ES2536200T3 - Preparación de compuestos de tipo 1-(bencilo sustituido)-5-trifluorometil-2-(1H)piridona, sales de estos y sus aplicaciones - Google Patents
Preparación de compuestos de tipo 1-(bencilo sustituido)-5-trifluorometil-2-(1H)piridona, sales de estos y sus aplicaciones Download PDFInfo
- Publication number
- ES2536200T3 ES2536200T3 ES10780057.5T ES10780057T ES2536200T3 ES 2536200 T3 ES2536200 T3 ES 2536200T3 ES 10780057 T ES10780057 T ES 10780057T ES 2536200 T3 ES2536200 T3 ES 2536200T3
- Authority
- ES
- Spain
- Prior art keywords
- trifluoromethyl
- preparation
- pyridin
- compound
- benzyl
- 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.)
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- -1 1- (substituted benzyl) -5-trifluoromethyl-2- (1H) pyridone Chemical class 0.000 title abstract 2
- 150000003839 salts Chemical class 0.000 title abstract 2
- 238000002360 preparation method Methods 0.000 title description 16
- 150000001875 compounds Chemical class 0.000 title description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 3
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 abstract 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 2
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 abstract 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 abstract 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 abstract 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 abstract 1
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 abstract 1
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 abstract 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 abstract 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 4
- AEPGAMSCRRFRMV-UHFFFAOYSA-N 1-[[2-(2-chloroethylamino)phenyl]methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound C1=C(C(F)(F)F)C=CC(=O)N1CC1=CC=CC=C1NCCCl AEPGAMSCRRFRMV-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- OVEJFWFNVHYQKE-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound C1=CC(F)=CC=C1CN1C(=O)C=CC(C(F)(F)F)=C1 OVEJFWFNVHYQKE-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 208000004608 Ureteral Obstruction Diseases 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 210000000626 ureter Anatomy 0.000 description 3
- CEOYOMVEWKDWMR-UHFFFAOYSA-N 1-[(2,6-dichlorophenyl)methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound C1=C(C(F)(F)F)C=CC(=O)N1CC1=C(Cl)C=CC=C1Cl CEOYOMVEWKDWMR-UHFFFAOYSA-N 0.000 description 2
- DNEGGUHDBWIXTQ-UHFFFAOYSA-N 1-[[2-[2-(4-methylpiperazin-1-yl)ethylamino]phenyl]methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound C1CN(C)CCN1CCNC1=CC=CC=C1CN1C(=O)C=CC(C(F)(F)F)=C1 DNEGGUHDBWIXTQ-UHFFFAOYSA-N 0.000 description 2
- KJHNIYLKVDPWOG-UHFFFAOYSA-N 1-[[4-(2-chloroethylamino)phenyl]methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound C1=C(C(F)(F)F)C=CC(=O)N1CC1=CC=C(NCCCl)C=C1 KJHNIYLKVDPWOG-UHFFFAOYSA-N 0.000 description 2
- YVLRQILTVNOKDC-UHFFFAOYSA-N 1-[[4-[2-[4-(2-hydroxyethyl)piperazin-1-yl]ethylamino]phenyl]methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound C1CN(CCO)CCN1CCNC(C=C1)=CC=C1CN1C(=O)C=CC(C(F)(F)F)=C1 YVLRQILTVNOKDC-UHFFFAOYSA-N 0.000 description 2
- BYRJSCNPUHYZQE-UHFFFAOYSA-N 5-(trifluoromethyl)-1h-pyridin-2-one Chemical compound OC1=CC=C(C(F)(F)F)C=N1 BYRJSCNPUHYZQE-UHFFFAOYSA-N 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- LBOBESSDSGODDD-UHFFFAOYSA-N 1,3-dichloro-2-(chloromethyl)benzene Chemical compound ClCC1=C(Cl)C=CC=C1Cl LBOBESSDSGODDD-UHFFFAOYSA-N 0.000 description 1
