JP2009523702A - 放射性画像診断のための窒化テクネチウム錯体の中間体化合物 - Google Patents
放射性画像診断のための窒化テクネチウム錯体の中間体化合物 Download PDFInfo
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- JP2009523702A JP2009523702A JP2008534589A JP2008534589A JP2009523702A JP 2009523702 A JP2009523702 A JP 2009523702A JP 2008534589 A JP2008534589 A JP 2008534589A JP 2008534589 A JP2008534589 A JP 2008534589A JP 2009523702 A JP2009523702 A JP 2009523702A
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- Prior art keywords
- compound
- formula
- bis
- ethyl
- dithiocarbamate
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 72
- -1 technetium nitride Chemical class 0.000 title claims abstract description 70
- 229910052713 technetium Inorganic materials 0.000 title abstract description 28
- 238000003384 imaging method Methods 0.000 title abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 38
- 239000000203 mixture Substances 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 31
- 229910052757 nitrogen Inorganic materials 0.000 claims description 31
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 25
- DKVNPHBNOWQYFE-UHFFFAOYSA-N carbamodithioic acid Chemical compound NC(S)=S DKVNPHBNOWQYFE-UHFFFAOYSA-N 0.000 claims description 14
- 239000012990 dithiocarbamate Substances 0.000 claims description 14
- 239000003638 chemical reducing agent Substances 0.000 claims description 13
- BQLHMMQUVJCTAN-UHFFFAOYSA-N 1-chloro-3-methoxypropane Chemical compound COCCCCl BQLHMMQUVJCTAN-UHFFFAOYSA-N 0.000 claims description 8
- SAOWARUCELFUFZ-UHFFFAOYSA-N 2-ethoxy-n,n-bis(2-phosphanylethyl)ethanamine Chemical compound CCOCCN(CCP)CCP SAOWARUCELFUFZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000012217 radiopharmaceutical Substances 0.000 claims description 7
- 229940121896 radiopharmaceutical Drugs 0.000 claims description 7
- 230000002799 radiopharmaceutical effect Effects 0.000 claims description 7
- 239000007809 chemical reaction catalyst Substances 0.000 claims description 6
- 238000006482 condensation reaction Methods 0.000 claims description 6
- 238000002059 diagnostic imaging Methods 0.000 claims description 6
- IOWOAQVVLHHFTL-UHFFFAOYSA-N technetium(vii) oxide Chemical compound [O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[Tc+7].[Tc+7] IOWOAQVVLHHFTL-UHFFFAOYSA-N 0.000 claims description 6
- ARQJWVBKSROCEQ-UHFFFAOYSA-N 2-methoxy-n,n-bis(2-phosphanylethyl)ethanamine Chemical compound COCCN(CCP)CCP ARQJWVBKSROCEQ-UHFFFAOYSA-N 0.000 claims description 4
- IVCCUCCULQKEHE-UHFFFAOYSA-N C(N)(S)=S.C(C)N1CCNCC1 Chemical compound C(N)(S)=S.C(C)N1CCNCC1 IVCCUCCULQKEHE-UHFFFAOYSA-N 0.000 claims description 4
