CA2062483A1 - Chelates, their metal complexes as well as their use in diagnosis and treatment - Google Patents
Chelates, their metal complexes as well as their use in diagnosis and treatmentInfo
- Publication number
- CA2062483A1 CA2062483A1 CA002062483A CA2062483A CA2062483A1 CA 2062483 A1 CA2062483 A1 CA 2062483A1 CA 002062483 A CA002062483 A CA 002062483A CA 2062483 A CA2062483 A CA 2062483A CA 2062483 A1 CA2062483 A1 CA 2062483A1
- Authority
- CA
- Canada
- Prior art keywords
- radical
- ppm
- stands
- optionally
- substituted
- 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.)
- Abandoned
Links
- 238000003745 diagnosis Methods 0.000 title claims abstract description 14
- 229910052751 metal Inorganic materials 0.000 title claims description 3
- 239000002184 metal Substances 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 76
- 125000000524 functional group Chemical group 0.000 claims abstract description 29
- 230000002285 radioactive effect Effects 0.000 claims abstract description 17
- 230000008878 coupling Effects 0.000 claims abstract description 16
- 238000010168 coupling process Methods 0.000 claims abstract description 16
- 238000005859 coupling reaction Methods 0.000 claims abstract description 16
- 229910052713 technetium Inorganic materials 0.000 claims abstract description 10
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 8
- 229910052702 rhenium Inorganic materials 0.000 claims abstract description 7
- -1 C1-6 alkyl radical Chemical class 0.000 claims description 82
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 229910001868 water Inorganic materials 0.000 claims description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 17
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 17
- 206010028980 Neoplasm Diseases 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 12
- 150000003254 radicals Chemical class 0.000 claims description 11
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 10
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical compound O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003446 ligand Substances 0.000 claims description 9
- 125000003277 amino group Chemical group 0.000 claims description 8
- 239000011616 biotin Substances 0.000 claims description 8
- 229960002685 biotin Drugs 0.000 claims description 8
- 235000020958 biotin Nutrition 0.000 claims description 8
- 239000012634 fragment Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 7
- 230000001588 bifunctional effect Effects 0.000 claims description 7
- OBBCSXFCDPPXOL-UHFFFAOYSA-N misonidazole Chemical compound COCC(O)CN1C=CN=C1[N+]([O-])=O OBBCSXFCDPPXOL-UHFFFAOYSA-N 0.000 claims description 7
- 229950010514 misonidazole Drugs 0.000 claims description 7
- 230000002829 reductive effect Effects 0.000 claims description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 7
- 235000011152 sodium sulphate Nutrition 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 150000001413 amino acids Chemical class 0.000 claims description 6
- 150000001720 carbohydrates Chemical class 0.000 claims description 6
- 150000002500 ions Chemical class 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 6
- 229910000085 borane Inorganic materials 0.000 claims description 5
- 239000005556 hormone Substances 0.000 claims description 5
- 229940088597 hormone Drugs 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000002858 neurotransmitter agent Substances 0.000 claims description 5
- 239000002798 polar solvent Substances 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- CPRNZALWAHPTRF-UHFFFAOYSA-N ac1l3jjh Chemical compound [CH]1CO1 CPRNZALWAHPTRF-UHFFFAOYSA-N 0.000 claims description 4
- 125000006193 alkinyl group Chemical group 0.000 claims description 4
- 239000000010 aprotic solvent Substances 0.000 claims description 4
- 230000000536 complexating effect Effects 0.000 claims description 4
- 238000001727 in vivo Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims description 4
- 239000008177 pharmaceutical agent Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- GGHDAUPFEBTORZ-UHFFFAOYSA-N propane-1,1-diamine Chemical compound CCC(N)N GGHDAUPFEBTORZ-UHFFFAOYSA-N 0.000 claims description 4
- 230000001681 protective effect Effects 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 4
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 claims description 4
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 3
- 102000004190 Enzymes Human genes 0.000 claims description 3
