CN1025735C - 异硫氰基官能化的金属配合物的制备方法 - Google Patents
异硫氰基官能化的金属配合物的制备方法 Download PDFInfo
- Publication number
- CN1025735C CN1025735C CN89109820A CN89109820A CN1025735C CN 1025735 C CN1025735 C CN 1025735C CN 89109820 A CN89109820 A CN 89109820A CN 89109820 A CN89109820 A CN 89109820A CN 1025735 C CN1025735 C CN 1025735C
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- CN
- China
- Prior art keywords
- tetraazacyclododecanand
- aminophenyl
- tetraacethyl
- amino
- methyl
- 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.)
- Expired - Lifetime
Links
- 229910052751 metal Inorganic materials 0.000 title claims description 13
- 239000002184 metal Substances 0.000 title claims description 13
- 238000004519 manufacturing process Methods 0.000 title abstract description 4
- 125000001810 isothiocyanato group Chemical group *N=C=S 0.000 title description 5
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 claims abstract description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 60
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 51
- 238000002360 preparation method Methods 0.000 claims description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- 239000003352 sequestering agent Substances 0.000 claims description 26
- -1 isothiocyanate compound Chemical class 0.000 claims description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 15
- KZUNJOHGWZRPMI-AKLPVKDBSA-N samarium-153 Chemical compound [153Sm] KZUNJOHGWZRPMI-AKLPVKDBSA-N 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- LFZVVVZIFIRGFT-UHFFFAOYSA-N CCCCCCCCCCC.N1C=CC=CC=C1 Chemical class CCCCCCCCCCC.N1C=CC=CC=C1 LFZVVVZIFIRGFT-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 7
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 6
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical group NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 claims description 6
- 239000010948 rhodium Substances 0.000 claims description 6
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 5
- 150000001538 azepines Chemical class 0.000 claims description 5
- DOSGOCSVHPUUIA-UHFFFAOYSA-N samarium(3+) Chemical compound [Sm+3] DOSGOCSVHPUUIA-UHFFFAOYSA-N 0.000 claims description 5
- 229910052727 yttrium Inorganic materials 0.000 claims description 5
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 claims description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- 239000013522 chelant Substances 0.000 claims description 4
- BGHCVCJVXZWKCC-UHFFFAOYSA-N tetradecane Chemical compound CCCCCCCCCCCCCC BGHCVCJVXZWKCC-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 229940120146 EDTMP Drugs 0.000 claims description 3
- 229910052772 Samarium Inorganic materials 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 claims description 3
- 229960003330 pentetic acid Drugs 0.000 claims description 3
- 239000002798 polar solvent Substances 0.000 claims description 3
- 229910052703 rhodium Inorganic materials 0.000 claims description 3
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 3