- VSWDORGPIHIGNW-UHFFFAOYSA-N Pyrrolidine dithiocarbamic acid Chemical group SC(=S)N1CCCC1 VSWDORGPIHIGNW-UHFFFAOYSA-N 0.000 claims description 4
- RBWFQWFQFWBVBP-UHFFFAOYSA-N carbamodithioic acid;piperidine Chemical compound NC(S)=S.C1CCNCC1 RBWFQWFQFWBVBP-UHFFFAOYSA-N 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- FAXDZWQIWUSWJH-UHFFFAOYSA-N 3-methoxypropan-1-amine Chemical compound COCCCN FAXDZWQIWUSWJH-UHFFFAOYSA-N 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- HDIWHOGGHQPQTI-UHFFFAOYSA-N 3-ethoxy-n,n-bis(2-phosphanylethyl)propan-1-amine Chemical compound CCOCCCN(CCP)CCP HDIWHOGGHQPQTI-UHFFFAOYSA-N 0.000 claims description 2
- MHCFAGZWMAWTNR-UHFFFAOYSA-M lithium perchlorate Chemical group [Li+].[O-]Cl(=O)(=O)=O MHCFAGZWMAWTNR-UHFFFAOYSA-M 0.000 claims description 2
- 229910001486 lithium perchlorate Inorganic materials 0.000 claims description 2
- 229960003750 ethyl chloride Drugs 0.000 claims 2
- 150000003496 technetium compounds Chemical class 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 92
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 21
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- 238000003786 synthesis reaction Methods 0.000 description 20
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- 239000003921 oil Substances 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 239000008346 aqueous phase Substances 0.000 description 15
- 229910052786 argon Inorganic materials 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 239000012071 phase Substances 0.000 description 15
- PINITSMLVXAASM-UHFFFAOYSA-N 1-bromo-2-diethoxyphosphorylethane Chemical compound CCOP(=O)(CCBr)OCC PINITSMLVXAASM-UHFFFAOYSA-N 0.000 description 13
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 239000003446 ligand Substances 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000012298 atmosphere Substances 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 8
- JDBBUKUREWGGHM-UHFFFAOYSA-N n,n-bis[2-(3,3-dimethoxypropylphosphanyl)ethyl]-2-ethoxyethanamine Chemical compound COC(OC)CCPCCN(CCOCC)CCPCCC(OC)OC JDBBUKUREWGGHM-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- BPGIOCZAQDIBPI-UHFFFAOYSA-N 2-ethoxyethanamine Chemical compound CCOCCN BPGIOCZAQDIBPI-UHFFFAOYSA-N 0.000 description 7
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- PQXBFLMXEYQDBG-UHFFFAOYSA-N bis(3-methoxypropyl)phosphane Chemical compound COCCCPCCCOC PQXBFLMXEYQDBG-UHFFFAOYSA-N 0.000 description 7
- 150000004767 nitrides Chemical group 0.000 description 7
- 241000699670 Mus sp. 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
