |
| AU2010335231A1 (en) | 2012-06-21 |
| EP2516397A1 (en) | 2012-10-31 |
| CA2783209A1 (en) | 2011-06-30 |
| WO2011076723A1 (en) | 2011-06-30 |
| AU2010335231B2 (en) | 2014-09-11 |
| CN102884048A (zh) | 2013-01-16 |
| EP2516397B1 (en) | 2016-07-13 |
| US8952001B2 (en) | 2015-02-10 |
| AU2010335231C1 (en) | 2015-04-16 |
| CA2783209C (en) | 2017-03-14 |
| BR112012015170A2 (pt) | 2016-03-29 |
| BR112012015170A8 (pt) | 2017-12-26 |
| JP2013515031A (ja) | 2013-05-02 |
| AR079543A1 (es) | 2012-02-01 |
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