- KZUNJOHGWZRPMI-UHFFFAOYSA-N samarium atom Chemical compound [Sm] KZUNJOHGWZRPMI-UHFFFAOYSA-N 0.000 claims description 3
- 239000011877 solvent mixture Substances 0.000 claims description 3
- URDCARMUOSMFFI-UHFFFAOYSA-N 2-[2-[bis(carboxymethyl)amino]ethyl-(2-hydroxyethyl)amino]acetic acid Chemical compound OCCN(CC(O)=O)CCN(CC(O)=O)CC(O)=O URDCARMUOSMFFI-UHFFFAOYSA-N 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 2
- 229910052688 Gadolinium Inorganic materials 0.000 claims description 2
- 229910052689 Holmium Inorganic materials 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052769 Ytterbium Inorganic materials 0.000 claims description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 2
- DDTBPAQBQHZRDW-UHFFFAOYSA-N cyclododecane Chemical compound C1CCCCCCCCCCC1 DDTBPAQBQHZRDW-UHFFFAOYSA-N 0.000 claims description 2
- 229910001873 dinitrogen Inorganic materials 0.000 claims description 2
- NFDRPXJGHKJRLJ-UHFFFAOYSA-N edtmp Chemical compound OP(O)(=O)CN(CP(O)(O)=O)CCN(CP(O)(O)=O)CP(O)(O)=O NFDRPXJGHKJRLJ-UHFFFAOYSA-N 0.000 claims description 2
- 230000008020 evaporation Effects 0.000 claims description 2
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 claims description 2
- KJZYNXUDTRRSPN-UHFFFAOYSA-N holmium atom Chemical compound [Ho] KJZYNXUDTRRSPN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052738 indium Inorganic materials 0.000 claims description 2
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- NAWDYIZEMPQZHO-UHFFFAOYSA-N ytterbium Chemical compound [Yb] NAWDYIZEMPQZHO-UHFFFAOYSA-N 0.000 claims description 2
- GRTBAGCGDOYUBE-UHFFFAOYSA-N yttrium(3+) Chemical compound [Y+3] GRTBAGCGDOYUBE-UHFFFAOYSA-N 0.000 claims description 2
- 229910052765 Lutetium Inorganic materials 0.000 claims 1
- OHSVLFRHMCKCQY-UHFFFAOYSA-N lutetium atom Chemical compound [Lu] OHSVLFRHMCKCQY-UHFFFAOYSA-N 0.000 claims 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims 1
- 229910052713 technetium Inorganic materials 0.000 claims 1
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 claims 1
- 150000002540 isothiocyanates Chemical class 0.000 abstract 1
- 239000000047 product Substances 0.000 description 16
- 239000003446 ligand Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000002738 chelating agent Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 230000002285 radioactive effect Effects 0.000 description 3
- 239000002994 raw material Substances 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 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 101000809257 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 4 Proteins 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 102100038463 Ubiquitin carboxyl-terminal hydrolase 4 Human genes 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
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- 239000002585 base Substances 0.000 description 2
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- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 2
- 238000010265 fast atom bombardment Methods 0.000 description 2
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- 229910052746 lanthanum Inorganic materials 0.000 description 2