- 239000012043 crude product Substances 0.000 description 6
- 229920001971 elastomer Polymers 0.000 description 6
- XXWPOEYZZGUUHI-UHFFFAOYSA-N n,n-bis[2-(2,2-dimethoxyethylphosphanyl)ethyl]-2-methoxyethanamine Chemical compound COC(OC)CPCCN(CCOC)CCPCC(OC)OC XXWPOEYZZGUUHI-UHFFFAOYSA-N 0.000 description 6
- 229940056501 technetium 99m Drugs 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- GWVHJFSXLMHBMO-UHFFFAOYSA-N n,n-bis(2-chloroethyl)-2-ethoxyethanamine Chemical compound CCOCCN(CCCl)CCCl GWVHJFSXLMHBMO-UHFFFAOYSA-N 0.000 description 5
- KNQBFGISEDULIP-UHFFFAOYSA-N n,n-bis[2-(2,2-dimethoxyethylphosphanyl)ethyl]-2-ethoxyethanamine Chemical compound COC(OC)CPCCN(CCOCC)CCPCC(OC)OC KNQBFGISEDULIP-UHFFFAOYSA-N 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- USECIYVEPXUVHT-UHFFFAOYSA-N 2-propan-2-yloxyethanamine Chemical compound CC(C)OCCN USECIYVEPXUVHT-UHFFFAOYSA-N 0.000 description 4
- 229920000858 Cyclodextrin Polymers 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 210000004100 adrenal gland Anatomy 0.000 description 4
- 230000002051 biphasic effect Effects 0.000 description 4
- LMBWSYZSUOEYSN-UHFFFAOYSA-N diethyldithiocarbamic acid Chemical compound CCN(CC)C(S)=S LMBWSYZSUOEYSN-UHFFFAOYSA-N 0.000 description 4
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 4
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 3
- DREPONDJUKIQLX-UHFFFAOYSA-N 1-[ethenyl(ethoxy)phosphoryl]oxyethane Chemical compound CCOP(=O)(C=C)OCC DREPONDJUKIQLX-UHFFFAOYSA-N 0.000 description 3
- XTIGGAHUZJWQMD-UHFFFAOYSA-N 1-chloro-2-methoxyethane Chemical compound COCCCl XTIGGAHUZJWQMD-UHFFFAOYSA-N 0.000 description 3
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- HCOMFAYPHBFMKU-UHFFFAOYSA-N butanedihydrazide Chemical compound NNC(=O)CCC(=O)NN HCOMFAYPHBFMKU-UHFFFAOYSA-N 0.000 description 3
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- RPQJPIFSJROINT-UHFFFAOYSA-N n,n-bis[2-(3,3-dimethoxypropylphosphanyl)ethyl]-2-methoxyethanamine Chemical compound COC(OC)CCPCCN(CCOC)CCPCCC(OC)OC RPQJPIFSJROINT-UHFFFAOYSA-N 0.000 description 3
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- VFMBLTLBOLHLSX-UHFFFAOYSA-N 2,2-diethoxyethylcarbamodithioic acid Chemical compound CCOC(OCC)CNC(S)=S VFMBLTLBOLHLSX-UHFFFAOYSA-N 0.000 description 2
- NFZNKNCBDITZCY-UHFFFAOYSA-N 2-ethoxyethyl(ethyl)carbamodithioic acid Chemical compound CCOCCN(CC)C(S)=S NFZNKNCBDITZCY-UHFFFAOYSA-N 0.000 description 2
- DBBUITKQDGZCDE-UHFFFAOYSA-N 2-ethoxyethyl(propan-2-yl)carbamodithioic acid Chemical compound CCOCCN(C(C)C)C(S)=S DBBUITKQDGZCDE-UHFFFAOYSA-N 0.000 description 2
