WO1997012850A2 - Bifunktionelle sulfidhaltige sulfonamid-chelatbildner vom typ xsny für radioaktive isotope - Google Patents
Bifunktionelle sulfidhaltige sulfonamid-chelatbildner vom typ xsny für radioaktive isotope Download PDFInfo
- Publication number
- WO1997012850A2 WO1997012850A2 PCT/DE1996/001826 DE9601826W WO9712850A2 WO 1997012850 A2 WO1997012850 A2 WO 1997012850A2 DE 9601826 W DE9601826 W DE 9601826W WO 9712850 A2 WO9712850 A2 WO 9712850A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ile
- asp
- cys
- leu
- phe
- Prior art date
Links
- 239000002738 chelating agent Substances 0.000 title description 17
- 230000002285 radioactive effect Effects 0.000 title description 9
- 230000001588 bifunctional effect Effects 0.000 title description 5
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- 239000003446 ligand Substances 0.000 claims abstract description 39
- 229910052713 technetium Inorganic materials 0.000 claims abstract description 13
- 229910052702 rhenium Inorganic materials 0.000 claims abstract description 8
- -1 polyalkenyloxy Chemical group 0.000 claims description 48
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 47
- 239000000203 mixture Substances 0.000 claims description 32
- 239000000126 substance Substances 0.000 claims description 31
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 claims description 25
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 24
- 229940056501 technetium 99m Drugs 0.000 claims description 23
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 125000005842 heteroatom Chemical group 0.000 claims description 17
- 239000012217 radiopharmaceutical Substances 0.000 claims description 17
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- 125000004122 cyclic group Chemical group 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 229940121896 radiopharmaceutical Drugs 0.000 claims description 16
- 230000002799 radiopharmaceutical effect Effects 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 125000004043 oxo group Chemical group O=* 0.000 claims description 15
- 125000003367 polycyclic group Chemical group 0.000 claims description 15
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 13
- 229910052785 arsenic Inorganic materials 0.000 claims description 12
- 229910052698 phosphorus Inorganic materials 0.000 claims description 12
- 125000006239 protecting group Chemical group 0.000 claims description 11
- 229910052711 selenium Inorganic materials 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 9
- 125000000304 alkynyl group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 239000003638 chemical reducing agent Substances 0.000 claims description 8
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- 238000001727 in vivo Methods 0.000 claims description 7
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 7
- VHCSBTPOPKFYIU-UHFFFAOYSA-N 2-chloroethanesulfonyl chloride Chemical group ClCCS(Cl)(=O)=O VHCSBTPOPKFYIU-UHFFFAOYSA-N 0.000 claims description 6
- 108010064733 Angiotensins Proteins 0.000 claims description 6
- 102000015427 Angiotensins Human genes 0.000 claims description 6
- 239000002416 angiotensin derivative Substances 0.000 claims description 6
- 150000002191 fatty alcohols Chemical class 0.000 claims description 6
- 230000036961 partial effect Effects 0.000 claims description 6
- 230000005855 radiation Effects 0.000 claims description 6
- 108050009340 Endothelin Proteins 0.000 claims description 5
- 102000002045 Endothelin Human genes 0.000 claims description 5
- 239000000654 additive Substances 0.000 claims description 5
- 125000006241 alcohol protecting group Chemical group 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- 230000037396 body weight Effects 0.000 claims description 5
- 239000012634 fragment Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 102000004169 proteins and genes Human genes 0.000 claims description 5
- 108090000623 proteins and genes Proteins 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 210000000056 organ Anatomy 0.000 claims description 4
- 101710163270 Nuclease Proteins 0.000 claims description 3
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Chemical class Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 claims description 3
- 125000003172 aldehyde group Chemical group 0.000 claims description 3
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 3
- 125000005248 alkyl aryloxy group Chemical group 0.000 claims description 3
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 3
- 239000000010 aprotic solvent Substances 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 230000015556 catabolic process Effects 0.000 claims description 3
- 238000006731 degradation reaction Methods 0.000 claims description 3
- DUEUCUPESSMDMI-VVKHCXNMSA-N (2s)-1-[(2s)-2-[[(2s,3s)-2-[[(2s)-2-[[(2s)-2-amino-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-methylpentanoyl]amino]-3-(1h-imidazol-5-yl)propanoyl]pyrrolidine-2-carboxylic acid Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(O)=O)NC(=O)[C@@H](N)C(C)C)C1=CC=C(O)C=C1 DUEUCUPESSMDMI-VVKHCXNMSA-N 0.000 claims description 2
- OERILMBTPCSYNG-MLCQCVOFSA-N (2s)-6-amino-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-formamido-4-methylsulfanylbutanoyl]amino]-4-methylpentanoyl]amino]-3-phenylpropanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](NC=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(O)=O)CC1=CC=CC=C1 OERILMBTPCSYNG-MLCQCVOFSA-N 0.000 claims description 2
- QSBGWDDCOJYQGY-KOQODJNWSA-N Angiotensin IV Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)C(C)C)C1=CC=C(O)C=C1 QSBGWDDCOJYQGY-KOQODJNWSA-N 0.000 claims description 2
- 229940123073 Angiotensin antagonist Drugs 0.000 claims description 2
- 101710091342 Chemotactic peptide Proteins 0.000 claims description 2
- NTSBFTNRWQVBCA-IVGDYKFASA-N His-leu-asp-ile-ile-trp Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)[C@@H](C)CC)C1=CN=CN1 NTSBFTNRWQVBCA-IVGDYKFASA-N 0.000 claims description 2
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 claims description 2
- 108010083387 Saralasin Proteins 0.000 claims description 2
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 claims description 2
- 239000002369 angiotensin antagonist Substances 0.000 claims description 2
- 239000005557 antagonist Substances 0.000 claims description 2
- 108010002990 endothelin (16-21) Proteins 0.000 claims description 2
- PFGWGEPQIUAZME-NXSMLHPHSA-N saralasin Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)CNC)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(O)=O)C1=CC=C(O)C=C1 PFGWGEPQIUAZME-NXSMLHPHSA-N 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 4
- OELDIVRKHTYFNG-WDSKDSINSA-N Cys-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H](N)CS OELDIVRKHTYFNG-WDSKDSINSA-N 0.000 claims 1
- 125000003158 alcohol group Chemical group 0.000 claims 1
- 230000008878 coupling Effects 0.000 abstract description 17
- 238000010168 coupling process Methods 0.000 abstract description 17
- 238000005859 coupling reaction Methods 0.000 abstract description 17