- 108090000790 Enzymes Proteins 0.000 claims description 3
- 102000015636 Oligopeptides Human genes 0.000 claims description 3
- 108010038807 Oligopeptides Proteins 0.000 claims description 3
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical class [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 210000000170 cell membrane Anatomy 0.000 claims description 3
- 230000003902 lesion Effects 0.000 claims description 3
- 150000002632 lipids Chemical class 0.000 claims description 3
- 102000006240 membrane receptors Human genes 0.000 claims description 3
- 108020004084 membrane receptors Proteins 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 235000005985 organic acids Nutrition 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 150000003431 steroids Chemical class 0.000 claims description 3
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 3
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 claims description 3
- 239000002168 alkylating agent Substances 0.000 claims description 2
- 229940100198 alkylating agent Drugs 0.000 claims description 2
- 150000001408 amides Chemical group 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- 239000012454 non-polar solvent Substances 0.000 claims description 2
- SXYFKXOFMCIXQW-UHFFFAOYSA-N propanedioyl dichloride Chemical class ClC(=O)CC(Cl)=O SXYFKXOFMCIXQW-UHFFFAOYSA-N 0.000 claims description 2
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims 1
- 239000013522 chelant Substances 0.000 claims 1
- 229910052802 copper Inorganic materials 0.000 claims 1
- 229910052738 indium Inorganic materials 0.000 claims 1
- 125000005647 linker group Chemical group 0.000 claims 1
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 abstract description 8
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 abstract description 5
- 239000000243 solution Substances 0.000 description 37
- 238000005160 1H NMR spectroscopy Methods 0.000 description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- 239000002738 chelating agent Substances 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 238000001704 evaporation Methods 0.000 description 14
- 230000008020 evaporation Effects 0.000 description 14
- 239000002904 solvent Substances 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- 101150041968 CDC13 gene Proteins 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- 229910052708 sodium Inorganic materials 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 6
- 239000008139 complexing agent Substances 0.000 description 6
- 230000004060 metabolic process Effects 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 150000004985 diamines Chemical class 0.000 description 5
- 238000002372 labelling Methods 0.000 description 5
- XXJGBENTLXFVFI-UHFFFAOYSA-N 1-amino-methylene Chemical compound N[CH2] XXJGBENTLXFVFI-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 150000004665 fatty acids Chemical class 0.000 description 4
- 230000000269 nucleophilic effect Effects 0.000 description 4
- 150000002923 oximes Chemical class 0.000 description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 4
- 230000005855 radiation Effects 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000007717 exclusion Effects 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 230000000302 ischemic effect Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000006894 reductive elimination reaction Methods 0.000 description 3
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 3
- KQLRFWVNJUCXQT-UHFFFAOYSA-N 3-formyl-4-hydroxybenzenesulfonic acid Chemical compound OC1=CC=C(S(O)(=O)=O)C=C1C=O KQLRFWVNJUCXQT-UHFFFAOYSA-N 0.000 description 2
- VOLRSQPSJGXRNJ-UHFFFAOYSA-N 4-nitrobenzyl bromide Chemical compound [O-][N+](=O)C1=CC=C(CBr)C=C1 VOLRSQPSJGXRNJ-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 239000004971 Cross linker Substances 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 2
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 2
- DBTDEFJAFBUGPP-UHFFFAOYSA-N Methanethial Chemical compound S=C DBTDEFJAFBUGPP-UHFFFAOYSA-N 0.000 description 2
- 208000012902 Nervous system disease Diseases 0.000 description 2