- FZLIPJUXYLNCLC-UHFFFAOYSA-N lanthanum atom Chemical compound [La] FZLIPJUXYLNCLC-UHFFFAOYSA-N 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- 150000003009 phosphonic acids Chemical class 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
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- 210000004881 tumor cell Anatomy 0.000 description 2
- NWJYINOBWKYMEC-UHFFFAOYSA-N 4-[2-(1,4,7,10-tetrazacyclododec-1-yl)ethyl]aniline Chemical compound C1=CC(N)=CC=C1CCN1CCNCCNCCNCC1 NWJYINOBWKYMEC-UHFFFAOYSA-N 0.000 description 1
- JKTORXLUQLQJCM-UHFFFAOYSA-N 4-phosphonobutylphosphonic acid Chemical compound OP(O)(=O)CCCCP(O)(O)=O JKTORXLUQLQJCM-UHFFFAOYSA-N 0.000 description 1
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- XGPZDTMJEMBFBO-UHFFFAOYSA-N NCCN(CC1=CC=CC=C1)[N+]([O-])=O Chemical compound NCCN(CC1=CC=CC=C1)[N+]([O-])=O XGPZDTMJEMBFBO-UHFFFAOYSA-N 0.000 description 1
- 101001068640 Nicotiana tabacum Basic form of pathogenesis-related protein 1 Proteins 0.000 description 1
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- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
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- 150000001728 carbonyl compounds Chemical class 0.000 description 1
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- 125000004093 cyano group Chemical group *C#N 0.000 description 1
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- VHJLVAABSRFDPM-ZXZARUISSA-N dithioerythritol Chemical compound SC[C@H](O)[C@H](O)CS VHJLVAABSRFDPM-ZXZARUISSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
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- 230000000058 esterolytic effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000004992 fission Effects 0.000 description 1
- IYWCBYFJFZCCGV-UHFFFAOYSA-N formamide;hydrate Chemical compound O.NC=O IYWCBYFJFZCCGV-UHFFFAOYSA-N 0.000 description 1
- LTYRAPJYLUPLCI-UHFFFAOYSA-N glycolonitrile Chemical compound OCC#N LTYRAPJYLUPLCI-UHFFFAOYSA-N 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- GRHBQAYDJPGGLF-UHFFFAOYSA-N isothiocyanic acid Chemical compound N=C=S GRHBQAYDJPGGLF-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- OHSVLFRHMCKCQY-NJFSPNSNSA-N lutetium-177 Chemical compound [177Lu] OHSVLFRHMCKCQY-NJFSPNSNSA-N 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
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- 230000001376 precipitating effect Effects 0.000 description 1
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- 238000010926 purge Methods 0.000 description 1
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- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
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- 238000010992 reflux Methods 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 229910021654 trace metal Inorganic materials 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
-
- 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
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
- C07C331/16—Isothiocyanates