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 abstract description 9
- 230000000536 complexating effect Effects 0.000 abstract description 4
- 238000003745 diagnosis Methods 0.000 abstract description 4
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 abstract description 4
- 229910021645 metal ion Inorganic materials 0.000 abstract description 3
- 238000002560 therapeutic procedure Methods 0.000 abstract description 3
- 230000001404 mediated effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 72
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 62
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
- 238000004458 analytical method Methods 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 210000001519 tissue Anatomy 0.000 description 18
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- 239000003480 eluent Substances 0.000 description 14
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000001488 sodium phosphate Substances 0.000 description 10
- 229910000162 sodium phosphate Inorganic materials 0.000 description 10
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 8
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 150000001299 aldehydes Chemical class 0.000 description 8
- 239000008139 complexing agent Substances 0.000 description 8
- 150000001944 cysteine derivatives Chemical class 0.000 description 8
- 235000011150 stannous chloride Nutrition 0.000 description 8
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 8
- 238000007792 addition Methods 0.000 description 7
- 238000010828 elution Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000011534 incubation Methods 0.000 description 7
- DXUZZMIANHJYIU-NRFANRHFSA-N methyl (2r)-2-amino-3-tritylsulfanylpropanoate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(SC[C@H](N)C(=O)OC)C1=CC=CC=C1 DXUZZMIANHJYIU-NRFANRHFSA-N 0.000 description 7
- 239000008363 phosphate buffer Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229910019142 PO4 Inorganic materials 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- LJSQFQKUNVCTIA-UHFFFAOYSA-N diethyl sulfide Chemical compound CCSCC LJSQFQKUNVCTIA-UHFFFAOYSA-N 0.000 description 6
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- 235000021317 phosphate Nutrition 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 5
- 239000010452 phosphate Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 238000001665 trituration Methods 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- JOXWSDNHLSQKCC-UHFFFAOYSA-N ethenesulfonamide Chemical compound NS(=O)(=O)C=C JOXWSDNHLSQKCC-UHFFFAOYSA-N 0.000 description 4
- 230000002349 favourable effect Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- GSJJCZSHYJNRPN-UHFFFAOYSA-N tert-butyl n-(2-sulfanylethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCS GSJJCZSHYJNRPN-UHFFFAOYSA-N 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 3
- 101100208721 Mus musculus Usp5 gene Proteins 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000009918 complex formation Effects 0.000 description 3
- 238000010668 complexation reaction Methods 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000007717 exclusion Effects 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 230000037406 food intake Effects 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 239000003102 growth factor Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 229960001913 mecysteine Drugs 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- YXGZUWUWRHHODJ-SFHVURJKSA-N octyl (2R)-2-(4-methoxy-N-methylanilino)-3-sulfanylpropanoate Chemical compound CCCCCCCCOC(=O)[C@H](CS)N(C)C1=CC=C(OC)C=C1 YXGZUWUWRHHODJ-SFHVURJKSA-N 0.000 description 3
- HVUOVEPPHLYCKA-PPHPATTJSA-N octyl (2r)-2-amino-3-sulfanylpropanoate;hydrochloride Chemical compound Cl.CCCCCCCCOC(=O)[C@@H](N)CS HVUOVEPPHLYCKA-PPHPATTJSA-N 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- PQPZSPJVMUCVAQ-JTQLQIEISA-N (2r)-2-azaniumyl-3-[(4-methoxyphenyl)methylsulfanyl]propanoate Chemical compound COC1=CC=C(CSC[C@H](N)C(O)=O)C=C1 PQPZSPJVMUCVAQ-JTQLQIEISA-N 0.000 description 2
- 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 2
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 2
- YFQCZVSCFPMHEF-UHFFFAOYSA-N CCCCOC(N(CCN)S(CCSCCS)(=O)=O)=O Chemical compound CCCCOC(N(CCN)S(CCSCCS)(=O)=O)=O YFQCZVSCFPMHEF-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000004809 Teflon Substances 0.000 description 2
- 229920006362 Teflon® Polymers 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000003143 atherosclerotic effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 229940126208 compound 22 Drugs 0.000 description 2
- 239000000356 contaminant Substances 0.000 description 2
- 239000007819 coupling partner Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- HCFPRFJJTHMING-UHFFFAOYSA-N ethane-1,2-diamine;hydron;chloride Chemical compound [Cl-].NCC[NH3+] HCFPRFJJTHMING-UHFFFAOYSA-N 0.000 description 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethyl mercaptane Natural products CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- MCYHPZGUONZRGO-VKHMYHEASA-N methyl L-cysteinate Chemical compound COC(=O)[C@@H](N)CS MCYHPZGUONZRGO-VKHMYHEASA-N 0.000 description 2
- 238000009206 nuclear medicine Methods 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- 125000000565 sulfonamide group Chemical group 0.000 description 2
- 150000003456 sulfonamides Chemical class 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- NLVXSWCKKBEXTG-UHFFFAOYSA-N vinylsulfonic acid Chemical compound OS(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-N 0.000 description 2
- 230000003313 weakening effect Effects 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- 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
- DLMYFMLKORXJPO-FQEVSTJZSA-N (2R)-2-amino-3-[(triphenylmethyl)thio]propanoic acid Chemical class C=1C=CC=CC=1C(C=1C=CC=CC=1)(SC[C@H](N)C(O)=O)C1=CC=CC=C1 DLMYFMLKORXJPO-FQEVSTJZSA-N 0.000 description 1
- BQHFYSWNHZMMDO-WDSKDSINSA-N (2r)-2-[2-[[(1r)-1-carboxy-2-sulfanylethyl]amino]ethylamino]-3-sulfanylpropanoic acid Chemical compound OC(=O)[C@H](CS)NCCN[C@@H](CS)C(O)=O BQHFYSWNHZMMDO-WDSKDSINSA-N 0.000 description 1
- VRYALKFFQXWPIH-PBXRRBTRSA-N (3r,4s,5r)-3,4,5,6-tetrahydroxyhexanal Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)CC=O VRYALKFFQXWPIH-PBXRRBTRSA-N 0.000 description 1
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- QHQZEEGNGSZBOL-UHFFFAOYSA-N 2-(aminomethyl)-2-(hydroxymethyl)propane-1,3-diol Chemical compound NCC(CO)(CO)CO QHQZEEGNGSZBOL-UHFFFAOYSA-N 0.000 description 1