- 208000025966 Neurological disease Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- LUFPJJNWMYZRQE-UHFFFAOYSA-N benzylsulfanylmethylbenzene Chemical compound C=1C=CC=CC=1CSCC1=CC=CC=C1 LUFPJJNWMYZRQE-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- UPQZOUHVTJNGFK-UHFFFAOYSA-N diethyl 2-methylpropanedioate Chemical compound CCOC(=O)C(C)C(=O)OCC UPQZOUHVTJNGFK-UHFFFAOYSA-N 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 150000002540 isothiocyanates Chemical class 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- WRIRWRKPLXCTFD-UHFFFAOYSA-N malonamide Chemical compound NC(=O)CC(N)=O WRIRWRKPLXCTFD-UHFFFAOYSA-N 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 150000002828 nitro derivatives Chemical class 0.000 description 2
- 239000012038 nucleophile Substances 0.000 description 2
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- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 150000002989 phenols Chemical class 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- KYKNRZGSIGMXFH-ZVGUSBNCSA-M potassium bitartrate Chemical compound [K+].OC(=O)[C@H](O)[C@@H](O)C([O-])=O KYKNRZGSIGMXFH-ZVGUSBNCSA-M 0.000 description 2
- 239000001472 potassium tartrate Substances 0.000 description 2
- 229940111695 potassium tartrate Drugs 0.000 description 2
- 235000011005 potassium tartrates Nutrition 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000003270 steroid hormone Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- YMXHPSHLTSZXKH-RVBZMBCESA-N (2,5-dioxopyrrolidin-1-yl) 5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoate Chemical compound C([C@H]1[C@H]2NC(=O)N[C@H]2CS1)CCCC(=O)ON1C(=O)CCC1=O YMXHPSHLTSZXKH-RVBZMBCESA-N 0.000 description 1
- YXTDAZMTQFUZHK-ZVGUSBNCSA-L (2r,3r)-2,3-dihydroxybutanedioate;tin(2+) Chemical compound [Sn+2].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O YXTDAZMTQFUZHK-ZVGUSBNCSA-L 0.000 description 1
- DJRFJAVPROZZFL-UHFFFAOYSA-N 1975-52-6 Chemical compound CC1=CC=C([N+]([O-])=O)C=C1C(O)=O DJRFJAVPROZZFL-UHFFFAOYSA-N 0.000 description 1
- QXYLYYZZWZQACI-UHFFFAOYSA-N 2,3,4,5-tetrafluorophenol Chemical class OC1=CC(F)=C(F)C(F)=C1F QXYLYYZZWZQACI-UHFFFAOYSA-N 0.000 description 1
- VJQUJFBMLKJQIY-UHFFFAOYSA-N 2-(bromomethyl)-5-nitrobenzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1CBr VJQUJFBMLKJQIY-UHFFFAOYSA-N 0.000 description 1
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Abstract
Abstract The invention relates to compounds of general formula I
Description
2~2~8~-3 Chelates, their Metal Complexes as well as their Use in Diagnosis and Treatment Description Radioactive metal ions, mostly bound to a complexing agent, have for some time been use~ for in vivo diagnosis. Among them, technetium-99m (~c-99m), because of its almost ideal physical properties for this purpose -- good absorption of radiation in corresponding detection devices (gamma camera, SPECT devices) relative to a low absorption in the human organism and easy availability with a molybdenum/technetium generator -- is the radionuclide most often used in clinical nuclear medicine. Its short half-life of 6.02 hours guarantees an only slight exposure of the patient to gamma radiation, particularly also the daughter product technetium-99 has only a negligible residual radiation.
But a drawback of the technetium is its complicated and still not completely known complex chemistry. Technetium can be present in a number of oxidation stages (+7 to -1), which can greatly change the pharmacological properties by changing the charge of a complex. It is therefore necessary to synthesize complexes which bind the technetium in a defined oxidation stage and to prevent redox reactions, which could lead to a redistribution of the pharmaceutical agent. A number of such Tc-99m complexing agents are already known and are clinically used. In the case of neutral complexes, systems, in which the Tc-99m is bound between 2-4 nitrogen atoms and 0-2 sulfur atoms (N2S2, N3S and propylenamine oxime complexes), are often involved. But often the 2 ~,?.~ ~ ~
insufficient stability of these Tc-ssm complexes is a significant drawback (Hung, J. C. et al.; J. Nucl. Med. 29: 1568, 1988). In clinical use, therefore, e.g., HMPAO (hexamethyl-propylenamine oxime) has to be administered shor~ly after its labeling with pertechnetate, so that the portion of decomposition products, which reduce the diagnostic informative value, is not too high.
A coupling of these chelates or chelating agents to other substances selectively accumulating in foci of disease is not possible. Therefore, most of said complexes are distributed according to the blood circulation and/or metabolic activity of an organ (e.g., Europ. Patent Appl. 0 194 843), so that, e.g., necrotic or ischemic regions can be represented after infarction or stroke in a scintigram.