- C07C331/28—Isothiocyanates having isothiocyanate groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
-
- 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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
-
- 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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0073—Rhodium compounds
- C07F15/008—Rhodium 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
- C07F19/00—Metal compounds according to more than one of main groups C07F1/00 - C07F17/00
-
- 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
- C07F19/00—Metal compounds according to more than one of main groups C07F1/00 - C07F17/00
- C07F19/005—Metal compounds according to more than one of main groups C07F1/00 - C07F17/00 without metal-C linkages
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Optics & Photonics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Physics & Mathematics (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
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Abstract
本发明是关于使氨基官能化螯合物与二氯硫化碳反应制备异硫氰酸酯官能化螯合物的新方法。
Description
本发明涉及制备异硫氰基官能化的金属配合物的新方法。所形成的配合物是双官能化合物,可用作多种治疗和/或诊断剂。
众所周知,官能化螯合剂,或双官能配位体能和具有癌细胞或肿瘤细胞抗原决定基和抗原特性的抗体共价结合。这种抗体/螯合剂轭合物的放射性核素配位体在治疗和/或诊断应用中被用作将放射性核素传递到癌或肿瘤细胞去的手段。例如,见Meares等,Anal,Biochem.,142 68-78(1984);和Krejcarek等,Biochem,and Biophys,Res.Comm.77 581-585(1977)。
本发明涉及制备异硫氰基官能化金属配合物的方法。在这些配合物中可以,并且优先使用放射性核素。
异硫氰基官能化的配位体在文献中已有报导,并被用于放射性同位素与抗体的共轭结合。例如,见Gansow等,Inorg.Chem.25,2772-81(1986);Meares等,Analytical Biochem.142,68-78(1984);USP4,454,106。
现有技术中制备这种配合物的方法包括用放射性核素处理抗体/螯合剂轭合物以形成配合物,然后纯化该配合物。这种方法的主要缺点是为了与抗体/螯合剂轭合物快速螯合,放射性核素(镧系或过渡金属元素)必须处于动力学不稳定态。
对抗体标记来说,另一个与使用不稳定放射性核素有关的缺点是某些替代的不稳定痕量元素(它们是非放射性的)常常混入螯合剂。由于被传送到目标位置的放射性核素的量较少,这种非活性痕量金属的竞争减小了抗体/螯合物配合物的生物功能。
Mikolar等,欧洲公开申请EP139,675说明了异硫氰酸酯官能化的螯合剂的制备,接着这些螯合剂与生物有机分子,如半抗原,抗原和抗体共轭结合。这些配合物可用与异硫氰酸酯官能化的配位体螯合制备。
与此相反,本发明是关于制备异氰酸酯的新方法,该方法包括使氨基官能化螯合物与二氯硫化碳反应。本发明涉及在金属与配位体螯合之后在配位体上生成异硫氰基官能团的方法。在配合物形成以后再在配位体上生成异硫氰基部分是重要的,其理由有以下几点:(1)当形成配合物需要加热或非常极端的pH值时,如与铑或镧的大环化合物形成配合物,本方法避免了螯合过程中异硫氰酸酯官能度的破坏;(2)当在配位体中有伯胺或仲胺存在时,由于有副反应,要在螯合作用前形成异硫氰酸酯官能化的配位体是不可能的;(3)由于尽可能在反应的初期阶段形成配合物,减少了不需要的金属配位作用,这样就提高了最终产物的纯度;(4)由于在引入异硫氰酸酯之前生成配合物,简化了配合物的纯化,如用离子交换色谱纯化,并且
减少了纯化过程中带来的异硫氰酸酯水解的不利因素。
令人惊讶的是,本发明的方法提供了一种用氨基官能化螯合物的二氯硫化碳作用制备异硫氰酸酯的方法,该方法速度快、产率高,并提供低金属污染的产品。由于本发明方法在螯合作用之前整个所要求的于配位体上的反应只有几个,因而减少了不希望有的金属污染的数量。
有利的配位体通常是许多不同金属的强螯合剂,这些金属可存在于用来存贮或转移配位体的试剂和容器中,尽管有多种类型的氨基官能化螯合物可以使用,但由氨基羧酸螯合剂、氨基膦酸螯合剂或多氮杂螯合剂的配位体形成的螯合物特别优先选用。
本方法中能使用的配位体类别之一是氨基羧酸螯合剂,某些能使用的氨基羧酸螯合剂的实例在下面表1中给出并命名如下:
ⅠA是对氨基苄基乙二胺四乙酸,其制备在USP4,622,420和J.Med.Chem.17(4),1304(1974)中给出:
ⅠB是对氨基苄基羟乙基乙二胺三乙酸,其制备在USP4,622,420中给出:
ⅠC是对氨基苄基二亚乙基三胺五乙酸,其制备在USP4,622,420和4,647,447中给出;
ⅠD是N′-对氨基苄基二亚乙基三胺,-N,N,N″,N″-四乙酸,其制备在J.Radioanalytical Chem.57(12),553(1980)中给出;
ⅠE是6-(对氨基苯基)-1,4,8,11-四氮杂环十四烷-1,4,8,11-四乙酸,其制备在An-alytical Biochem.148,249-253(1985)中给出;
ⅠF是1-〔2-(4-氨基苯基)乙基〕-1,4,7,10-四氮杂环十四烷-4,7,10-三乙酸,其制备在沙特阿拉伯专利3277A(1989年10月10日公布)中给出;
ⅠG是α-〔2-(4-氨基苯基)乙基〕-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸,其制备在沙特阿拉伯专利3277A(1989年10月10日公布)中给出;
ⅠH是1-(5-氨基-2-甲氧基苄基)-1,4,7,10-四氮杂环十二烷-4,7,10-三乙酸,其制备在沙特阿拉伯专利3277A(1989年10月10日公布)中给出;