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- GFKRGNZAFGSDOM-UHFFFAOYSA-N n,n-bis[2-(2,2-diethoxyethylphosphanyl)ethyl]-2-methoxyethanamine Chemical compound CCOC(OCC)CPCCN(CCOC)CCPCC(OCC)OCC GFKRGNZAFGSDOM-UHFFFAOYSA-N 0.000 description 2
- ICGXFICIBRZTPD-UHFFFAOYSA-N n,n-bis[2-(3,3-diethoxypropylphosphanyl)ethyl]-2-ethoxyethanamine Chemical compound CCOC(OCC)CCPCCN(CCOCC)CCPCCC(OCC)OCC ICGXFICIBRZTPD-UHFFFAOYSA-N 0.000 description 2
- XZVRWXUHMCZROH-UHFFFAOYSA-N n,n-bis[2-(3,3-diethoxypropylphosphanyl)ethyl]-2-methoxyethanamine Chemical compound CCOC(OCC)CCPCCN(CCOC)CCPCCC(OCC)OCC XZVRWXUHMCZROH-UHFFFAOYSA-N 0.000 description 2
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- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 2
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- QTGYSZFXCNTRNB-UHFFFAOYSA-N n,n-bis[2-(3,3-diethoxypropylphosphanyl)ethyl]-3-propan-2-yloxypropan-1-amine Chemical compound CCOC(OCC)CCPCCN(CCCOC(C)C)CCPCCC(OCC)OCC QTGYSZFXCNTRNB-UHFFFAOYSA-N 0.000 description 1
- GEMQHYHSGBJJNX-UHFFFAOYSA-N n,n-bis[2-(3,3-dimethoxypropylphosphanyl)ethyl]-2-propan-2-yloxyethanamine Chemical compound COC(OC)CCPCCN(CCOC(C)C)CCPCCC(OC)OC GEMQHYHSGBJJNX-UHFFFAOYSA-N 0.000 description 1
- CYZHMVHMKQDZJE-UHFFFAOYSA-N n,n-bis[2-(3,3-dimethoxypropylphosphanyl)ethyl]-3-ethoxypropan-1-amine Chemical compound COC(OC)CCPCCN(CCCOCC)CCPCCC(OC)OC CYZHMVHMKQDZJE-UHFFFAOYSA-N 0.000 description 1
- CFSQBPBUYILAOE-UHFFFAOYSA-N n,n-bis[2-(3,3-dimethoxypropylphosphanyl)ethyl]-3-propan-2-yloxypropan-1-amine Chemical compound COC(OC)CCPCCN(CCCOC(C)C)CCPCCC(OC)OC CFSQBPBUYILAOE-UHFFFAOYSA-N 0.000 description 1
- GBOWXFLTZMFGCS-UHFFFAOYSA-N n,n-bis[2-[2,2-di(propan-2-yloxy)ethylphosphanyl]ethyl]-2-ethoxyethanamine Chemical compound CC(C)OC(OC(C)C)CPCCN(CCOCC)CCPCC(OC(C)C)OC(C)C GBOWXFLTZMFGCS-UHFFFAOYSA-N 0.000 description 1
- SUCJENFNVKBHCE-UHFFFAOYSA-N n,n-bis[2-[2,2-di(propan-2-yloxy)ethylphosphanyl]ethyl]-2-methoxyethanamine Chemical compound CC(C)OC(OC(C)C)CPCCN(CCOC)CCPCC(OC(C)C)OC(C)C SUCJENFNVKBHCE-UHFFFAOYSA-N 0.000 description 1
- OTSUFAGSNJIAER-UHFFFAOYSA-N n,n-bis[2-[2,2-di(propan-2-yloxy)ethylphosphanyl]ethyl]-3-ethoxypropan-1-amine Chemical compound CC(C)OC(OC(C)C)CPCCN(CCCOCC)CCPCC(OC(C)C)OC(C)C OTSUFAGSNJIAER-UHFFFAOYSA-N 0.000 description 1
- JYNSWIQEXHQYKN-UHFFFAOYSA-N n,n-bis[2-[2,2-di(propan-2-yloxy)ethylphosphanyl]ethyl]-3-propan-2-yloxypropan-1-amine Chemical compound CC(C)OC(OC(C)C)CPCCN(CCCOC(C)C)CCPCC(OC(C)C)OC(C)C JYNSWIQEXHQYKN-UHFFFAOYSA-N 0.000 description 1
- MPWWQJOBFZNWAX-UHFFFAOYSA-N n,n-bis[2-[3,3-di(propan-2-yloxy)propylphosphanyl]ethyl]-2-ethoxyethanamine Chemical compound CC(C)OC(OC(C)C)CCPCCN(CCOCC)CCPCCC(OC(C)C)OC(C)C MPWWQJOBFZNWAX-UHFFFAOYSA-N 0.000 description 1