- WFIYPADYPQQLNN-UHFFFAOYSA-N 2-[2-(4-bromopyrazol-1-yl)ethyl]isoindole-1,3-dione Chemical compound C1=C(Br)C=NN1CCN1C(=O)C2=CC=CC=C2C1=O WFIYPADYPQQLNN-UHFFFAOYSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- KLDLRDSRCMJKGM-UHFFFAOYSA-N 3-[chloro-(2-oxo-1,3-oxazolidin-3-yl)phosphoryl]-1,3-oxazolidin-2-one Chemical compound C1COC(=O)N1P(=O)(Cl)N1CCOC1=O KLDLRDSRCMJKGM-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- NFEIXBWFAIILJS-UHFFFAOYSA-N CCCCOC(=O)C=CS(=O)(=O)NCCN Chemical compound CCCCOC(=O)C=CS(=O)(=O)NCCN NFEIXBWFAIILJS-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 102400001368 Epidermal growth factor Human genes 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- BPNZYADGDZPRTK-UDUYQYQQSA-N Exametazime Chemical compound O/N=C(\C)[C@@H](C)NCC(C)(C)CN[C@H](C)C(\C)=N\O BPNZYADGDZPRTK-UDUYQYQQSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 239000004201 L-cysteine Substances 0.000 description 1
- 235000013878 L-cysteine Nutrition 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- 102000007330 LDL Lipoproteins Human genes 0.000 description 1
- 108010001831 LDL receptors Proteins 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 102100024640 Low-density lipoprotein receptor Human genes 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- YDBYJHTYSHBBAU-YFKPBYRVSA-N S-methyl-L-methioninate Chemical compound C[S+](C)CC[C@H](N)C([O-])=O YDBYJHTYSHBBAU-YFKPBYRVSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical class [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 230000036523 atherogenesis Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical class N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 210000003850 cellular structure Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 229940127042 diagnostic and therapeutic radiopharmaceutical Drugs 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 150000002019 disulfides Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 230000009395 genetic defect Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 150000004676 glycans Chemical class 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
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- OBBCSXFCDPPXOL-UHFFFAOYSA-N misonidazole Chemical compound COCC(O)CN1C=CN=C1[N+]([O-])=O OBBCSXFCDPPXOL-UHFFFAOYSA-N 0.000 description 1
- 229950010514 misonidazole Drugs 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- RPFVQQXYZAISJF-UHFFFAOYSA-N n-(2-aminoethyl)-2-(2-sulfanylethylsulfanyl)ethanesulfonamide Chemical compound NCCNS(=O)(=O)CCSCCS RPFVQQXYZAISJF-UHFFFAOYSA-N 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- WUAPFZMCVAUBPE-IGMARMGPSA-N rhenium-186 Chemical compound [186Re] WUAPFZMCVAUBPE-IGMARMGPSA-N 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 210000002356 skeleton Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 108020003113 steroid hormone receptors Proteins 0.000 description 1
- 102000005969 steroid hormone receptors Human genes 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- IUTCEZPPWBHGIX-UHFFFAOYSA-N tin(2+) Chemical class [Sn+2] IUTCEZPPWBHGIX-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/57536—Endothelin, vasoactive intestinal contractor [VIC]
-
- 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
-
- 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
- A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
-
- 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
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/004—Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/64—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
- C07C323/67—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfonamide groups, bound to the carbon skeleton
-
- 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
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/081—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
- C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/14—Angiotensins: Related peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/64—Cyclic peptides containing only normal peptide links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
Definitions
- the invention relates to new chelating agents containing sulfonamide groups, pharmaceutical compositions containing these compounds, their use in radiodiagnostics and radiotherapy, processes for the preparation of these compounds and compositions, and conjugates of these compounds with selectively enriching substances in diseased tissue, in particular peptides.
- radiopharmaceuticals for diagnostic and therapeutic purposes has long been known in the field of biological and medical research.
- radiopharmaceuticals are used to represent certain structures such as the skeleton, organs or tissues.
- the diagnostic application presupposes the use of such radioactive agents, which are specific to those after application
- suitable detectors such as, for example, imaging cameras or other suitable recording methods.
- the distribution and relative intensity of the detected radioactive agent characterizes the location of a structure in which the radioactive agent is located and can be the presence of abnormalities in structure and function, pathological
- radiopharmaceuticals can be used as therapeutic agents to irradiate certain pathological tissues or areas. Such treatment requires the production of radioactive therapeutic agents that accumulate in certain structures, tissues or organs. By enriching these agents, the therapeutic radiation is carried directly to the pathological tissue.
- radio-labeled compounds the metal can be in free form as an ion or in the form of a metal complex with one or more ligands.
- metallic radionuclides that can form complexes are technetium-99m and the various rhenium isotopes. The first is used in diagnostics and the second in therapy.
- the radiopharmaceuticals contain suitable carriers and additives which allow injection, inhalation or ingestion by the patient, as well as physiological buffers, salts etc.
- radionuclide for nuclear medicine questions is technetium-99m, which due to its favorable physical properties (no corpuscular radiation, 6 h physical half-life, 140 KeV gamma radiation) and the resulting low radiation exposure is particularly good as a radioisotope for in vivo Diagnostics are suitable.
- Technetium-99m can be easily obtained from nuclide generators as pertechnetate and can be used directly in this form for the production of kits for routine clinical needs.
- radiopharmaceuticals first requires the synthesis of a suitable ligand. Then the complex with the radionuclide is shown separately (marking).
- the ligand produced always in the form of a lyophilized kit, is combined with a
- the solutions containing the radionuclide can be obtained from an available Mo-99 / Tc-99m nuclide generator, as in the case of technetium-99m, or from a manufacturer, as in the case of rhenium-186.
- the complex formation reaction is carried out at suitable temperatures (e.g. 20 ° -100 ° C) within a few minutes to several hours. In order to ensure complete complex formation, a large excess (more than 100-fold excess to the metal radionuclide) of the ligand produced and a sufficient amount of reducing agent are required for a complete reduction of the radionuclide used.
- Radiopharmaceuticals are made by combining the radionuclide complex, in an amount sufficient for diagnostic or therapeutic use, with pharmacologically acceptable radiological carriers.