ⅠI是1-(5-氨基-2-羟基苄基)-1,4,7,10-四氮杂环十二烷-4,7,10-三乙酸,其制备在沙特阿拉伯专利3277A(1989年10月10日公布)中给出;
ⅠJ是2-〔(2-{〔双(羧甲基)〕氨基}乙基)-(羧甲基)氨基〕-2-〔5-氨基-2-(羧甲氧基)苯基〕乙酸,其制备在下面给出:
ⅠK是2-〔(2-{〔双(羧甲基)〕氨基}乙基)-(羧甲基)氨基〕-2-(5-氨基-2-(羧基苯基)乙酸,其制备在下面给出:
ⅠL是2,6-双{〔(2-{〔双(羧甲基)〕氨基}乙基)-(羧甲基)〕氨基甲基]-4-(氨基)苯酚,其制备在下面给出:
ⅠM是α-(4-氨基苯基)-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸,其制备在沙特阿拉伯专利3277A(1989年10月10日公布)中给出;
ⅠN是α-(4-氨基苯基)-1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸,其制备在沙特阿拉伯专利3277A(1989年10月10日公布)中给出;
ⅠO是α-(4-氨基苯基)乙基〕-1,4,7,10-四氮杂环十二烷-1-(R,S)乙酸-4,7,10-三-(R-甲基乙酸),其制备在沙特阿拉伯专利3277A(1989年10月10日公布)中给出;
上述实例ⅠJ、ⅠK和ⅠL的化合物可用现有技术中熟知的方法制备,例如,参见螯合剂和金属螯合物(Chelating Agents and Metal Chelates)Dwyer & Mellor,Academic Press(1964),第7章,也可参见氨基酸的合成和利用(Synthetic Production and Utilization of Amino Acids),(由Kameko等出版),John Willey & Sons(1974)中氨基酸的制备方法。例如,用相应于实例ⅠJ,但有一个乙酰胺基代替氨基的化合物,使乙酰胺基在水中用NaOH水解,可给出化合物实例ⅠJ。要制备相应于实例ⅠK的化合物,将5-氨基-2-羟基苯基化合物与适当的直链或支链的胺或聚烯胺和醛或醛的前体在苛性的和适当的溶剂中,于20℃或更低的温度下等当量进行反应,接着加热并分离所需产物,然后使所得到的产物与乙醇腈在苛性条件下,pH为9或更高,在20℃或更低的温度下反
应,接着在水中用HCl水解氰基,给出产物实例ⅠK。要得到实例ⅠL化合物,用相应于实例ⅠN,但以乙酰胺基代替氨基的化合物,使乙酰胺基在加热条件下,在D2O中用DCl水解,得到产物实例ⅠL。
上述各阶段的反应条件和试剂如下,当温度为“20℃或更低”时,通常是用冰水浴完成的,“加热”或者是指在回流条件或是在高于室温的条件下进行;优选的“苛性”是氢氧化钠,但任何可保持理想的pH,对反应中形成的产物没有相反影响的适宜的碱是可以接受的。“适当的溶剂”是惰性的,对反应物有溶解性,这些溶剂的实例是水,和醇,如甲醇。目的产物可用常规方法,如从溶剂,如丙酮中沉淀。
在此方法中可能使用的其它几组配位体之一是氨基膦酸螯合剂,某些可能的氨基膦酸螯合剂的实例在下面表Ⅱ中给出,并命名如下:
ⅡA是对氨基苄基乙二胺四亚甲基膦酸,其制备在下文给出;
ⅡB是6-(对氨基苯基)-1,4,8,11-四氮杂环十四烷-1,4,8,11-四亚甲基膦酸,其制备在下文给出;
ⅡC是1-〔2-(4-氨基苯基)乙基〕-1,4,7,10-四氮杂环十二烷-4,7,10-三亚甲基膦酸,其制备在下文给出。
氨基膦酸可用数种已知的合成技术制备。其中特别重要的是在胺上至少有一个易反应的氢的化合物与羰基化合物(醛或酮)以及膦酸或其衍生物反应。〔参见Moeoritzer和Irani的方法,J.Org.Chem.,31,1603(1966)〕。使对一硝基苄基乙二胺与甲醛和膦酸反应可转化成对一硝基苄基乙二胺四亚甲基膦酸,还原硝基会生成对一氨基苄基乙二胺基四亚甲基膦酸。
在本发明的方法中可使用的另一组适宜的配位体是多氮杂螯合剂,某些多氮杂螯合剂的实例在表Ⅲ中给出,并命名如下:
ⅢA是3-〔(4-氨基苯基)甲基〕1,5,8,12-四氮杂环十四烷,其制备在欧洲公开申请296,522中给出,1988年12月28日公布;
ⅢB是6-〔(4-氨基苯基)甲基〕1,4,8,11-四氮杂环十一烷,其制备在欧洲公开申请296,522中给出,1988年12月28日公布;
ⅢC是1,4,7,10-四氮杂-1-〔(4-氨基苯基)甲基〕环十二烷,其制备在欧洲公开申请296,522中给出,1988年12月28日公布;以及
ⅢD是6-(3-氨基丙基)-1,4,7,11-四氮杂环十一烷,其制备在欧洲公开申请296,522中给出,1988年12月28日公布。
表Ⅲ
将过量的二氯硫化碳加入混合物中,过量使用的数量取决于起始氨基官能化螯合物的浓度。为保证胺能快速、完全的转化成异硫氰酸酯,螯合物的浓度越低,二氯硫化碳过量越多。例如,若螯合物浓度是10-3M,二氯硫化碳与螯合剂之比为5-20∶1;若螯合物浓度是10-8M,则二氯硫化碳与螯合剂之比就要比上述比例高几千倍(即105∶1)。过量的二氯硫化碳可用常规技术,如蒸发、色谱法或萃取法去除。
该方法在极性溶剂中进行,特别是在水或配合
物在其中为可溶性的极性有机溶剂中,例如乙醇、乙腈、二甲基甲酰胺、四氢呋喃或二烷。溶剂混合物,如水和非活性溶剂的混合物是特别优选的,例如,水/乙腈、水/二甲基甲酰胺、水/氯仿、水/四氢呋喃、水/二氯甲烷、水/乙腈、水/二烷和水/丁醇。溶剂可以是单相或两相体系,但希望配合物可在其中溶解。
反应的pH可由2到10,优选的是6-8,配合物的pH稳定性会限制实施的pH值范围。某些配合物,如镧的乙二胺四乙酸螯合物在pH为2时不太稳定。添加碱可使pH保持在所需范围之内,或者也可使用常用的缓冲剂。
用过量二氯硫化碳进行反应时,反应时间很快,在室温(15-25℃)下通常用5-10分钟完成反应,也可使用较高或较低的温度(如0°-50℃),但室温是优选的。尽管可以采用较高或较低的压力,但还是采用常压,压力不是本发明方法的主要特征。
本方法的产率至少为50%(以重量计)。
虽然任何金属都可用来与氨基官能化螯合剂配合,不论它们是否是放射性的,但是,所形成的配合物应该具有较好的稳定性,这样,这些配合物就不易离解。稳定常数为105的配合物是适宜的。由于最终产物用作治疗和/或诊断药物,放射性核素是优选的,特别优选的放射性同位素是钐(Sm-153)、钬(Ho-166)、镱(Yb-175)、镥(Lu-177)、钆(Gd-159)、钇(Y-90)、铑(Rh-105)、铟(In-111)和锝(Tc-99m)。
起始原料制备
所用的某些化学品可由各种来源买到。如二氯硫化碳来自Aldrich Chemicals。
本方法的许多起始原料的制备可在文献中找到。按照M.W.Brechbiel等,Inorg.Chem.25,2772-2781(1986)的方法制备1-(4-氨基苯基)二亚乙基三胺五乙酸。
α-(4-氨基苯基)-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸钐(Ⅲ)配合物、α-(4-氨基苯基)1-,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸钇配合物和1-〔2-(4-氨基苯基)乙基〕-1,4,7,10-四氮杂环十二烷-4,7,10三乙酸的制备在沙特阿拉伯专利3277A中说明(1989年10月10日公布)。