- AMYDOFLSLBBBJV-UHFFFAOYSA-N n,n-bis[2-[3,3-di(propan-2-yloxy)propylphosphanyl]ethyl]-2-methoxyethanamine Chemical compound CC(C)OC(OC(C)C)CCPCCN(CCOC)CCPCCC(OC(C)C)OC(C)C AMYDOFLSLBBBJV-UHFFFAOYSA-N 0.000 description 1
- LUCJKKGCYBUPRF-UHFFFAOYSA-N n,n-bis[2-[3,3-di(propan-2-yloxy)propylphosphanyl]ethyl]-3-ethoxypropan-1-amine Chemical compound CC(C)OC(OC(C)C)CCPCCN(CCCOCC)CCPCCC(OC(C)C)OC(C)C LUCJKKGCYBUPRF-UHFFFAOYSA-N 0.000 description 1
- CNWUNDIBSRYEFP-UHFFFAOYSA-N n,n-bis[2-[3,3-di(propan-2-yloxy)propylphosphanyl]ethyl]-3-propan-2-yloxypropan-1-amine Chemical compound CC(C)OC(OC(C)C)CCPCCN(CCCOC(C)C)CCPCCC(OC(C)C)OC(C)C CNWUNDIBSRYEFP-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000005121 nitriding Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 238000000607 proton-decoupled 31P nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000010408 sweeping Methods 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/5004—Acyclic saturated phosphines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0489—Phosphates or phosphonates, e.g. bone-seeking phosphonates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
- C07F13/005—Compounds without a metal-carbon linkage
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
- C07F9/4009—Esters containing the structure (RX)2P(=X)-alk-N...P (X = O, S, Se)
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Physics & Mathematics (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Crystallography & Structural Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Optics & Photonics (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
(式中、R1及びR2は上で定義されている通りである)のビニルホスホノ化合物と、次式(III):
(式中、R3、R4、R5及びnは上で定義されている通りである)のホスホノアミン化合物とを縮合反応触媒の存在下で反応させる工程を含む、式(I)で表されるビスホスホノアミン化合物の調製方法に関する。
(式中、R5及びnは上で定義されている通りであり、R6は1〜6個の炭素原子を有するアルキル基であり、mは1〜6の整数である)のビスホスフィノアミン化合物の調製方法であって、
式(I)で表されるビスホスホノアミン化合物を還元剤で還元して、次式(V)
(式中、R5及びnは上で定義されている通りである)のビスホスフィノアミン化合物を製造する工程、及び
式(V)の化合物と、次式(VI):
X−(CH2)m−OR6 (VI)
(式中、Xはハロゲン原子であり、R6及びmは上で定義されている通りである)のハロゲン化化合物とを反応させる工程を含む方法に関する。
[99mTc(N)(PNP)(DTC)]+ (VII)
(式中、PNPは、式(IV)のビスホスフィノアミン化合物であり、DTCは、ジチオカルバメートである)の窒化テクネチウム錯体の調製方法であって、
式(IV)のビスホスフィノアミンを製造するために上述の方法を実施する工程、
式(IV)のビスホスフィノアミン化合物及びジチオカルバメートと酸化テクネチウムとを窒素供与体の存在下で反応させる工程を含む方法に関する。
N,N−ビス[(ジメチル 2−ホスホノ)エチル]メトキシエチルアミン;
N,N−ビス[(ジメチル 2−ホスホノ)エチル]メトキシプロピルアミン;
N,N−ビス[(ジメチル 2−ホスホノ)エチル]エトキシエチルアミン;
N,N−ビス[(ジメチル 2−ホスホノ)エチル]エトキシプロピルアミン;
N,N−ビス[(ジメチル 2−ホスホノ)エチル]n−プロポキシエチルアミン;
N,N−ビス[(ジメチル 2−ホスホノ)エチル]n−プロポキシプロピルアミン;
N,N−ビス[(ジメチル 2−ホスホノ)エチル]イソ−プロポキシエチルアミン;