- This radiological carrier should have favorable properties for the application of the radiopharmaceutical in the form of an injection, inhalation or ingestion. Examples of such
- Carriers are HSA, aqueous buffer solutions, eg tris (hydroxymethyl) aminoethane (or their salts), phosphate, citrate, bicarbonate etc., sterile water, physiological saline, isotonic chloride or dicarbonate ion solutions or normal plasma ions such as Ca. 2+ , Na + , K + and Mg 2+ . Because technetium can exist in a number of oxidation states (+7 to -1), it is often necessary for radiopharmaceutical agents to contain additional agents known as stabilizers. These keep the radionuclide in a stable form until it has reacted with the ligand.
- aqueous buffer solutions eg tris (hydroxymethyl) aminoethane (or their salts), phosphate, citrate, bicarbonate etc.
- sterile water physiological saline
- isotonic chloride or dicarbonate ion solutions or normal plasma ions such as Ca. 2+ , Na + , K + and Mg 2+
- These stabilizers can include agents known as transfer or auxiliary ligands that are particularly useful in stabilizing and complexing the metal in a well-defined oxidation state until the target ligand complexes the metal via ligand exchange.
- auxiliary ligand including its salts
- gluconheptonic acid, tartaric acid, citric acid or other common ligands are gluconheptonic acid, tartaric acid, citric acid or other common ligands, as will be explained in more detail later.
- radionuclide-containing radiopharmaceuticals are prepared by first synthesizing the ligand and then reacting it with the metal radionuclide in a suitable manner to form a corresponding complex in which the ligand necessarily remains unchanged after complexation, with the exception of any protective groups or hydrogen ions which may be present, must be present. Removal of these groups facilitates coordination of the ligand to the metal ion and thus leads to rapid complexation.
- pertechnetate is first obtained from a nuclide generator and converted into a lower oxidation level by using suitable reducing agents (eg SnCl2 / S2O4 2 " etc.), which is then stabilized by a suitable chelator.
- suitable reducing agents eg SnCl2 / S2O4 2 " etc.
- the efficiency of radionuclides in in vivo diagnostics as well as therapy depends on the specificity and the selectivity of the labeled chelates to the target cell. These properties can be improved by coupling the chelates to biomolecules according to the "drug targeting" principle. Antibodies, their fragments, hormones, growth factors and substrates of receptors and enzymes are suitable biomolecules.
- the British patent application GB 2,109,407 describes the use of radioactively labeled monoclonal antibodies against tumor-associated antigens for tumor diagnosis in vivo. Likewise, direct protein labels via donor groups (amino, amide, thiol, etc.) of the protein (Rhodes, BA et al., J. Nukl. Med.
- Rhenium isotopes are, for example, cyclic amines such as those from Volkert et al. (Appl. Radiol. Isot. 1982, 33; 891) and Troutner et al. (J. Nucl. Med. 1980, 21; 443), but they have the disadvantage that they are often only able to bind technetium-99m in good yields from a pH> 9.
- N 2 ⁇ 2 systems (Pillai, MRA, Troutner, DE et al.; Inorg. Chem. 1990, 29; 1850) are in clinical use.
- a major disadvantage of non-cyclic N4 systems such as HMPAO is their low complex stability. Tc-99m-HMPAO, because of its instability (Ballinger, JR et al., Appl.
- N 2 s 2 " chelators (Bormans , G. et al.; Nucl. Med. Biol. 1990, 17; 499) such as, for example, ethylenedicysteine (EC; Verbruggen, AM et al .; J. Nucl. Med. 1992, 33; 551) meet the requirement for sufficient stability of the corresponding technetium-99m complex, but only form> 9 radiodiagnostics with a purity of greater than 69% from a pH value of the complexing medium.
- N3S systems (Fritzburg, A.; EP-0173424 and EP-0250013) form stable technetium-99m complexes, but they have to be heated to temperatures of approximately 100 ° C. in order to form a uniform radiopharmaceutical.
- bifunctional complexing agents which carry both functional groups for binding the desired metal ion and one (other, several) functional group for binding the selectively enriching molecule, or to design complexing agents in such a way that they are only selectively coupled to one enriching substance the desired complexing agent structure is formed and thus a weakening of the complex stability is excluded.
- Such ligands enable a specific, chemically defined binding of technetium or rhenium isotopes to various biological materials, even if so-called prelabeling is carried out.
- Some chelators have been linked to monoclonal antibodies (e.g. EP-0247866 and EP-0188256) or
- the invention is therefore based on the object of providing stable complex compounds which are coupled or capable of coupling to different selectively enriching compounds without their specificity and selectivity being significantly affected.
- the requirements for the use of these compounds in humans with regard to the absorbed radiation dose, stability and solubility of the compounds must be fulfilled.
- this object is achieved in that new chelating agents containing bifunctional sulfonamide groups and their coupling products with specifically enriching compounds are made available.
- the invention relates to compounds of the general formula (I)
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are the same or different and each represents a hydrogen atom and / or a branched or unbranched C 1-6 alkyl radical,
- R represents a hydrogen atom, a branched or unbranched C ] __g alkyl radical or a radical -CO-R 15 , wherein R 15 is a hydroxyl- a branched or straight-chain, cyclic or polycyclic C ⁇ _3o-alkoxy-, alkenyloxy-, polyalkenyloxy-, alkynyloxy -, polyalkynyloxy, aryloxy, alkylaryloxy or arylalkyloxyy group, which may be combined with hydroxyl, oxy, oxo, carboxy, aminocarbonyl,
- Alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms is substituted and / or optionally interrupted and / or substituted by one or more heteroatoms from the series O, N, S, P, As, Se or an N ( R a R b ) group, where R a and R * 3 are identical or different and / or a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C 1 _3 Q alkyl, alkenyl,
- R 9 and R 10 are the same or different and each represents a hydrogen atom and / or a branched or unbranched C] __ g alkyl radical,
- B represents a radical -SR 11 , -NHR 12 or -OR 13 , wherein
- R 11 represents a hydrogen atom, a branched or unbranched C 1-6 alkyl radical or one
- R 12 represents a hydrogen atom, an amino protecting group or branched or straight-chain, cyclic or polycyclic C ⁇ _3Q-alkyl, alkenyl, polyalkenyl, alkynyl, polyalkynyl, aryl, alkylaryl or arylalkyl group, optionally with hydroxy, oxy, Oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms are substituted and / or optionally interrupted by one or more heteroatoms from the series O, N, S, P, As, Se and / or is substituted,
- R 13 represents a hydrogen atom or an alcohol protecting group
- R 14 represents a hydrogen atom, a branched or unbranched C ] __g alkyl radical or a sulfur protecting group
- B represents a radical SR 11 , also for a radical -NHR 16 or -OR 17 , in which
- R 16 is a hydrogen atom, an amino protecting group or a branched or straight-chain, cyclic or polycyclic C 1 _3 0 alkyl, alkenyl,
- R 17 represents a hydrogen atom or an alcohol protecting group
- Preferred compounds of the general formula (I) are characterized in that n and m each represent 1 and that R 1 , R 2 , R 5 , R 6 , R 8 and R 9 are hydrogen atoms.