放射性核素可用几种方法生产。在核反应堆中用中子轰击核素得到放射性核素,如:
Sm-152+中子→Sm-153+γ
得到核素的另一种方法是用直线加速器或回旋加速器中产生的粒子轰击核素。还有一种方法是由裂变产物的混合物中分离放射性核素。本发明中所采用的得到核素的方法不是本发明的关键。
本发明方法已被用来制备放射性药物的有价值的合成前体。〔参见沙特阿拉伯专利3277A,1989年10月10日公布,以及欧洲公开申请296,522,1988年12月28日公布。〕
除另外给定的以外,在下面的实施例中使用了下述术语和条件。
术语
BA-2,3,2-tet是指6-〔(4-氨基苯基)甲基〕-1,4,8,11-四氮杂十一烷;
BITC-2,3,2-tet是指6-〔(4-异硫氰基苯基)甲基〕-1,4,8,11-四氮杂十一烷;
HEPES是指N-2-羟乙基哌嗪-N′-2-乙磺酸;以及TLC是指薄层色谱法。
一般实验
质谱图用VG ZAB-MS高分辨质谱仪(用氙作快速原子轰击,使用3∶1的二硫苏糖醇∶二硫赤藓糖醇)得到。
报导的Rf值使用了溶剂体系和可购买到的,正相,硅胶TLC板(GHLF 250μm,Analtek TM InC)。
分析和样品分离采用下述HPLC体系:
系统Ⅰ由LKB 2150泵,2152控制器,一台紫外(UV)检测器-LKB2238UV线,一台Berthold TM LB 506 A HPLC放射性检测器(In-ternational Berthold Group产品)和一台Gilson TM馏分收集器201-202(Gilson TM Interna-tional,Middleton,WI)构成。
除另有说明者外所有的百分数均为重量百分数。
钐-153由密苏里大学(哥伦比亚,MO)的Reserarch反应堆生产,以钐在0.1N盐酸(HCl)中浓度为0.2-0.3mmol的溶液提供。
本发明将用下面的实施例进一步阐明,而这些实施例仅仅是作为本发明应用的范例。
本发明的方法
实施例1
〔105Rh(BITC-2,3,2-tet)Cl2〕+的制备
将2ml〔105Rh(BA-2,3,2-tet)Cl2〕+(近似于5mci/ml,1×-4M)与0.002ml二氯硫化碳混合,使〔105Rh(BA-2,3,2-tet)Cl2〕+转化成活性的〔105Rh(BITC-2,3,2-tet)Cl2〕+衍生物,反应在室温下进行15分钟。使溶液通过-Hamilton PRP-1 Chrompak分离产物,用2ml乙腈把〔105Rh(BITC-2,3,2-tet)cl2〕+洗出。用阳离子交换和反相色谱法将其与已知标准品比较进行鉴定,用这种方法产率为50-85%之间。
实施例2
〔Rh(BITC-2,3,2-tet)Cl2〕+的制备
把〔Rh(BA-2,3,2-tet)Cl2〕+(10mg)溶于5ml pH7的磷酸盐缓冲溶液(0.3M),0.5ml乙腈和1g氯化钠的混合物中,将反应混合物在室温下(大约22℃)搅拌并加入10μl二氯硫化碳。15分钟后将雾状混合物离心。黄色固体用乙腈洗涤并离心。把乙腈溶液在减压下汽提,生成3.1mg〔Rh(BITC-2,3,2-tet)Cl2〕+;离心分离后的水相混合物加入先用饱和氯化钠,再用水洗涤的Chrom-Prep。柱,并用乙腈洗出。然后将乙腈馏分减压浓缩得到5.6g目的产物,总产率为80%。
实施例3
〔105Rh(BITC-2,3,2-tet)Cl2〕+制备
将10μl新配制的二氯硫化碳溶液(10μl二氯硫化碳溶在5ml90%乙腈中)加入400μl〔105Rh(BA-2,3,2-tet)Cl2〕+于90%乙腈的溶液中,将溶液立即混合,使其在室温(约22℃)下静置20分钟,然后把反应混合物放在加热块(大约37℃)上。溶剂以及来反应的二氯硫化碳在缓慢的氮气流下蒸发1小时,无水〔105Rh(BITC-2,3,2-tet)Cl2〕+可脱去全部未反应二氯硫化碳,产率大于95%。
实施例4
α-(4-异硫氰基苄基)-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸钐(Ⅲ)配合物的制备
把少量样品,7mg(10.8μmol)α-(4-氨基苄基)-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸钐(Ⅲ)配合物溶解于400μl水中,加入过量的二氯硫化碳(50μl),接着再加入400μl CHCl3,在剧烈搅拌下的两相反应进行30分钟。在此时间结束时,用500μlCHCl3萃取水层4次,然后将水层冰冻干燥给出定量产率的目的标题化合物。
UV指出该化合物在272和282nm有二条谱带;TLC,硅胶,用75∶25的CH3CN∶H2O(V/V)展开,给出Rf=0.38;起始原料的Rf=0.19;IR(KBr压片)指出-SCN的振动在2100cm-1;快速原子轰击质谱〔M+H〕+=687。
实施例5
α-(4-异硫氰基苄基)-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸钠盐,钇(Ⅲ)配合物的制备
把α-(4-氨基苯基)-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸钇配合物的少量样品(10mg,17μmol)溶于400μl水,在此溶液中加入64μl二氯硫化碳(500μmol)和400μl CHCl3,并将得到的混合物剧烈搅拌40分钟。在此期间,几次少量添加固体NaHCO3,以保持pH大约为8。反应结束时,分离水层并用1ml CHCl3萃取4次,冷冻干燥,标题产物用TLC和UV光谱鉴定。
实施例6
α-〔2-(4-异硫氰基苯基)乙基〕-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸钐-153配合物的制备
在由150μl153Sm在0.1N HCl的溶液(大约4.6mci)制得的α-〔2-(4-氨基苯基)-乙基〕-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸,钐-153配合物的溶液中加入2μlHEPES缓冲溶液(0.5M,pH8.9)、2μl二氯硫化碳和200μl氯仿。将混合物剧烈的涡流搅拌2或3次,每次数秒钟。弃去氯仿层,收集主要含有目的产物的水层并进一步纯化。以用系统Ⅰ,HPLC,GF-250柱进行的153Sm活性测定为基础计算,α-〔2-(4-异硫氰基苯基)乙基〕-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸,钐-153配合物的产率大约为85-90%。为了纯化,将水层通过Sep-PakTMC-18柱,并用水中含90%乙腈的溶剂洗出。弃去前面的300μl洗出物,在后面的900μl中洗脱出的SCN-衍生物用HPLC,GF-250柱鉴定。153Sm放射活性的回收率一般大于90%。然后
在Speed VacTM浓缩器上用1.5-2小时的时间蒸出大部分溶剂。