N,N−ビス[(ジメチル 2−ホスホノ)エチル]イソ−プロポキシプロピルアミン;
N,N−ビス[(ジエチル 2−ホスホノ)エチル]メトキシエチルアミン;
N,N−ビス[(ジエチル 2−ホスホノ)エチル]メトキシプロピルアミン;
N,N−ビス[(ジエチル 2−ホスホノ)エチル]エトキシエチルアミン;
N,N−ビス[(ジエチル 2−ホスホノ)エチル]エトキシプロピルアミン;
N,N−ビス[(ジエチル 2−ホスホノ)エチル]n−プロポキシエチルアミン;
N,N−ビス[(ジエチル 2−ホスホノ)エチル]n−プロポキシプロピルアミン;
N,N−ビス[(ジエチル 2−ホスホノ)エチル]イソ−プロポキシエチルアミン;及び
N,N−ビス[(ジエチル 2−ホスホノ)エチル]イソ−プロポキシプロピルアミン
が挙げられる。
ビス[(ジメトキシエチルホスフィノ)エチル]メトキシエチルアミン;
ビス[(ジメトキシエチルホスフィノ)エチル]メトキシプロポキシルアミン;
ビス[(ジメトキシエチルホスフィノ)エチル]エトキシエチルアミン;
ビス[(ジメトキシエチルホスフィノ)エチル]エトキシプロピルアミン;
ビス[(ジメトキシエチルホスフィノ)エチル]n−プロポキシエチルアミン;
ビス[(ジメトキシエチルホスフィノ)エチル]n−プロポキシプロピルアミン;
ビス[(ジメトキシエチルホスフィノ)エチル]イソプロポキシエチルアミン;
ビス[(ジメトキシエチルホスフィノ)エチル]イソプロポキシプロピルアミン;
ビス[(ジメトキシプロピルホスフィノ)エチル]メトキシエチルアミン;
ビス[(ジメトキシプロピルホスフィノ)エチル]メトキシプロポキシルアミン;
ビス[(ジメトキシプロピルホスフィノ)エチル]エトキシエチルアミン;
ビス[(ジメトキシプロピルホスフィノ)エチル]エトキシプロピルアミン;
ビス[(ジメトキシプロピルホスフィノ)エチル]n−プロポキシエチルアミン;
ビス[(ジメトキシプロピルホスフィノ)エチル]n−プロポキシプロピルアミン;
ビス[(ジメトキシプロピルホスフィノ)エチル]イソプロポキシエチルアミン;
ビス[(ジメトキシプロピルホスフィノ)エチル]イソプロポキシプロピルアミン;
ビス[(ジエトキシエチルホスフィノ)エチル]メトキシエチルアミン;
ビス[(ジエトキシエチルホスフィノ)エチル]メトキシプロポキシルアミン;
ビス[(ジエトキシエチルホスフィノ)エチル]エトキシエチルアミン;
ビス[(ジエトキシエチルホスフィノ)エチル]エトキシプロピルアミン;
ビス[(ジエトキシエチルホスフィノ)エチル]n−プロポキシエチルアミン;
ビス[(ジエトキシエチルホスフィノ)エチル]n−プロポキシプロピルアミン;
ビス[(ジエトキシエチルホスフィノ)エチル]イソプロポキシエチルアミン;
ビス[(ジエトキシエチルホスフィノ)エチル]イソプロポキシプロピルアミン;
ビス[(ジエトキシプロピルホスフィノ)エチル]メトキシエチルアミン;
ビス[(ジエトキシプロピルホスフィノ)エチル]メトキシプロポキシルアミン;
ビス[(ジエトキシプロピルホスフィノ)エチル]エトキシエチルアミン;
ビス[(ジエトキシプロピルホスフィノ)エチル]エトキシプロピルアミン;
ビス[(ジエトキシプロピルホスフィノ)エチル]n−プロポキシエチルアミン;
ビス[(ジエトキシプロピルホスフィノ)エチル]n−プロポキシプロピルアミン;
ビス[(ジエトキシプロピルホスフィノ)エチル]イソプロポキシエチルアミン;
ビス[(ジエトキシプロピルホスフィノ)エチル]イソプロポキシプロピルアミン;
ビス[(ジ−n−プロポキシエチルホスフィノ)エチル]メトキシエチルアミン;
ビス[(ジ−n−プロポキシエチルホスフィノ)エチル]メトキシプロポキシルアミン;
ビス[(ジ−n−プロポキシエチルホスフィノ)エチル]エトキシエチルアミン;
ビス[(ジ−n−プロポキシエチルホスフィノ)エチル]エトキシプロピルアミン;
ビス[(ジ−n−プロポキシエチルホスフィノ)エチル]n−プロポキシエチルアミン;
ビス[(ジ−n−プロポキシエチルホスフィノ)エチル]n−プロポキシプロピルアミン;
ビス[(ジ−n−プロポキシエチルホスフィノ)エチル]イソプロポキシエチルアミン;
ビス[(ジ−n−プロポキシエチルホスフィノ)エチル]イソプロポキシプロピルアミン;
ビス[(ジ−n−プロポキシプロピルホスフィノ)エチル]メトキシエチルアミン;
ビス[(ジ−n−プロポキシプロピルホスフィノ)エチル]メトキシプロポキシルアミン;
ビス[(ジ−n−プロポキシプロピルホスフィノ)エチル]エトキシエチルアミン;
ビス[(ジ−n−プロポキシプロピルホスフィノ)エチル]エトキシプロピルアミン;
ビス[(ジ−n−プロポキシプロピルホスフィノ)エチル]n−プロポキシエチルアミン;
ビス[(ジ−n−プロポキシプロピルホスフィノ)エチル]n−プロポキシプロピルアミン;
ビス[(ジ−n−プロポキシプロピルホスフィノ)エチル]イソプロポキシエチルアミン;
ビス[(ジ−n−プロポキシプロピルホスフィノ)エチル]イソプロパノキシプロピルアミン;
ビス[(ジ−イソ−プロポキシエチルホスフィノ)エチル]メトキシエチルアミン;
ビス[(ジ−イソ−プロポキシエチルホスフィノ)エチル]メトキシプロポキシルアミン;
ビス[(ジ−イソ−プロポキシエチルホスフィノ)エチル]エトキシエチルアミン;
ビス[(ジ−イソ−プロポキシエチルホスフィノ)エチル]エトキシプロピルアミン;
ビス[(ジ−イソ−プロポキシエチルホスフィノ)エチル]n−プロポキシエチルアミン;
ビス[(ジ−イソ−プロポキシエチルホスフィノ)エチル]n−プロポキシプロピルアミン;
ビス[(ジ−イソ−プロポキシエチルホスフィノ)エチル]イソプロポキシエチルアミン;
ビス[(ジ−イソ−プロポキシエチルホスフィノ)エチル]イソプロポキシプロピルアミン;
ビス[(ジ−イソ−プロポキシプロピルホスフィノ)エチル]メトキシエチルアミン;
ビス[(ジ−イソ−プロポキシプロピルホスフィノ)エチル]メトキシプロポキシルアミン;