But for a successful diagnosis of tumors, neurological diseases or diseases of the cardiovascular system, substances are more promising which can produce molecular changes of diseased tissue, by being bound specifically to these diseased tissues or being infiltrated in their metabolism. The findings of the biological and biochemical basic research allow the selection of a number of substances, which selectively accumulate in foci of disease: various tumors develop increased or reduced surface concentrations on receptors, e.g., for growth factors or steroid hormones (Sledge, G. W.; Adv. Cancer Res. 38: 61-75 [1983]).
Also, in neurological diseases, a change of the concentration of receptors for neutrotransmitters results in specific areas of the brain (Frost, J. J.; Trends Pharmacol. Sci. 7: 490-496 [19873).
Further, diseased, damaged or cells transformed into tumor cells 3 ~ ;3 often show great changes of their metabolism and an oxygen deficiency inside the tumor. The use of such physiological characteristics can be used in in vivo diagnosis, by, e.g., hormones, neurotransmitters or certain metabolic products such as fatty acids, saccharides, peptides or amino acids being coupled to chelating agents for Tc-99m. Also, substances such as misonidazole (a radiosensitizer) or other compounds reacting to radicals in the absence of oxygen can be used for specific accumulation of radioactive isotopes and thus graphic representation of tumors or ischemic regions. Finally, also the coupling to monoclonal antibodies is possible, which because of their high specificity have become a promising instrument in the diagnosis of tumors.
For the production of diagnostic agents according to the described principle, it is necessary that chelating agents for radioactive metal ions, in particular Tc-99m, can be coupled to substances selectively accumulating in diseased tissues.
Since the isotopes of rhenium (Re-188 and Re-186) have chemical properties similar to Tc-99m, the chelating agents can also be used to complex these isotopes. Said Re-isotopes are ~-radiators. Thus, the selectively accumulating substances complexed with rhenium instead of with teçhnetium are also usable in the treatment cf tumors.
The previously known attempts to couple chelating agents to selectively accumulating substances in many cases can be considered as unsatisfactory. If the functional groups of the complexing agent are used to bind the chelating agent to such a 4 2 ~ u 3 molecule, a weakening of the complex stability often results, i.e., a diagnostically intolerable portion of the isotope is released from the conjugate. ~Brechbiel, M. W. et al., Inorg.
Chem. 25: 2772 [1986]). It is therefore necessary to produce bifunctional complexing agents, i.e. complexing agents which carry both functional groups for coordinative bonding of the desired metal ion and a (another) functional group for bonding the selectively accumulating molecule. Such bifunctional ligands make possible a specific, chemically defined bonding of technetium to the most varied biological materials, also then when a so-called prelabeling is performed. Since according to this method, first the labeling with Tc-99m and the isolation of the complexes is performed and this complex is linked only in a second step with a selectively accumulating molecule, the labeled compounds are obtained with a high degree of purity.
Some chelating agents coupled to monoclonal antibodies (e.g., Europ. Patent App. 0 247 866 and 0 188 256) or fatty acids (Europ. Patent Appl. 0 200 492) were described. But as chelating agents, the already mentioned N2S2 systems are used, which are not very suitable because of their low stability. The somewhat more stable N3S chelates showed, coupled to monoclonal antibodies, not so great a loss of Tc-99m from the conjugates (J.
Lister-James; J. Nucl. Med. 30: 793 and Europ. Patent Appl. 0 284 071).
Since both the selectively accumulating substances in their properties and the mechanisms, according to which they are accumulated, are very different, it is further necessary to be 2`~2~i2)~
able to vary the couplable chel.ating agents and match the physiological requirements of the coupling participant with respect to lipophilia and hydrophilia, membrane permeability or impermeability, etc.
For these reasons, there exists an urgent need for stable complex compounds, which are coupled or able to couple to various selectively accumulating compounds.
The object of the invention is thus to make available stahle chelating agents, which contain a functional group for coupling to a selectively accumulating compound or a selectively accumulating compound coupled with the help of this functional group.