- Particularly preferred compounds of the general formula (I) are distinguished in that n and m each represent 1 and in that R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 ⁇ R 9 and R 10 Are hydrogen atoms and R 7 for a radical -CO-R 15 , wherein R 15 is a hydroxyl, a branched or straight-chain C] __ 30 alkoxy group or an N (R a R b ) group, where R a and R b are identical or different and / or a hydrogen atom, a branched or straight-chain, C ] __3g-
- Alkyl radical which is optionally substituted with carboxy, aminocarbonyl, alkoxycarbonyl or amino groups having up to 20 carbon atoms and / or optionally by one or more heteroatoms from the
- Row O, N, S is interrupted and / or substituted, represents.
- Particularly preferred compounds according to the invention are those in which R 3 and R 4 each represent a hydrogen atom and R 7 represents a hydrogen atom, a branched or unbranched C ] __g alkyl radical or a radical -CO-R 15 , where R 15 is a hydroxyl, a branched or straight-chain C ] _.39 alkoxy or an N (R a R b ) group, where R a and R b are identical or different and / or a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C ⁇ _3o -Alkylrest, which is optionally substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino or alkoxy groups with up to 20 carbon atoms and / or optionally by represents one or more heteroatoms from the series 0, N, S interrupted and / or substituted.
- the invention further relates to the new bifunctional sulfur-atom-interrupted sulfonamide ligands of the general formula (II)
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 ⁇ R 7 , R 8 , R 9 , R 10 , n, m, B and D each have the meaning given above.
- Preferred compounds of the general formula (II) are characterized in that n and m each represent 1.
- R 1 , R 2 , R 5 , R 6 , R 8 , R 9 and R 1 ⁇ are hydrogen atoms.
- Particularly preferred compounds of the general formula (II) are distinguished in that n and m each represent 1 and in that R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 -R 9 and R 10 Are hydrogen atoms and R 7 for a radical -CO-R 15 , wherein R 15 is a hydroxyl, a branched or straight-chain C ⁇ .30 alkoxy group or an N (R a R b ) group, wherein
- R a and R b are the same or different and / or represent a hydrogen atom, a branched or straight-chain, C ] __3o-alkyl radical which may be substituted with carboxy, aminocarbonyl, Alkoxycarbonyl or amino groups with up to 20 carbon atoms is substituted and / or optionally interrupted and / or substituted by one or more heteroatoms from the O, N, S series.
- the invention furthermore relates to conjugates containing a compound of the general formula (I and / or II) and nucleotides of the DNA and RNA type and substances which accumulate selectively in diseased tissue, a convex bond between them and this in the case of carboxyl - or amino group-containing substances such as naturally occurring or modified oligonucleotides in which the degradation is prevented or made more difficult by naturally occurring nucleases, peptides, proteins, antibodies or their fragments amidically or in the case of substances containing hydroxyl groups such as
- Fatty alcohols are ester-like or imidic in the case of substances containing aldehyde groups.
- Substances mean peptides such as endotheline, partial sequences of endothelin, endothelin analogs, endothelin derivatives, endothelin antagonists or angiotensins, partial sequences of angiotensins, angiotensin analogs, angiotensin derivatives and angiotensin antagonists, and chemotactic peptides.
- the peptides have the following sequences Cys-Ser-Cys-Ser-Ser-Leu-Met-Asp-Lys-Glu-Cys-Val-Tyr
- the present invention furthermore further relates to compounds of the general formula (II)
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are the same or different and each represents a hydrogen atom and / or a branched or unbranched C 1 -C 6 -alkyl radical,
- R 8 represents a hydrogen atom, a branched or unbranched C ] __g-alkyl radical or a radical -CO-R 15 , where R 15 is a hydroxyl- a branched or straight-chain, cyclic or polycyclic C ] __30-alkoxy-, alkenyloxy-, polyalkenyloxy -, alkynyloxy, polyalkynyloxy, aryloxy, alkylaryloxy or arylalkyloxyy groups, which may be combined with hydroxyl, oxy, oxo, carboxy, aminocarbonyl,
- Alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms is substituted and / or optionally by one or more heteroatoms from the series 0, N, S, P, As, Se interrupted and / or substituted or an N (R a R b ) group, where R a and R b are identical or different and / or a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C 1 _3 0 alkyl, Represent alkenyl, polyalkenyl, alkynyl, polyalkynyl, aryl, alkylaryl or arylalkyl radicals, optionally with hydroxyl, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl,
- Amino, aldehyde or alkoxy groups with up to 20 carbon atoms is substituted and / or optionally interrupted and / or substituted by one or more heteroatoms from the series O, N, S, P, As, Se,
- R 9 and R 10 are the same or different and each represents a hydrogen atom and / or a branched or unbranched C ⁇ _g alkyl radical
- B represents a radical -SR 11 , -NHR 12 or -OR 13 , wherein R 11 represents a hydrogen atom, a branched or unbranched C _g alkyl radical or one
- R 12 represents a hydrogen atom, an amino protecting group or branched or straight-chain, cyclic or polycyclic C ] _.30-alkyl, alkenyl, polyalkenyl, alkynyl, polyalkynyl, aryl, alkylaryl or arylalkyl group, which are optionally substituted with hydroxy , Oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups having up to 20 carbon atoms and / or optionally interrupted and / or substituted by one or more heteroatoms from the series 0, N, S, P, As, Se,
- R 13 represents a hydrogen atom or an alcohol protecting group
- R 14 represents a hydrogen atom, a branched or unbranched C ] __g alkyl radical or a sulfur protecting group
- B represents a radical SR 11 , also for a radical -NHR 16 or -OR 17 , in which
- R 16 is a hydrogen atom, an amino protecting group or a branched or straight-chain, cyclic or polycyclic C ] __3g-alkyl, alkenyl, polyalkenyl, alkynyl, polyalkynyl, aryl, alkylaryl or arylalkyl group, which are optionally linked with hydroxy, Oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and / or optionally substituted by one or more heteroatoms from the series O, N, S, P, As , Se is interrupted and / or substituted,
- R 17 represents a hydrogen atom or an alcohol protecting group
- Substances containing carboxyl or amino groups such as naturally occurring or modified oligonucleotides, in which the degradation by naturally occurring nucleases is prevented or made more difficult, peptides, proteins, antibodies or fragments thereof are amidic or, in the case of substances containing hydroxyl groups, such as fatty alcohols, or in the case of substances containing aldehyde groups, imidic
- the present invention further provides a process for the preparation of a compound of the general formula (I), characterized in that technetium-99m or Re in the form of pertechnetate or perrhenate in the presence of a reducing agent and, if appropriate, an auxiliary ligand with a compound of the general formula (II)
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , n, m, B and D have the meaning given above.