- NVNPLEPBDPJYRZ-UHFFFAOYSA-N 1-(bromomethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CBr)C=C1 NVNPLEPBDPJYRZ-UHFFFAOYSA-N 0.000 description 1
- VCEIADJZYAARBC-UHFFFAOYSA-N 1-[(2-nitrophenyl)methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound [O-][N+](=O)C1=CC=CC=C1CN1C(=O)C=CC(C(F)(F)F)=C1 VCEIADJZYAARBC-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- TUEOKAUVWSUGTM-UHFFFAOYSA-N 1-[[2-(2-hydroxyethylamino)phenyl]methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound OCCNC1=CC=CC=C1CN1C(=O)C=CC(C(F)(F)F)=C1 TUEOKAUVWSUGTM-UHFFFAOYSA-N 0.000 description 1
- NQJQDEKDVRSXRX-UHFFFAOYSA-N 1-[[4-(2-piperazin-1-ylethylamino)phenyl]methyl]-5-(trifluoromethyl)pyridin-2-one Chemical compound C1=C(C(F)(F)F)C=CC(=O)N1CC(C=C1)=CC=C1NCCN1CCNCC1 NQJQDEKDVRSXRX-UHFFFAOYSA-N 0.000 description 1
- HNKRYZAGBVUXNZ-UHFFFAOYSA-N 1-[[4-[2-(4-methylpiperazin-1-yl)ethylamino]phenyl]methyl]-5-(trifluoromethyl)pyridin-2-one;dihydrochloride Chemical compound Cl.Cl.C1CN(C)CCN1CCNC(C=C1)=CC=C1CN1C(=O)C=CC(C(F)(F)F)=C1 HNKRYZAGBVUXNZ-UHFFFAOYSA-N 0.000 description 1
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
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- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- QTCANKDTWWSCMR-UHFFFAOYSA-N costic aldehyde Natural products C1CCC(=C)C2CC(C(=C)C=O)CCC21C QTCANKDTWWSCMR-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- ISTFUJWTQAMRGA-UHFFFAOYSA-N iso-beta-costal Natural products C1C(C(=C)C=O)CCC2(C)CCCC(C)=C21 ISTFUJWTQAMRGA-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Compuestos tipo 1-(bencilo sustituido)-5-trifluorometil-2-(1H)piridona, que tienen la fórmula estructural (XIII),**Fórmula** donde R1-R4, R12 se seleccionan entre H, NO2, hidroxilo, amino, átomo de halógeno, alcoxilo C1-C6, NR10R11, OR13, C(O)R14, O-C(O)R14, alquilo C1-C6, haloalquilo C1-C6, alquenilo C2-C6; donde R1~R4, R12 no son simultáneamente H, R14 se selecciona entre alquilo C1-C6, R13 se selecciona entre hidroxialquilo o alcoxialquilo; donde en NR10R11, R10 y R11 se seleccionan entre H, hidroxialquilo C1-C6, hidroxialquilo C1-C6 esterificado, alcoxialquilo C1-C6 o la fórmula estructural XIV y R10 y R11 no son simultáneamente H;**Fórmula** donde R5 se selecciona entre H, alquilo C1-C6, haloalquilo C1-C6, hidroxialquilo C1-C6 y alquenilo C2-C6; R6-R9 se seleccionan entre H, alcoxilo C1-C6, >=O, alquilo C1-C4, haloalquilo C1-C4, hidroxialquilo C1-C4 y alquenilo C2-C4; X se selecciona entre N y CH; Y se selecciona entre N, O y CH; y cuando Y es O, entonces R5 está ausente y n es 1-6; y sales farmacéuticamente aceptables de estos.
Description
E10780057
04-05-2015
La preparación de 1-(4-((2-(piperazin-l-il)etil)amino)bencil)-5-(trifluorometil)piridin-2(1H)-ona incluye los pasos de: disolver 0.39 g (1.2 mmol) de 1-(4-((2-cloroetil)amino)bencil)-5-(trifluorometil)piridin-2(1H)-ona en 30 mL de 5 acetonitrilo; añadir 0.82 g (9.6 mmol) de piperazina; llevar a cabo la reacción a reflujo durante 18 horas; filtrar; evaporar el filtrado hasta sequedad y separar por cromatográfica en columna con acetato de etilo y metanol en una proporción de 1:1 como eluyente para obtener un aceite incoloro de 0.37 g. EI-MS(m/z): 380 [M]+. 1H-RMN (CDCl3, 300 MHz) δppm: 2.445 (a, 4H, -CH2-), 2.593∼2.632 (t, 2H, -CH2-), 2.855∼2.915 (t, 4H, -CH2-), 3.132∼3.170 (t, 2H, -CH2-), 4.438 (a, 1H, -NH-), 5.011 (s, 2H, -CH2-), 6.595∼6.650 (t, 3H, Ar-H), 7.147∼7.175 (d, 2H, Ar-H), 7.377∼7.417
10 (dd, 1H, J=2.4 Hz, 9.6 Hz, Ar-H), 7.625 (s, 1H, Ar-H).