实施例7
α-(4-异硫氰基苯基)-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸钐-153配合物的的制备
在由220μl0.1N HCl中的153Sm溶液中制备的α-(4-氨基苯基)-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸钐-153配合物溶液中加入2μlHEPES缓冲溶液(0.5M,pH8.9)、2μl二氯硫化碳和200μl氯仿。将其剧烈的涡流搅拌2或3次,每次数秒钟。弃去氯仿层,收集主要含有目的产物的水层并纯化。以用HPLC系统Ⅰ测得的153Sm放射活性为基础,由HPLC,GF-250柱分析,α-(4-异硫氰基苯基)-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸钐-153配合物的产率通常大于90%。为了纯化,将水层通过Sep-PakTMC-18柱,并用水中含90%乙腈的溶剂洗涤。弃去前面的300μl洗出物,在后面的1200μl中洗出目的产物,回收率86-93%。然后,用Speed VacTM浓缩器在大约2小时的时间内蒸除大部分溶剂。
对本专业技术人员来说,由本说明书或这里所公开的本发明的实践考虑,本发明的其它实施方案是很明显的。这就是说本说明书和实施例仅作为范例,本发明的真正范围和要点由权利要求书说明。
Claims (20)
1、制备异硫氰酸酯化合物的方法,该方法包括使氨基官能化的螯合物与二氯硫化碳反应。
2、按照权利要求1的方法,其中有极性溶剂或溶剂混合物。
3、按照权利要求2的方法,其中溶剂混合物为水与乙醇、丁醇、乙腈、二甲基甲酰胺、二氯甲烷、四氢呋喃、氯仿或二噁烷。
4、按照权利要求2的方法,其中极性溶剂是水、乙醇、乙腈、二甲基甲酰胺、四氢呋喃或二烷。
5、按照权利要求1的方法,其中反应的pH为由2至10。
6、按照权利要求1的方法,其中温度为0-50℃。
7、按照权利要求1的方法,其中氨基官能化螯合物是氨基羧酸螯合剂与金属的螯合物。
8、按照权利要求7的方法,其中的氨基羧酸螯合剂是下述的任意一种:
对氨基苄基乙二胺四乙酸;
对氨基苄基羟乙基乙二胺三乙酸;
对氨基苄基二亚乙基三胺五乙酸;
N′-对氨基苄基二亚乙基三胺-N,N,N″,N″-四乙酸;
6-(对氨基苄基)-1,4,8,11-四氮杂环十四烷-1,4,8,11-四乙酸;
1-〔2-(4-氨基苯基)乙基〕-1,4,7,10-四氮杂环十二烷-4,7,10-三乙酸;
α-〔2-(4-氨基苯基)乙基〕-1,4,7,10-四氮杂环十二烷-1,4,7,10-乙酸;
1-(5-氨基-2-甲氧基苄基)-1,4,7,10-四氮杂环十二烷-4,7,10-三乙酸;
1-(5-氨基-2-羟基苄基)-1,4,7,10-四氮杂环十二烷-4,7,10-三乙酸;
2-〔(2-{〔双(羧甲基)〕氨基}乙基)-(羧甲基)氨基〕-2-〔5-氨基-2-(羧甲氧基)苯基〕乙酸;
2-〔(2-{〔双(羧甲基)〕氨基}乙基-(羧甲基)氨基〕2-(5-氨基-2-羟基苯基)乙酸;
2,6-双{〔(2-{〔双(羧甲基)〕氨基}乙基)羧甲基〕氨基-甲基}-4-(氨基)酚;
α-(4-氨基苯基)-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸;
α-(4-氨基苯基)-1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸;或
α-〔2-(4-氨基苯基)乙基〕-1,4,7,10-四氮杂环十二烷-1-(R、S)-乙酸-4,7,10-三(R-甲基乙酸)。
9、按照权利要求1的方法,其中氨基官能化螯合物是氨基膦酸螯合剂与金属的螯合物。
10、按照权利要求9的方法,其中氨基膦酸螯合剂是下述的任何一种:
对氨基苄基乙二胺四亚甲基膦酸;
6-(对氨基苄基)-1,4,8,11-四氮杂环十四烷-1,4,8,11-四亚甲基膦酸;或
1-〔2-(4-氨基苯基)乙基〕-1,4,7,10-四氮杂环十二烷-4,7,10-三乙酸。
11、按照权利要求1的方法,其中氨基官能化螯合剂是多氮杂螯合剂与金属的螯合物。
12、按照权利要求11的方法,其中多氮杂螯合剂是下述的任何一种:
3-〔(4-氨基苯基)甲基〕-1,5,8,12-四氮杂环十四烷;
6-〔(4-氨基苯基)甲基〕-1,4,8,11-四氮杂十一烷;
1,4,7,10-四氮杂-1-〔(4-氨基苯基)甲基〕环十二烷;或
6-(3-氨基丙基)-1,4,7,11-四氮杂十一烷。
13、按照权利要求7、9或11的方法,其中的金属是钐、钬、镱、镥、钆、钇、铑、铟或锝。
14、按照权利要求1制备〔105Rh(6-〔(4-异硫氰基苯基)甲基〕-1,4,8,11-四氮杂十一烷)Cl2〕+的方法,该方法包括使〔105Rh(6-〔(4-氨基苯基)甲基〕-1,4,8,11-四氮杂十一烷)Cl2〕+在水中,于室温下与二氯硫化碳反应。
15、按照权利要求1制备〔105Rh(6-〔(4-异硫氰基苯基)甲基〕-1,4,8,11-四氮杂十一烷)Cl2〕+的方法,该方法包括使〔105Rh(6-〔(4-氨基苯基)甲基〕-1,4,8,11-四氮杂十一烷)Cl2〕+在水/乙腈中,于室温下与二氯硫化碳反应。
16、按照权利要求1制备〔105Rh(6-〔(4-异硫氰基苯基)甲基〕-1,4,8,11-四氮杂十一烷)Cl2〕+的方法,该方法包括使〔105Rh(6-〔(4-氨基苯基)甲基〕-1,4,8,11-四氮杂十一烷)Cl2〕+在水/乙腈中,于室温下与二氯硫化碳反应,并用蒸发和氮气流去除溶剂。
17、按照权利要求1制备α-(4-异硫氰基苄基)-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸钐(Ⅲ)配合物的方法,该方法包括使α-(4-氨基苯基)-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸钐(Ⅲ)配合物与二氯硫化碳于水/氯仿中,在室温下进行反应。
18、按照权利要求1制备α-(4-异硫氰基苄基)-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸钠盐,钇(Ⅲ)配合物的方法,该方法包括使α-(4-氨基苯基)-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸钇配合物与二氯硫化碳在室温下,于水/氯仿中进行反应。
19、按照权利要求1制备α-〔2-(4-异硫氰基苯基)-乙基〕-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸钐-153配合物的方法,该方法包括使α-〔2-(4-氨基苯基)-乙基〕-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸钐-153配合物与二氯硫化碳在室温下,于水/氯仿中进行反应。
20、按照权利要求1制备α-〔4-异硫氰基苯基)-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸钐-153配合物的方法,该方法包括使α-(4-氨基苯基)-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸钐-153配合物与二氯硫化碳在室温下,于水/氯仿中进行反应。