According to the invention, this object is achieved by the compounds of general formula I
Rl R2A
R3\ ~ ~ R3 R4 y N N ~ R4 Rs l ~ Rs (I) in which Rl stands for hydrogen or a C1_6 alkyl radical optionally substituted with one or two hydroxyl groups, R2 stands for a Cl_6 alkylene radical optionally substituted with a hydroxyl group, R3 stands for a hydrogen atom, a C1_6 alkyl radical, a carboxymethyl radical or a (Cl-6 alkoxycarbonyl)methyl radical, R4 stands for a hydrogen atom, a C1-6 alkyl radical optionally substituted with a hydroxyl group or for the meaning indicated under RX, R5 stands for a hydrogen atom or a C1-6 alkyl radical optionally substituted with a hydroxyl group, B stands for a pyrrolyl radical, a substituted phenyl radical of formula II or a substituted pyridine radical of formula III
~Z ~ Z
in which Z means a hydroxyl group, amino group or a mercapto group and Y means a hydrogen atom, a carboxy radical or a sulfonyl radical 7 2'~ 2~
or B stands for a nitrosomethyl radical of formula IV
NOH
--C
RX
in which Rx means a Cl_6~alkyl radical or, together with R4,is a trimethylene or tetramethylene group to form a 5- or 6-membered ring.
and A stands for an amino radical, a mercapto radical, a carboxy radical, a C2_6 alkinyl or C2_6 alkenyl radical, an oxiranyl radical, a fluorinated phenoxycarbonyl radical, a succinimidoxycarbonyl radical optionally substituted with a sodium sulfate radical, an aminophenyl radical or isothiocyanatophenyl radical, and the phenyl group optionally can be substituted in addition by a carboxy radical, a chlorosulfonyl radical or a sulfonic acid radical or contains a compound T selectively accumulating in lesions or specific tissues -- optionally bound by a bifunctional linker radical L with the help of said functional group and T stands for monoclonal antibodies or their fragments, hormones, enzymes, ligands for cell membrane receptors, neurotransmitters, lipids, steroids, saccharides, amino acids and oligopeptides, biotin, as well as radiosensitizers, such as, e.g., misonidazole, NOH
and in the case of B = -C, pyrrolyl radical or I X
~3^,32.;~
Y = H, R2 is to stand for a hydroxylated C1_6 alkylene chain or A
is to stand for a substituted aminophenyl or isothiocyanatophenyl radical, as well as their ~omplexes with radioactive metal ions --suitable for diagnosis and treatment of tumors -- as well as their salts with inorganic and organic acids or bases.
According to the invention, those compounds according to claim 1 are preferred in which R4 and R5 mean hydrogen atoms or methyl radicals, as well as those compounds according to claim 1, in which A stands for an amino radical, a mercapto radical, a carboxy radical, a C2_6 alkinyl or C2_6 alkenyl radical, an oxiranyl radical, a fluorinated phenoxycarbonyl radical, a succinimidoxycarbonyl radical optionally substituted with a sodium sulfate radical, an aminophenyl or isothiocyanatophenyl radical, and the phenyl group can be substituted by another carboxyl or sulfonic acid radical, and the selectively accumulating compound T optionally contained in A stands for monoclonal antibodies, their fragments, biotin or misonidazole.
Surprisingly, many of the chelates synthesized and labeled with Tc-99m showed a higher stability than the comparable N2S2, N3S and propylenamine oxime chelates. Thus, no decomposition products were able to be observed after 5 hours, e.g., in a substance according to the invention (example 2), which was coupled by an aminophenyl radical to biotin, while this was the case in the comparable HMPAO known in the literature (Hung, J. ~.
et al.; J. Nucl. Med. 29: 1568, 1988). Also, by competitive tests, it was possible to be determined that the Tc-99m chelates 9 2 ~2 ~ s ~3 described in this invention complex better than the comparable N2S2, N3S and propylenamine oxime chelates. The chelates described in the invention are thus definitely better suitable for diagnostic and therapeutic purposes than the previously known chelates.