- the compounds of the general formula (II) according to the invention are prepared by reacting 2-chloroethanesulfonic acid chloride which is optionally substituted with R 5 and R 6 in a manner known per se in an aprotic solvent with addition of a suitable base with compounds of the general formula (III)
- auxiliary bases can be, for example, tertiary amines, alkali and alkaline earth hydroxides, alkali and alkaline earth carbonates.
- kits which are used to produce radiopharmaceuticals, consisting of a compound of the general formula (II) or a conjugate according to the invention containing compounds of the general formula (I and / or II) and substances which accumulate selectively in tissues, a Reducing agents and optionally an auxiliary ligand, which are in the dry state or in solution, as well as instructions for use with a reaction instruction for reacting the described compounds with technetium-99m or Re in the form of a pertechnetate solution or perrhenate solution.
- the invention also relates to a radiopharmaceutical composition for the non-invasive in vivo presentation of organs, receptors and receptor-containing tissue and / or of atherosclerotic plaques, which contain a compound of the general formula (I) or a conjugate according to the invention containing compounds of the general formula (I and / or II) and substances which accumulate selectively in tissues, optionally with the additives customary in galenics, the compound being prepared in a kit with Technetium-99m or Re in the form of a pertechnetate or perrhenate solution.
- the radiopharmaceutical composition is administered to a patient in an amount of 0.1 to 30 mCi, preferably 0.5 to 10 mCi per 70 kg of body weight, and the radiation emitted by the patient is recorded.
- many of the chelates synthesized and labeled with technetium-99m or Re show a higher stability than comparable N2S 2 and N3S systems which are described in the literature.
- a substance according to the invention (example 2) which was coupled to a fatty alcohol, no decomposition products could be observed after 24 hours.
- the Tc-99m or re-chelators described in this invention complex better than the comparable N 2 S2, N 3 S and propylene amine oxime system.
- the chelates and chelating agents described in the present invention are thus clearly more suitable for diagnostic and therapeutic purposes than the previously known systems.
- the mild marking conditions are a particular advantage.
- the ligands according to the invention and their coupling products can be labeled on substances which accumulate selectively in diseased tissues at room temperature and at a physiological pH.
- suitable protective groups which can be split off with different reaction conditions depending on the coupling product, always ensures that undesired side reactions cannot occur during the purification of the coupling products.
- the coupling partners include different biomolecules used. So e.g. Ligands that bind to specific receptors and thus show changes in receptor density, these include Peptides, steroid hormones, growth factors and neurotransmitters. Coupling products with steroid hormone receptors
- Substances enable improved diagnosis of breast and prostate carcinomas (S.J. Brandes and J.A. Katzenellenbogen, Nucl .Med.Biol. 15, 53, 1988).
- Different tumor cells show an altered density of receptors for peptide hormones or
- EgF epidermal growth factor
- concentration differences can be used for the selective enrichment of cytostatics in tumor cells (E. Abound-Pirak et al.; Proc.Natl.Acad. Se. USA 86, 3778, 1989).
- Other biomolecules are metabolites that can be introduced into the metabolism of the cells and indicate a changed metabolism; these include, for example, fatty acids, saccharides, peptides and amino acids. Fatty acids coupled to the less stable N 2 S 2 systems have been described in EP-0200492.
- Polypeptides such as polylysine and nucleotides of the DNA or RNA type are possible.
- Coupling products of the chelates according to the invention or their complexes with technetium-99m or Re with fatty alcohols, fatty alcohol derivatives or with fatty alcohol amines or their derivatives have proven to be favorable for the detection of atherosclerotic vascular diseases.
- These derivatives were applied to WHHL rabbits which, due to a genetic defect in the LDL receptor, have high LDL concentrations in the blood and thus have atherosclerotic lesions. About 1 to 6 h after application of the derivatives in WHHL rabbits, a high accumulation in atherosclerotic plaques could be demonstrated. So far, only very late stages of atherogenesis have been diagnosed with invasive procedures. The compounds according to the invention therefore offer the decisive advantage of diagnosing much earlier stages of atherosclerosis using a non-invasive method.
- Chelating agent with technetium-99m is carried out before or after coupling to the selectively enriching molecule.
- Agents are carried out in a manner known per se, in which the complexing agents according to the invention are added in aqueous form with the addition of a reducing agent, preferably tin (II) salts such as chloride, pyrophosphate or tartrate and, if appropriate, with the addition of the additives customary in galenics Medium dissolves and then sterile filtered.
- a reducing agent preferably tin (II) salts such as chloride, pyrophosphate or tartrate
- Suitable additives are, for example, physiologically harmless buffers (e.g. tromethamine), small additions of electrolytes (e.g. sodium chloride), stabilizers (e.g. gluconate, phosphates or phosphonates).
- the pharmaceutical composition according to the invention is in the form of a solution or in lyophilized form and is added shortly before application with a solution of Tc-99m pertechnetate, eluted from commercially available Mo / Tc generators, or a perrhenate solution.
- the pharmaceutical compositions according to the invention are dosed in amounts from 1x10 " ⁇ to 5xl0 4 nmol / kg body weight, preferably in amounts between lxlO -3 to 5xl0 2 nmol / kg body weight.
- the amount of radioactivity for diagnostic applications is between 0.05 to 50 mCi, preferably 5 to 30 mCi per 70 kg application, for therapeutic applications between 5 and 500 mCi, preferably 10 to 350 mCi.
- the application is normally carried out by intravenous, intraarterial, peritoneal or intertumor injection of 0.1 to 2 ml of a solution of the agents according to the invention, intravenous application is preferred.
- intravenous application is preferred.