Ejemplo 11
Preparación de 1-(4-((2-(4-(2-hidroxietil)piperazin-1-il)etil)amino)bencil)-5-(trifluorometil)piridin-2(1H)-ona
15 La preparación de 1-(4-((2-(4-(2-hidroxietil)piperazin-1-il)etil)amino)bencil)-5-(trifluorometil)piridin-2(1H)-ona incluye los pasos de: disolver 0.83 g (2.5 mmol) de 1-(4-((2-cloroetil)amino)bencil)-5-(trifluorometil)piridin-2(1H)-ona y 2.6 g (20 mmol) de hidroxietilpiperazina en 30 mL de acetonitrilo; añadir una cantidad de yoduro de sodio; llevar a cabo la reacción a reflujo durante 29 horas; filtrar; evaporar el filtrado hasta sequedad y separar por cromatografía en
20 columna con éter de petróleo y acetato de etilo en una proporción de 10:1 como eluyente para obtener un aceite amarillo de 0.60 g. EI-MS(m/z): 424[M]+. 1H-RMN (CDCl3, 300 MHz) δppm: 2.572∼2.268 (m, 12H, -CH2-), 3.151∼3.150 (t, 2H, -CH2-), 3.638∼3.673 (t, 2H, -CH2-), 5.011 (s, 2H, -CH2-), 6.593∼6.649 (t, 3H, Ar-H), 7.148∼7.176 (d, 2H, J=8.4 Hz, Ar-H), 7.377∼7.418 (dd, 1H, J=2.7 Hz, 9.6 Hz, Ar-H), 7.620 (s, 1H, Ar-H).
Ejemplo 12
25 Preparación del diclorhidrato de la 1-(4-((2-(4-metilpiperazin-1-il)etil)amino)bencil)-5-(trifluorometil)piridin-2(1H)-ona
12
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La preparación de 1-(2,6-diclorobencil)-5-(trifluorometil)piridin-2(1H)-ona incluye los pasos de: disolver 0.49 g (3.0 mmol) de 5-(trifluorometil)piridin-2(1H)-ona en 30 mL de DMF; añadir 0.5 g (3.6 mmol) de carbonato de sodio y
5 0.88 g (4.5 mmol) 1,3-dicloro-2-(clorometil)benceno; llevar a cabo la reacción a reflujo durante 3 horas; filtrar; evaporar el filtrado y separar el residuo por cromatografía en columna con éter de petróleo como eluyente para obtener el producto 1-(2,6-diclorobencil)-5-(trifluorometil)piridin-2(1H)-ona como un sólido amarillo claro de 0.72 g. p.f.: 74.0∼76.0 °C. EI-MS(m/z): 321[M-1]+. 1H-RMN (CDCl3, 300 MHz) δppm: 5.442 (s, 2H, -CH2-), 6.665∼6.697 (d, 1H, J=9.6 Hz, Ar-H), 7.266 (1H, Ar-H), 7.318∼7.431 (dd, 1H, J= 7.2 Hz, 9.3 Hz, Ar-H), 7.413∼7.460 (m, 3H, Ar-H).
Preparación de 1-(4-fluorobencil)-5-(trifluorometil)piridin-2(1H)-ona
15 La preparación de 1-(4-fluorobencil)-5-(trifluorometil)piridin-2(1H)-ona incluye los pasos de: disolver 0.49 g (3.0 mmol) de 5-(trifluorometil)piridin-2(1H)-ona en 30 mL de DMF; añadir 0.5 g (3.6 mmol) de carbonato de sodio y 0.85 g (4.5 mmol) de 1-(bromometil)-4-fluorobenceno; llevar a cabo la reacción a reflujo durante 3 horas; filtrar; evaporar el filtrado y separar el residuo por cromatografía en columna con éter de petróleo como eluyente para obtener el producto 1-(4-fluorobencil)-5-(trifluorometil)piridin-2(1H)-ona como un sólido blanco de 0.72 g. p.f.: 70.1∼72.0 °C.