The production of the compounds according to claim 1 takes place, by a) a 1,3-propanediamine of general formula v Rl R2A' H2N ~ 2 ~V) in which R1 and R2 have the above-mentioned meanings, and ~' means A or a radical able to be converted to A
being reacted with a compound of general formula VI
B - R4C = 0 ~VI) in which R4 and B have the above-mentioned meanings, in a polar solvent, preferably ethanol, or by using a water separator in a nonpolar solvent, preferably benzene, at temperatures of 25-180C within 6 hours to 3 days, the imino function being reduced in a way known in the art, preferably with sodium borohydride in a polar solvent, preferably a methanol/water mixture, at temperatures of 25-100C within 0.5 to 24 hours, preferably 2 hours, or b) by a propanediamine of general formula V
1 o 2 ~ $ 2 t. i ~3 Rl~R2A' H2N NH2 (V) (V) in which Rl, R2 and A' have the above-mentioned meanings, being reacted with a compound of general formula VII
B - CO-X ~VII), in which B has the above-mentioned meaning, functional groups contained in B optionally are present in protected form and X stands for a halogen atom, preferably for a chlorine atom, or c) by a propanediamine of general formula V
Rl R2A' H2N ~ 2 (V) in which Rl, R2 and A' have the above-mentioned meanings, being reacted with a compound of general formula VIII
B~C-R5 X (VIII) in which R4, R5, B and X have the above-mentioned meanings and functional groups contained in B optionally are present in protected form, or d) substituted malonic actd halides, preferably malonic acid chlorides of general formula IX
?~
R~2A~
XOC COX (IX) in which R1, R2, ~' and X have the above-mentioned meanings and functional groups contained in B optionally are present in protected form, being reacted with an amine of general formula X
NHR3 (X) in whi.ch R4, R5 and B have the above-mentioned meanings, R3 stands for a hydrogen atom or for a Cl_6 al~yl radical and functional groups contained in B optionally are present in protected form, in an aprotic solvent, preferably dichloromethane, at temperatures of 0-180C, preferably at room temperature, within 2 to 24 hours, preferably 4 hours, optionally by adding suitable bases, e.g., triethylamine, the amide function obtained according to process d) being reduced in a way known in the art, preferably with borane in THF
or with lithium aluminum hydride in an aprotic solvent, preferably diethyl ether, at temperatures of 25-150C within 0.5 to 24 hours, preferably 8 hours to the corresponding amino ~unction, the amino groups, in the case that R3 stands for a hydrogen atom, optionally being alkylated in a way known in the art with an alkylating agent introducing R3 and present protecting g~oups being cleaved 12 2 ~
and in the thus obtained compounds, group A' optionally converted to A -- optionally after protecting the free amino groups and functional groups Z with protective ions, e.g., as a Cu complex -- being generated and then optionally the thus obtained compounds being coupled by these functional groups to selectively accumulating compounds T and substituents B
optionally being complexed with the radioactive isotope desired in each case, and protective ions optionally present in the product in advance being removed according to methods known in the literature and the sequence of the steps of complexing with radioactive isotopes and coupling to T being able to be interchanged.
As hydroxy protecting groups, e.g., the benzyl, 4-methoxybenzyl, 4-nitrobenzyl, trityl, diphenylmethyl, trimethylsilyl, dimethyl-t-butylsilyl and diphenyl-t-butylsilyl groups are suitable. In the case of polyols, the hydroxy groups can also be protected in the form of ketals with, e.g., acetone, acetaldehyde, cyclohexanone or benzaldehyde. Further, the hydroxy groups can also be present, e.g., as THP-ether, ~-alkoxyethyl ether, MEM ether or as esters with aromatic or aliphatic carboxylic acids, such as, e.g., acetic acid or benzoic acid. The hydroxy protecting groups can be released according to methods in the literature known to one skilled in the art, e.g., by hydrogenolysis, reductive cleavage with lithium/ammonia, acid treatment of the ethers and ketals or alkali treatment of the esters ~s~e, e.g., "Protective Groups in Organic Synthesis," T.
W. Greene, John Wiley and Sons 1981).
13 2 ~3 ~
As amino protecting groups, e.g., trifluoroacetyl, t-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzoxycarbonyl and acetyl groups are suitable. The amino protecting groups can be cleaved according to methods known in the literature, e.g., by basic or acid hydrolysis, reductive cleavage with zinc in acetic acid or hydrogenolysis.