- N-vinylsulfonyl-S- (4-methoxybenzyl) cysteine ethyl ester (2) An ice-cooled solution of 3.06 g (10 mmol) of the S-protected cysteine derivative __ and 1.79 g of chloroethanesulfonyl chloride (11 mmol) in 10 ml of dichloromethane becomes slow dry pyridine (44 mmol) was added while cooling with ice. The mixture is allowed to warm to RT and, after the reaction has ended, 20 ml of dilute HCl are added and the dichloromethane phase is separated off.
- 10 mg of compound 5_ are dissolved in 1.0 ml of ethanol. 50 ul of this ligand solution are mixed with 100 ul ethanol, 150 ul phosphate buffer pH 8.5, 50 ul of a deoxygenated aqueous citrate solution (50 mg / ml), 2.5 ul of a deoxygenated tin (II) chloride solution (5 mg / ml 0.1 N HCl) and 100 ⁇ l of a pertechnetate solution (400-1000 ⁇ Ci) are added.
- a deoxygenated tin (II) chloride solution 50 mg / ml 0.1 N HCl
- a pertechnetate solution 400-1000 ⁇ Ci
- the reaction mixture is examined for the purity of the Tc complex formed by means of HPLC: LiChrospher RP-18 column, 5 ⁇ , 125 x 4.6 mm; Gradient elution from 100% A to 100% B within 15 min (eluent A: acetonitrile / sodium phosphate 5 mM, pH 2.0 (10/90); eluent B: acetonitrile / sodium phosphate 5 mM pH 2.0 ( 75/25); 1 ml / min.
- the radiochemical purity is> 97%.
- N-vinylsulfonyl-S- (4-methoxybenzyl) cysteine (6) 3.59 g (10 mmol) 2. are stirred in aqueous methanolic potassium hydroxide solution at 50 ° C. for 3 hours. After cooling, it is diluted with 400 ml of water and the undissolved solution is filtered off. The filtrate is acidified with HCl, extracted with dichloromethane, dried and concentrated. Yield: 80% Analysis: calc.
- 10 mg of the compound j_ are dissolved in 1.0 ml of ethanol. 50 ul of this ligand solution with 250 ul phosphate buffer pH 8, 5, 50 ul of a deoxygenated aqueous citrate solution (50 mg / ml), 2.5 ul of a deoxygenated tin (II) chloride solution (5 mg / ml 0.1 N HCl) and 100 ⁇ l of a pertechnetate solution (400-1000 ⁇ Ci) were added.
- the reaction mixture is examined for the purity of the Tc complex formed by means of HPLC: LiChrospher RP-18 column, 5 ⁇ , 125 x 4.6 mm; Gradient elution from 100% A to 100% B within 15 min (eluent A: acetonitrile / sodium phosphate 5 mM, pH 2.0 (10/90); eluent B: acetonitrile / sodium phosphate 5 mM, pH 2.0 (75/25); 1 ml / min.
- the radiochemical purity is> 97%.
- reaction mixture After an incubation time of 10 min, the reaction mixture is examined for the purity of the Tc complex formed by means of HPLC: LiChrospher RP-18 column, 5 ⁇ , 125 ⁇ 4.6 mm; Gradient elution from 100% A to 100% B within 15 min (eluent A:
- 50 ⁇ l of this ligand solution are mixed with 100 ⁇ l ethanol, 150 ⁇ l phosphate buffer pH 8.5, 50 ⁇ l deoxygenated aqueous citrate solution (50 mg / ml), 2.5 ⁇ l deoxygenated tin (II) chloride solution (5 mg / ml 0.1 N HCl) and 100 ⁇ l of a pertechnetate solution (400-1000 ⁇ Ci) were added.
- the reaction mixture is examined for the purity of the Tc complex formed by means of HPLC: LiChrospher RP-18 Column, 5 ⁇ , 125 x 4.6 mm; Gradient elution from 100% A to 100% B within 15 min (eluent A: acetonitrile / sodium phosphate 5 mM, pH 2.0 (10/90); eluent B : acetonitrile / sodium phosphate 5 mM, pH 2.0 (75/25); 1 ml / min.
- the radiochemical purity is> 98%.
- N- ⁇ 5-mercapto-3-thiapentylsulfonyll-S-t r.tyl-cysteine (25) 6.08 g (10 mmol) 24. are stirred in aqueous methanolic potassium hydroxide solution at 50 ° C. for 3 hours. After cooling, it is diluted with 400 ml of water and the undissolved solution is filtered off. The filtrate is acidified with HCl, extracted with dichloromethane, dried, concentrated and recrystallized. Yield: 52% Analysis:
- 10 mg of compound 22 are dissolved in 1.0 ml of ethanol. 50 ⁇ l of this ligand solution are mixed with 100 ⁇ l ethanol, 150 ⁇ l phosphate buffer pH 8.5, 50 ⁇ l deoxygenated aqueous citrate solution (50 mg / ml), 2.5 ⁇ l deoxygenated tin (II) chloride solution (5 mg / ml 0.1 N HCl) and 100 ⁇ l of a pertechnetate solution (400-1000 ⁇ Ci) were added.
- a pertechnetate solution 400-1000 ⁇ Ci
- the reaction mixture is examined for the purity of the Tc complex formed by means of HPLC: LiChrospher RP-18 column, 5 ⁇ , 125 ⁇ 4.6 mm; Gradient elution from 100% A to 100% B within 15 min (eluent A: acetonitrile / sodium phosphate 5 mM, pH 2.0 (10/90); eluent B: acetonitrile / sodium phosphate 5 mM, pH 2.0 (75/25); 1 ml / min.