20 ESI-MS(m/z): 294[M+Na]+. 1H-RMN (CDCl3, 300 MHz) δppm: 5.112 (s, 2H, -CH2-), 6.658∼6.690 (d, 1H, J=9.6 Hz, Ar-H), 7.035∼7.093 (m, 2H, Ar-H), 7.299∼7.345 (m, 2H, Ar-H), 7.423∼7.464 (dd, 1H, J=2.7 Hz, 9.6 Hz, Ar-H), 7.649 (s, 1H, Ar-H).
Ejemplo 16
Preparación de 1-(2-nitrobencil)-5-(trifluorometil)piridin-2(1H)-ona
25
14
E10780057
04-05-2015
Ejemplo 22
Preparación de 1-(2-(2-(piperazin-1-il)etilaminof)bencil)-5-(trifluorometil)piridin-2(1H)-ona
5 A Preparación de 1-(2-((2-cloroetil)amino)bencil)-5-(trifluorometil)piridin-2(1H)-ona. La preparación de 1-(2-((2cloroetil)amino)bencil)-5-(trifluorometil)piridin-2(1H)-ona incluye los pasos de: disolver 2.2 g de 1-(2-((2hidroxietil)amino)bencil)-5-(trifluorometil)piridin-2(1H)-ona en 40 mL de diclorometano; añadir 1.7 g de dicloruro sulfuroso y 1.2 g de trietilamina; permitir que el sistema resultante reaccione a temperatura ambiente durante 10 horas con agitación y separar el residuo por cromatografía en columna para obtener un sólido blanco de 1.5 g.
10 p.f.: 93.5∼95.0 °C. EI-MS(m/z): 330[M]+. 1H-RMN (CDCl3, 300 MHz): δppm: 3.483∼3.543 (t, 2H, -CH2-), 3.628∼3.672 (t, 2H, -CH2-), 5.089 (s, 2H, -CH2-), 5.737∼5.753 (1H, -NH-), 6.618~6.757 (m, 3H, Ar-H), 7.206∼7.235 (dd, 1H, J=1.2 Hz, 7.5 Hz, Ar-H), 7.250∼7.307 (dd, 1H, J=8.1 Hz, 9.0 Hz, Ar-H), 7.732 (s, 1H, Ar-H).
B Preparación de 1-(2-(2-(piperazin-1-il)etilaminof)bencil)-5-(trifluorometil)piridin-2(1H)-ona. La preparación de 1
15 (2-(2-(piperazin-1-il)etilaminof)bencil)-5-(trifluorometil)piridin-2(1H)-ona incluye los pasos de: disolver 0.33 g (1 mmol) de 1-(2-((2-cloroetil)amino)bencil)-5-(trifluorometil)piridin-2(1H)-ona en 20 mL de acetonitrilo; añadir 0.53 g (6 mmol) de piperazina anhidra y una cantidad catalítica de yoduro de sodio; llevar a cabo la reacción a reflujo durante 20 horas; filtrar; evaporar el filtrado hasta sequedad y separar por cromatografía en columna con metanol para obtener un aceite amarillo de 0.26 g. EI-MS(m/z): 380[M]+. 1H-RMN (CDCl3, 300 MHz): δppm:
20 2.434 (s, 4H, -CH2-), 2.575∼2.615 (t, 2H, -CH2-), 2.839∼2.853 (d, 4H, -CH2-), 3.181∼3.200 (d, 2H, -CH2-) ,5.153 (s, 2H, -CH2-), 5.275 (s, 1H, -NH-), 6.636∼6.740 (m, 3H, Ar-H), 7.150∼7.174 (d, 1H, J=7.2 Hz, Ar-H), 7.283∼7.309 (m, 1H, Ar-H), 7.426∼7.458 (d, 1H, J=9.6 Hz, Ar-H), 7.632 (s, 1H, Ar-H).