As mercapto protecting groups, Cl_6 alkyl radicals or benzylthioether are suitable. The cleavage of the mercapto protecting groups takes place selectively with alkali alkylthiolates, alkali alcoholates or alkali metals, preferably with sodium methylthiolate in a polar solvent, preferably in HMPT, DMF or dimethylacetamide or by reductive cleavage with sodium/ammonia.
The functional group in radical A is suitable for producing a stable compound to proteins or other selectively accumulating molecules. By the corresponding selection of the functional group in radical A, the coupling is possible under gentle reaction conditions, which do not influence the biological function and/or selectivity.
The coupling to the desired compounds also takes place according to methods known in the art (e.g., Fritzberg et al.; J.
Nucl. Med.: 26, 7 [1987]~, for example, by reaction of the corresponding functional groups in radical A with nucleophilic groups of the selectively accumulating molecule or, if a nucleophile is involved in the corresponding functional group in radical A itself, with activated groups of the selectively accumulating molecule.
The functional group in radical A represents every substituent which on the one hand allows a coupling to a selectively accumulating molecule under mild conditions (e.g., by acylation or amidation) as well as every activated group, which can react with nucleophilic groups of proteins, antibodies, hormones or other biomolecules, such as the amino, phenol, sulfhydryl, formyl or imidazole group. By activated group is to be understood a function which is capable of reacting with the formation of a conjugate with a nucleophilic substituent of a selectively accumulating molecule or of the complex ligand itself in aqueous solution within a suitably short time, under reaetion conditions which entail neither denaturation nor loss of the biologieal activity. Examples in this respect are imide esters, alkylimide esters, amidoalkylimide esters, succinimide esters, acylsuccinimides, phenol esters, substituted phenol esters, tetrafluorophenol esters, anhydrides, and Michael acceptors. The functional group in radical A is preferably an activated ester (sueh as phenol or imide ester), a mereaptan or isothioeyanate, in particular for the eoupling with nucleophilic groups of amino aeids or an aliphatic or aromatie primary amine for the eoupling to earbohydrate radieals of proteins.
If a nucleophile is involved in the functional group in radieal A itself, it ean reaet with aetivated groups of a seleetively aceumulating moleeule, and groups of the molecule reaeted with so-called "crosslinking reagents" are also enelosed, such as homobifunctional imido esters, homobifunetional N-hydroxysueeinimide esters (NHS) and heterobifunctional ~ ~ ~ 2 ~
"crosslinkers," which contain various functional groups, such as NHS esters, pyridyl disulfides and activated halogens, such as ~-keto halides. Such crosslinkers are commercially available.
As coupling participants (= compound T), i.a., various biomolecules are provided: ligands, which bind to specific receptors and thus can detect a tissue changed in its receptor density; they include, i.a., peptide and steroid hormones and neurotransmitters. With ligands for steroid hormone receptors, the possibility of an improved diagnosis of breast and p~ostate carcinomas was demonstrated (S. J. Brandes & J. A.
Katzenellenbogen, Nucl. Med. Biol. 15: 53, 1988~. Often, ligands labeled with positron-emitting isotopes for neuroreceptors were able to be used for diagnosis of various brain diseases (J. J.
Forst, Trends in Pharmacol. Sci. 7: 490, 1987). Other biomolecules are metabolites able to infiltrate the metabolism of the cells, which make a changed metabolism recognizable; they include, for example, fatty acids, saccharides, peptides and amino acids. Fatty acids coupled to the more unstable N2S2 chelating agents were described in EPA 0 200 492. Other metabolism products such as saccharides (dexoxyglucose), lactate, pyruvate and amino acids (leucine, methylmethionine, glycine) were used with the help of the PET technique for graphic representation of changed metabolic processes (R. Weinreich, Swiss Med. 8, 10, 1986). Also, nonbiological substances such as misonidazole and its derivatives, which in tissues or tissue parts with reduced oxygen concentration bind irreversibly to cell ' components, can be used for specific accumulation of radioactive 16 2~ 3 isotopes and thus graphic representation of tumors or ischemic regions (M. E. Shelton, J. Nucl. Med. 30: 351, 1989). Finally, the coupling of the bifunctional chelating agents to monoclonal antibodies or their fragments is also possible. The compounds according to the invention containing biotin make possible the bonding of the radioactive conjugates to substances containing avidin or streptavidin. This can be used to accumulate antibody-streptavidin conjugates on the tumor and only later to administer the radioactive biotin-containing components, which results in a reduced exposure of the patient to radioactive radiation (D. J.