- the radiochemical purity is> 94%.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Pharmacology & Pharmacy (AREA)
- Physics & Mathematics (AREA)
- Optics & Photonics (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Vascular Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Toxicology (AREA)
- Endocrinology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP96945341A EP0851847A2 (de) | 1995-09-21 | 1996-09-19 | Bifunktionelle sulfidhaltige sulfonamid-chelatbildner vom typ xsny für radioaktive isotope |
AU15399/97A AU1539997A (en) | 1995-09-21 | 1996-09-19 | Bifunctional, sulphide-containing sulphonamide-chelating agents of xsny type for radioactive isotopes |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19536780.4 | 1995-09-21 | ||
DE1995136780 DE19536780A1 (de) | 1995-09-21 | 1995-09-21 | Bifunktionelle sulfidhaltige Sulfonamid-Chelatbildner vom Typ XSNY für radioaktive Isotope |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1997012850A2 true WO1997012850A2 (de) | 1997-04-10 |
WO1997012850A3 WO1997012850A3 (de) | 1997-07-10 |
Family
ID=7773887
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/DE1996/001826 WO1997012850A2 (de) | 1995-09-21 | 1996-09-19 | Bifunktionelle sulfidhaltige sulfonamid-chelatbildner vom typ xsny für radioaktive isotope |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0851847A2 (de) |
AU (1) | AU1539997A (de) |
CA (1) | CA2232620A1 (de) |
DE (1) | DE19536780A1 (de) |
WO (1) | WO1997012850A2 (de) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998024482A2 (de) * | 1996-12-04 | 1998-06-11 | Schering Aktiengesellschaft | Verwendung von endothelin-konjugaten in der therapie, neue endothelin-konjugate, diese enthaltende mittel, sowie verfahren zu deren herstellung |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0188256A2 (de) * | 1985-01-14 | 1986-07-23 | NeoRx | Metall-Radionuklid markiertes Protein für Diagnose und Therapie |
EP0200492A1 (de) * | 1985-04-26 | 1986-11-05 | The President And Fellows Of Harvard College | Radiodiagnostische Mittel |
EP0247866A1 (de) * | 1986-05-29 | 1987-12-02 | Mallinckrodt, Inc. (a Delaware corporation) | Kupplungsmittel zum Radiomarkieren von Proteinen |
EP0618191A1 (de) * | 1993-04-02 | 1994-10-05 | AMERSHAM INTERNATIONAL plc | Metall-chelatierende Verbindungen |
-
1995
- 1995-09-21 DE DE1995136780 patent/DE19536780A1/de not_active Withdrawn
-
1996
- 1996-09-19 AU AU15399/97A patent/AU1539997A/en not_active Abandoned
- 1996-09-19 CA CA 2232620 patent/CA2232620A1/en not_active Abandoned
- 1996-09-19 EP EP96945341A patent/EP0851847A2/de not_active Withdrawn
- 1996-09-19 WO PCT/DE1996/001826 patent/WO1997012850A2/de not_active Application Discontinuation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0188256A2 (de) * | 1985-01-14 | 1986-07-23 | NeoRx | Metall-Radionuklid markiertes Protein für Diagnose und Therapie |
EP0200492A1 (de) * | 1985-04-26 | 1986-11-05 | The President And Fellows Of Harvard College | Radiodiagnostische Mittel |
EP0247866A1 (de) * | 1986-05-29 | 1987-12-02 | Mallinckrodt, Inc. (a Delaware corporation) | Kupplungsmittel zum Radiomarkieren von Proteinen |
EP0618191A1 (de) * | 1993-04-02 | 1994-10-05 | AMERSHAM INTERNATIONAL plc | Metall-chelatierende Verbindungen |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998024482A2 (de) * | 1996-12-04 | 1998-06-11 | Schering Aktiengesellschaft | Verwendung von endothelin-konjugaten in der therapie, neue endothelin-konjugate, diese enthaltende mittel, sowie verfahren zu deren herstellung |
WO1998024482A3 (de) * | 1996-12-04 | 1999-04-01 | Schering Ag | Verwendung von endothelin-konjugaten in der therapie, neue endothelin-konjugate, diese enthaltende mittel, sowie verfahren zu deren herstellung |
Also Published As
Publication number | Publication date |
---|---|
WO1997012850A3 (de) | 1997-07-10 |
DE19536780A1 (de) | 1997-03-27 |
EP0851847A2 (de) | 1998-07-08 |
CA2232620A1 (en) | 1997-04-10 |
AU1539997A (en) | 1997-04-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0417870B1 (de) | Chelatbildner zur Komplexierung von radioaktiven Isotopen, deren Metallkomplexe sowie ihre Verwendung in Diagnostik und Therapie | |
DE69837038T2 (de) | Tetraaza- oder n2s2-komplexanten, und deren verwendung in der radiodiagnostik oder radiotherapie | |
EP0692976B1 (de) | Chelatbildner vom typ xn 1?s 1?o 1? für radioaktive isotope, deren metallkomplexe und ihre verwendung in diagnostik und therapie | |
WO1997010852A2 (de) | Bifunktionelle sulfidhaltige sulfonamid-chelatbildner vom typ xsns für radioaktive isotope | |
WO1997010853A2 (de) | Bifunktionelle nicotinamid-chelatbildner vom typ n2s2 für radioaktive isotope | |
WO1997012636A2 (de) | Bifunktionelle sulfidhaltige sulfonamid-chelatbildner vom typ s2ny für radioaktive isotope | |
EP0692979A1 (de) | Bifunktionelle chelatbildner und ihre anwendung in der radiopharmazeutik | |
EP0692981B1 (de) | Chelatbildner vom typ xn 1?s 1?x' für radioaktive isotope, deren metallkomplexe und ihre verwendung in diagnostik und therapie | |
DE19860289C2 (de) | Neue Chelatoren sowie deren Tricarbonyl-Komplexe mit Technetium und Rhenium | |
EP0502595A2 (de) | Amid-Chelate, deren Metallkomplexe sowie ihre Verwendung in Diagnostik und Therapie | |
EP0502594A1 (de) | Chelate, deren Metallkomplexe sowie ihre Verwendung in Diagnostik und Therapie | |
EP0692980B1 (de) | Chelatbildner vom typ s3n2 für radioaktive isotope, deren metallkomplexe und ihre verwendung in diagnostik und therapie | |
WO1997012850A2 (de) | Bifunktionelle sulfidhaltige sulfonamid-chelatbildner vom typ xsny für radioaktive isotope | |
DE4425781A1 (de) | Technetium-Sulfonamid-Komplexe, deren Verwendung, diese enthaltende pharmazeutische Mittel, sowie Verfahren zur Herstellung der Komplexe und Mittel | |
WO1995012610A1 (de) | N-alkyl-peptidchelatbildner, deren metallkomplexe mit radionukliden, verfahren zu ihrer herstellung und diese verbindungen enthaltende radiopharmazeutische zusammensetzungen |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AU CA HU JP KR NO NZ US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
AK | Designated states |
Kind code of ref document: A3 Designated state(s): AU CA HU JP KR NO NZ US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 1996945341 Country of ref document: EP |
|
ENP | Entry into the national phase in: |
Ref country code: CA Ref document number: 2232620 Kind code of ref document: A Format of ref document f/p: F Ref document number: 2232620 Country of ref document: CA |
|
WWP | Wipo information: published in national office |
Ref document number: 1996945341 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1996945341 Country of ref document: EP |