Ejemplo 23
25 Preparación de 1-(2-(2-(4-metilpiperazin-1-il)etilamino)bencil)-5-(trifluorometil)piridin-2(1H)-ona
La preparación de 1-(2-(2-(4-metilpiperazin-1-il)etilamino)bencil)-5-(trifluorometil)piridin-2(1H)-ona incluye los pasos 30 de: disolver 0.33 g (l mmol) de 1-(2-((2-cloroetil)amino)bencil)-5-(trifluorometil)piridin-2(1H)-ona en 20 mL de
18
E10780057
04-05-2015
- Compuestos medidos
-
48 horas
imagen23 72 horasimagen24
- CI50 relativa (mM)
- Múltiplo CI50 relativa (mM) Múltiplo
- Compuesto 6
- 1.011 4.38 0,638 5.51
- Compuesto 7
- 4.179 1.06 0.340 10.36
- Compuesto 8
- 0.367 12.07 0.229 15.36
- Compuesto 9
- 0.181 24.53 0.120 29.38
- Compuesto 11
- 0.526 8.42 0.131 26.88
- Compuesto 13
- 0.128 34.55 0.068 52.14
- Compuesto 14
- 0.346 12.81 0.182 19.29
- Compuesto 15
- 1.078 4.11 1.093 3.22
- Compuesto 16
- 1.035 4.28 1.032 3.41
- Compuesto 17
- 1.808 2.45 1.271 2.77
- Compuesto 18
- 1.457 3.04 1.349 2.61
- Compuesto 19
- 0.301 14.72 0.384 9.16
- Compuesto 20
- 0.273 16.25 0.393 8.95
- Compuesto 21
- 0.664 6.67 0.587 6.00
- Compuesto 22
- 0.168 26.31 0.291 12.10
- Compuesto 25
- 0.368 12.04 0.264 13.33
- Notas: múltiplo es el valor de CI50 de los compuestos respecto al valor de CI50 de la fluorofenidona
Ejemplo 28
Observación del efecto de tratamiento del compuesto 13 en un modelo de fibrosis renal con obstrucción ureteral unilateral en ratas
5 Materiales y métodos
1. Compuestos químicos experimentales
Se preparó el compuesto 13 de acuerdo con el método que se proporciona en la invención.
Se iluminaron nueve ratas SD macho de 188-213 g que provenían de Hunan Slac Laboratory Animals Co., Ltd, 10 durante 12 horas cada día; Shanghai Slac Laboratory Animals Co., Ltd. proporcionó el alimento y el Departamento de Ciencias de Animales de Laboratorio de la Universidad Central de Sur proporcionó el agua.
(1) Aleatorización: se dividieron las nueve ratas en tres grupos aleatoriamente, concretamente un grupo normal
(n=3); un grupo modelo (n=3) y un grupo de tratamiento (n=3) tratado con 15 mg/kg del compuesto 13; tres ratas 15 están en una madriguera; y los animales experimentales se alimentan adaptativamente durante dos días.