ビス[(ジ−イソ−プロポキシプロピルホスフィノ)エチル]エトキシエチルアミン;
ビス[(ジ−イソ−プロポキシプロピルホスフィノ)エチル]エトキシプロピルアミン;
ビス[(ジ−イソ−プロポキシプロピルホスフィノ)エチル]n−プロポキシエチルアミン;
ビス[(ジ−イソ−プロポキシプロピルホスフィノ)エチル]n−プロポキシプロピルアミン
ビス[(ジ−イソ−プロポキシプロピルホスフィノ)エチル]イソプロポキシエチルアミン;及び
ビス[(ジ−イソ−プロポキシプロピルホスフィノ)エチル]イソプロポキシプロピルアミン;
が挙げられる。
より好ましくは、ビスホフィノアミン化合物には、次のもの:
ビス[(ジメトキシエチルホスフィノ)エチル]メトキシエチルアミン;
ビス[(ジメトキシエチルホスフィノ)エチル]エトキシエチルアミン;
ビス[(ジメトキシプロピルホスフィノ)エチル]メトキシエチルアミン;
ビス[(ジメトキシプロピルホスフィノ)エチル]エトキシエチルアミン;
ビス[(ジエトキシエチルホスフィノ)エチル]メトキシエチルアミン;
ビス[(ジエトキシエチルホスフィノ)エチル]エトキシエチルアミン;
ビス[(ジエトキシプロピルホスフィノ)エチル]メトキシエチルアミン;及び
ビス[(ジエトキシプロピルホスフィノ)エチル]エトキシエチルアミンが挙げられる。
最も好ましくは、ビスホフィノアミン化合物には、次のもの:
ビス[(ジメトキシエチルホスフィノ)エチル]メトキシエチルアミン;
ビス[(ジメトキシエチルホスフィノ)エチル]エトキシエチルアミン;
ビス[(ジメトキシプロピルホスフィノ)エチル]メトキシエチルアミン;及び
ビス[(ジメトキシプロピルホスフィノ)エチル]エトキシエチルアミンが挙げられる。
[99mTc(N)(PNP)(DTC)]+ (VII)
(式中、PNPは、式(IV)のビスホスフィノアミン化合物であり、DTCは、ジチオカルバメートである)の窒化テクネチウム錯体は、式(IV)のビスホスフィノアミン化合物及びジチオカルバメートと酸化テクネチウムとを窒素供与体の存在下で反応させることにより調製することができる。
99m TcN−PNP5−DBODCの調製
99mTcN−PNP5−DBODCの窒化テクネチウム錯体を実施例4で調製した。ここで、PNP5及びDBODCは、次の通り:
PNP5:ビス(ジメトキシプロピルホスフィノエチル)エトキシエチルアミン
DBODC:ジエトキシエチルジチオカルバメート
を示す。
TLCプレート:シリカゲル60(Merck)
展開相:エタノール/クロロホルム/トルエン/0.5M酢酸アンモニウム=5/3/3/0.5
展開長:10cm
検出器:Radiochlomatoglamschana(Aroka、PS−201型)
99m TcN−PNP7−DBODC及び 99m TcN−PNP10−DBODCの調製
99mTcN−PNP7−DBODC及び99mTcN−PNP10−DBODCの窒化テクネチウム錯体を実施例5で調製した。ここで、PNP7及びPNP10は、次の通り:
PNP7:ビス(ジメトキシエチルホスフィノエチル)エトキシエチルアミン
PNP10:ビス(ジメトキシエチルホスフィノエチル)メトキシエチルアミン
を示す。
カラム:Beckman Ultrasphere ODS 4.6mm×25cm+Guard Column 4.6mm×4.5cm
移動相:80% MeOH/20% 0.02 MPB(pH7.4)
流量:1.0mL/分
検出器:RI Detector(Steffi)、紫外線吸光光度法
TLCプレート:シリカゲル60(Merck)
展開相:エタノール/クロロホルム/トルエン/0.5M酢酸アンモニウム=5/3/3/0.5
展開長:10cm
検出器:Radiochromatogramschana(Aroka、PS−201型)
窒化テクネチウム錯体の生体内分布
実施例4及び5で得た窒化テクネチウム錯体の生体内分布を、これらの錯体をネズミに投与した場合で評価した。
各組織における蓄積速度(%ID/g)=(各組織の放射能(cpm)−バックグラウンド(cpm))/(各組織の放射能の合計(時間について補正された値)×各組織の重量(g))×100
Claims (13)
- R1、R2、R3及びR4が互いに同じである、請求項1記載の化合物。
- R1、R2、R3及びR4が、メチル、エチル、n−プロピル又はイソ−プロピルである、請求項2記載の化合物。
- R5が、メチル、エチル、n−プロピル又はイソ−プロピルである、請求項1〜3のいずれか一項に記載の化合物。
- 縮合反応触媒が過塩素酸リチウムである、請求項5記載の方法。
- 還元剤が、アルミニウムリチウム水素化物又はジクロロアランである、請求項7記載の方法。
- 式(V)のビスホスフィンアミン化合物が、N,N−ビス(2−ホスフィノエチル)メトキシエチルアミン、N,N−ビス(2−ホスフィノエチル)エトキシエチルアミン、N,N−ビス(2−ホスフィノエチル)メトキシプロピルアミン又はN,N−ビス(2−ホスフィノエチル)エトキシプロピルアミンである、請求項7又は8に記載の方法。
- 式(VI)のハロゲン化化合物が、1−メトキシ−3−クロロプロパン、1−メトキシ−3−クロロエタン又は1−エトキシ−3−クロロエタンである、請求項7〜9のいずれか一項に記載の方法。
- 次式(VII):
[99mTc(N)(PNP)(DTC)]+ (VII)
(式中、PNPは、式(IV)のビスホスフィノアミン化合物であり、DTCは、ジチオカルバメートである)の窒化テクネチウム錯体の調製方法であって、
式(IV)のビスホスフィノアミンを製造するために請求項7〜10のいずれか一項に記載の方法を実施する工程、
式(IV)のビスホスフィノアミン化合物及びジチオカルバメートと酸化テクネチウムとを窒素供与体及び還元剤の存在下で反応させる工程、
を含む方法。 - ジチオカルバメートが、ピロリジンジチオカルバメート、ピペリジンジチオカルバメート、4−エチル−ピペラジンジチオカルバメート又はN−ジエトキシエチルジチオカルバメートである、請求項11記載の方法。