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US28917288A | 1988-12-23 | 1988-12-23 | |
US289,172 | 1988-12-23 | ||
US383,103 | 1989-07-20 | ||
US07/383,103 US5006643A (en) | 1987-06-24 | 1989-07-20 | Process for preparing isothiocyanato functionalized metal complexes |
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US5410043A (en) * | 1991-12-06 | 1995-04-25 | Schering Aktiengesellschaft | Process for the production of mono-N-substituted tetraaza macrocycles |
WO1993020852A2 (en) * | 1992-04-13 | 1993-10-28 | The Dow Chemical Company | Macrocyclic chelating agents, chelates and conjugates thereof |
US5310535A (en) * | 1992-04-24 | 1994-05-10 | The Dow Chemical Company | Carboxamide modified polyamine chelators and radioactive complexes thereof for conjugation to antibodies |
DE4218744C2 (de) * | 1992-06-04 | 1997-11-06 | Schering Ag | Verfahren zur Herstellung von N-ß-Hxdroxyalkyl-tri-N-carboxylalkyl-1,4,7,10-tetraazacyclododecan- und N-ß-Hydroxyalkyl-tri-N-carboxyalkyl-1,4,8,11-tetraazacyclotetradecan-Derivaten und deren Metallkomplexe |
US5505931A (en) * | 1993-03-04 | 1996-04-09 | The Dow Chemical Company | Acid cleavable compounds, their preparation and use as bifunctional acid-labile crosslinking agents |
EP0588229A3 (en) * | 1992-09-12 | 1994-06-15 | Hoechst Ag | Macrocyclic chelating agents for the preparation of technetium or rhenium complexes |
WO1995001346A1 (en) * | 1993-06-30 | 1995-01-12 | Akzo Nobel N.V. | Chelating compounds |
US5582814A (en) * | 1994-04-15 | 1996-12-10 | Metasyn, Inc. | 1-(p-n-butylbenzyl) DTPA for magnetic resonance imaging |
US6693190B1 (en) | 1994-05-11 | 2004-02-17 | Bracco International B.V. | Enhanced relaxivity monomeric and multimeric compounds |
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US3994966A (en) * | 1972-09-28 | 1976-11-30 | The Board Of Trustees Of The Leland Stanford Junior University | Chelating agents |
US3931201A (en) * | 1974-01-22 | 1976-01-06 | The Dow Chemical Company | Substituted pyridinyloxy(thio)phenyl -acetamides, -ureas and urea derivatives |
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HU896768D0 (en) | 1990-03-28 |
PT92670A (pt) | 1990-06-29 |
DE68921582D1 (de) | 1995-04-27 |
EP0374947A1 (en) | 1990-06-27 |
DE68921582T2 (de) | 1995-07-06 |
DK665589A (da) | 1990-06-24 |
KR900009565A (ko) | 1990-07-04 |
HU209459B (en) | 1994-06-28 |
NO895236L (no) | 1990-06-25 |
BR8907282A (pt) | 1991-03-12 |
CA2006372A1 (en) | 1990-06-23 |
KR0163758B1 (ko) | 1999-01-15 |
IL92860A0 (en) | 1990-09-17 |
JP2930708B2 (ja) | 1999-08-03 |
MX166369B (es) | 1993-01-05 |
GR3015661T3 (en) | 1995-07-31 |
CN1044461A (zh) | 1990-08-08 |
WO1990007342A1 (en) | 1990-07-12 |
JPH03502937A (ja) | 1991-07-04 |
ES2068881T3 (es) | 1995-05-01 |
IL92860A (en) | 1995-08-31 |
CA2006372C (en) | 2002-07-02 |
PT92670B (pt) | 1995-09-12 |
EP0374947B1 (en) | 1995-03-08 |
FI896248A0 (fi) | 1989-12-22 |
DK665589D0 (da) | 1989-12-22 |
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