La modelización de la obstrucción ureteral unilateral comprende los pasos de: inyectar en la zona lumbar de cada rata hidrato de cloral al 10% según una pauta de 0.35 mL/100 g para la anestesia, fijar en una placa de fijación para ratas; humedecer la piel de la espalda con agua, estirar la piel; eliminar el pelo con tijeras quirúrgicas acodadas en 20 una manera que se una próximamente a la piel; esterilizar un paño de manera convencional; realizar una incisión de
1.0 cm en una dirección longitudinal en una intersección de una posición 1.0 cm por debajo del margen costal izquierdo y próxima en 0.8 cm a la línea media de la columna vertebral; separar las sucesivas capas para exponer el riñón izquierdo y el uréter izquierdo; ligar el uréter izquierdo contra el polo inferior del riñón izquierdo con un hilo de
4.0 cm y otra porción 1.0 más abajo; aislar el uréter entre esos dos puntos; lavar la cavidad abdominal con una 25 solución salina fisiológica con gentamicina y coser las capas sucesivas del espacio retroperitoneal y la piel de la
21
Claims (1)
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imagen1 imagen2
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910043502 | 2009-05-25 | ||
| CN200910043502 | 2009-05-25 | ||
| PCT/CN2010/073131 WO2010135976A1 (zh) | 2009-05-25 | 2010-05-24 | 1-（取代苄基）-5-三氟甲基-2-（1h）吡啶酮化合物及其盐，其制备方法及其用途 |
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| US (1) | US8377932B2 (es) |
| EP (1) | EP2474533B1 (es) |
| JP (1) | JP5722883B2 (es) |
| KR (1) | KR101478133B1 (es) |
| CN (1) | CN102149683B (es) |
| AU (1) | AU2010252451B2 (es) |
| DK (1) | DK2474533T3 (es) |
| ES (1) | ES2536200T3 (es) |
| WO (1) | WO2010135976A1 (es) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP2296653B1 (en) | 2008-06-03 | 2016-01-27 | Intermune, Inc. | Compounds and methods for treating inflammatory and fibrotic disorders |
| JP5924984B2 (ja) * | 2012-03-06 | 2016-05-25 | 国立大学法人東京農工大学 | トリフルオロメチルピリジノン化合物およびその製造方法 |
| US9434695B2 (en) | 2012-07-18 | 2016-09-06 | Sunshine Lake Pharma Co., Ltd | Nitrogenous heterocyclic derivatives and their application in drugs |
| AR092742A1 (es) | 2012-10-02 | 2015-04-29 | Intermune Inc | Piridinonas antifibroticas |
| KR20150018127A (ko) * | 2013-08-09 | 2015-02-23 | 삼성전자주식회사 | 디스플레이 장치 및 그 방법 |
| JP6454348B2 (ja) | 2013-12-19 | 2019-01-16 | サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ． | 窒素複素環誘導体およびその医薬品への応用 |
| RU2692485C2 (ru) | 2014-04-02 | 2019-06-25 | Интермьюн, Инк. | Противофиброзные пиридиноны |
| CN106466318B (zh) * | 2015-08-21 | 2019-01-01 | 中南大学 | 1-杂环取代苄基吡啶酮类化合物在制备治疗糖尿病肾病药物中的应用 |
| CN107663167A (zh) * | 2016-10-19 | 2018-02-06 | 广州南新制药有限公司 | 1‑（取代苄基）‑5‑三氟甲基‑2(1h)‑吡啶酮盐酸盐的晶型及制备方法 |
| CN107652228B (zh) * | 2016-10-28 | 2020-04-14 | 广州南新制药有限公司 | 抗肾纤维化药物1-（取代苄基）-5-三氟甲基-2(1h)-吡啶酮盐酸盐的合成方法 |
| CN113456642B (zh) * | 2021-07-09 | 2022-09-06 | 中南大学 | 一种美氟尼酮在制备治疗急性肾损伤药物中的应用 |
| WO2023168650A1 (zh) * | 2022-03-10 | 2023-09-14 | 广州南新制药有限公司 | 一种美氟尼酮晶型的制备方法 |
| WO2023168649A1 (zh) * | 2022-03-10 | 2023-09-14 | 广州南新制药有限公司 | 一种美氟尼酮盐酸盐的制备方法 |
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| US4052509A (en) | 1972-12-18 | 1977-10-04 | Affiliated Medical Research, Inc. | Method for reducing serum uric acid levels |
| US4042699A (en) | 1972-12-18 | 1977-08-16 | Affiliated Medical Research, Inc. | Method for reducing serum glucose levels |
| GB8523126D0 (en) * | 1985-09-19 | 1985-10-23 | Ici Plc | Aryl pyridones |
| GB8621217D0 (en) | 1986-09-03 | 1986-10-08 | Ici Plc | Chemical compounds |
| GB8825314D0 (en) | 1988-10-28 | 1988-11-30 | Ici Plc | Chemical compounds |