- 活性成分として、請求項11又は12に記載の方法により調製される放射能標識テクネチウム化合物を含む、画像診断のための放射性薬剤組成物。
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WO1998027100A1 (fr) * | 1996-12-18 | 1998-06-25 | Nihon Medi-Physics Co., Ltd. | Heterocomplexe a nitrure de metal de transition radioactif |
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CN1583770A (zh) * | 2004-05-24 | 2005-02-23 | 北京师范大学 | 99mTcN核标记配合物及其制备和应用 |
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US3711577A (en) * | 1970-02-11 | 1973-01-16 | Monsanto Co | Nitrilo(ethylenephosphonic acid esters) |
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DE68909245T2 (de) | 1988-11-25 | 1994-03-17 | Cis Bio International Saclay | Übergangsmetall-stickstoffkomplex enthaltendes radiopharmazeutisches produkt mit einer neigung zum herzgewebe. |
FR2664166A1 (fr) | 1990-07-04 | 1992-01-10 | Cis Bio Int | Procede de preparation de complexes nitruro de metaux de transition utilisables comme produits radiopharmaceutiques ou pour la synthese de nouveaux produits radiopharmaceutiques. |
FR2679452B1 (fr) | 1991-07-22 | 1993-11-12 | Cis Bio International | Produit radiopharmaceutique ayant notamment un tropisme cerebral, comportant un complexe nitruro d'un metal de transition, et son procede de preparation. |
AU5973496A (en) | 1995-06-06 | 1996-12-24 | Merck & Co., Inc. | Bisphosphonate cement composition to prevent aseptic loosening of orthopedic implant devices |
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Publication number | Priority date | Publication date | Assignee | Title |
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WO1998027100A1 (fr) * | 1996-12-18 | 1998-06-25 | Nihon Medi-Physics Co., Ltd. | Heterocomplexe a nitrure de metal de transition radioactif |
JP2004505064A (ja) * | 2000-07-28 | 2004-02-19 | 日本メジフィジックス株式会社 | テクネチウム−99m窒化物ヘテロ錯体を含有する放射性画像診断剤 |
CN1583770A (zh) * | 2004-05-24 | 2005-02-23 | 北京师范大学 | 99mTcN核标记配合物及其制备和应用 |
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JP2020504103A (ja) * | 2016-12-15 | 2020-02-06 | ブラッコ イメージング エス.ピー.エー. | テクネチウム系化合物により高感受性及び感熱性の標的指向性生体分子を標識化する方法 |
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CA2636499A1 (en) | 2007-07-26 |
AU2006335853A1 (en) | 2007-07-26 |
EP1973923A1 (en) | 2008-10-01 |
US8182789B2 (en) | 2012-05-22 |
CA2636499C (en) | 2013-02-05 |
JP5027144B2 (ja) | 2012-09-19 |
US20100160615A1 (en) | 2010-06-24 |
AU2006335853B2 (en) | 2011-12-08 |
EP1973923A4 (en) | 2010-02-17 |
WO2007083395A1 (en) | 2007-07-26 |
ES2369027T3 (es) | 2011-11-24 |
EP1973923B1 (en) | 2011-08-17 |
NO20083440L (no) | 2008-08-07 |
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