| GB9006479D0 (en) | 1989-04-17 | 1990-05-23 | Ici Plc | Novel compounds |
| US5716632A (en) | 1989-11-22 | 1998-02-10 | Margolin; Solomon B. | Compositions and methods for reparation and prevention of fibrotic lesions |
| US5518729A (en) | 1989-11-22 | 1996-05-21 | Margolin; Solomon B. | Compositions and methods for reparation and prevention of fibrotic lesions |
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| AP1822A (en) | 2002-02-14 | 2008-01-30 | Pharmacia Corp | Substituted pyridinones as modulators of P38 MAP kinase. |
| CN1218942C (zh) * | 2002-06-11 | 2005-09-14 | 中南大学湘雅医学院 | 抗纤维化吡啶酮化合物及其生产工艺方法 |
| US7166603B2 (en) | 2003-07-23 | 2007-01-23 | Bristol-Myers Squibb Co. | Dihydropyrimidone inhibitors of calcium channel function |
| GB0324159D0 (en) * | 2003-10-15 | 2003-11-19 | Glaxo Group Ltd | Novel compounds |
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| DE102004027359A1 (de) | 2004-06-04 | 2005-12-29 | Abbott Gmbh & Co. Kg | Pyridin-2-onverbindungen und deren Verwendung |
| AP2007004244A0 (en) | 2005-05-10 | 2007-12-31 | Intermune Inc | Method of modulating stress-activated protein kinase system |
| ZA200709593B (en) | 2005-05-10 | 2009-06-24 | Intermune Inc | Pyridone derivatives for modulating stress-activated protein kinase system |
| WO2007053610A2 (en) | 2005-11-01 | 2007-05-10 | The Regents Of The University Of California | Methods of treating atrial fibrillation wtih pirfenidone |
| US20110034495A1 (en) | 2005-11-23 | 2011-02-10 | Intermune, Inc. | Method of Modulating Stress-Activated Protein Kinase System |
| CN101235030A (zh) * | 2007-01-30 | 2008-08-06 | 中南大学 | 1-取代-5-三氟甲基-2-(1h)吡啶酮化合物、制备方法及其用途 |
| US20090118135A1 (en) | 2007-06-08 | 2009-05-07 | The Burnham Institute | Methods and compounds for regulating apoptosis |
| CN101371833A (zh) * | 2007-08-23 | 2009-02-25 | 中南大学 | 1-芳基-2(1h)-吡啶酮类化合物在制备治疗皮肤瘙痒药物中的应用 |
| EP2296653B1 (en) | 2008-06-03 | 2016-01-27 | Intermune, Inc. | Compounds and methods for treating inflammatory and fibrotic disorders |
| EP2389227A4 (en) | 2009-01-26 | 2012-08-08 | Intermune Inc | METHOD FOR THE TREATMENT OF ACUTE MYOCARDINE CARDS AND ASSOCIATED ILLNESSES THEREOF |
| WO2010135470A1 (en) | 2009-05-19 | 2010-11-25 | Intermune, Inc. | Pifenidone derivatives for treating bronchial asthma |
-
2010
- 2010-05-24 EP EP10780057.5A patent/EP2474533B1/en not_active Not-in-force
- 2010-05-24 ES ES10780057.5T patent/ES2536200T3/es active Active
- 2010-05-24 CN CN2010800025776A patent/CN102149683B/zh active Active
- 2010-05-24 KR KR1020117030958A patent/KR101478133B1/ko not_active Expired - Fee Related
- 2010-05-24 US US13/322,153 patent/US8377932B2/en not_active Expired - Fee Related
- 2010-05-24 DK DK10780057.5T patent/DK2474533T3/en active
- 2010-05-24 AU AU2010252451A patent/AU2010252451B2/en not_active Ceased
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Also Published As
| Publication number | Publication date |
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| US20120129859A1 (en) | 2012-05-24 |
| KR101478133B1 (ko) | 2014-12-31 |
| JP5722883B2 (ja) | 2015-05-27 |
| KR20120060785A (ko) | 2012-06-12 |
| CN102149683B (zh) | 2013-10-02 |
| CN102149683A (zh) | 2011-08-10 |
| AU2010252451A1 (en) | 2011-12-15 |
| WO2010135976A1 (zh) | 2010-12-02 |
| DK2474533T3 (en) | 2015-05-18 |
| EP2474533A1 (en) | 2012-07-11 |
| JP2012527488A (ja) | 2012-11-08 |
| EP2474533B1 (en) | 2015-02-25 |
| EP2474533A4 (en) | 2012-11-14 |
| HK1166791A1 (en) | 2012-11-09 |
| US8377932B2 (en) | 2013-02-19 |
| AU2010252451B2 (en) | 2014-04-03 |
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