Hnatowich et al., J. Nucl. Med. 28: 1294, 1987). By complexing the conjugates with Tc-99m or rhenium isotopes, a diagnosis and treatment of tumors can be made possible.
It is unimportant whether a labeling of the chelating agents with Tc-99m or a rhenium isotope is performed before or after the coupling to the selectively accumulating molecule. But for a coupling to the selectively accumulating molecule after a complexing, it is a prerequisite that the reaction of the radioactive complex with the accumulating compound occurs quickly, under gentle conditions and almost quantitatively, and no subsequent purification is necessary.
The production of the pharmaceutical agents according to the invention takes place in a way known in the art, by the complexing agents according to the invention being dissolved while adding a reducing agent, preferably tin ~II) salts such as tin chloride or tin tartrate -- and optionally by adding the 17 ~ 3 additives usual in galenicals -- in aqueous medium and then being sterilized by filtration.
Suitable additives are, for example, physiologically harmless buffers (e.g., tromethamine), small additions of electrolytes (e.g., sodium chloxide), stabilizers ~e.g., gluconate, phosphates or phosphonates). The pharmaceutical agent according to the invention is present in the form of a solution or in freeze-dried form and is mixed shortly before the administration with a solution of Tc-99m pertechnetate, eluted from commercially available generators, or a perrhenate solution.
In the nuclear medical in vivo use, the agents according to the invention are provided in amounts of 1 10-5 to 5 104 nmol/kg of body weight, preferably in amounts between 1 10-3 and 5-102 nmol/kg of body weight. Starting from an average body weight or 70 kg, the amount of radioactivity for diagnostic uses is between 0.05 and 50 mCi, preferably 5 to 30 mCi per administration. For therapeutic uses, between 5 and 500 mCi, preferably 10-350 mCi is administered. The administration is normally performed by intravenous, intraarterial, peritoneal or intratumoral injection of 0.1 to 2 ml of a solution of the agent according to the invention. The intravenous administration is preferred.
The following examples are used to explain the object of the invention in more detail.
18 ;~ ?.'~1 r~
Example 1:
2-Methvl-2-(4-nitrobenzyl)-malonic acid dimethvl ester ~1l 11.5 g (0.5 mol) of sodium under a nitrogen stream is added in a dry three-necked flask holding 1000 ml with a reflux condenser and drying tube as well as a dropping funnel with pressure compensation. Then, 350 ml of methanol is carefully instilled and stirred until the sodium is completely dissolved.
In the still warm sodium methanolate solution, the methanolic solution of 87 g (0.5 mol) of methylmalonic acid diethyl ester is instilled very slowly. After completion of the addition, it is stirred for another 30 minutes and then the 4-nitrobenzyl bromide is added in portions with the help of a powder funnel. After everything has dissolved, it is first refluxed for 2 hours and then stirred overnight at room temperature. The solvent is drawn off on a rotary evaporator, the residue is mixed with water and extracted several times with ethyl acetate (250 ml each time).
The combined organic extracts are washed with saturated common salt solution and dried on sodium sulfate. After removal of the solvent, pale yellow crystals remain. The recrystallization takes place from dimethylformamide (DMF)/water.
Melting point: 94.5 - 95.0C
Yield: 74~
H-NMR data in DMSO/TMS
1.4 ppm (s,3H,Me); 3.5 ppm (s,2H,CH2Ar); 3.8 ppm (s,6H,MeOOC); 7.2 ppm (d,2H,ArH); 8.2 ppm (d,2H,ArH) 19 2~S~2~ 3 2-Methyl-2-(4-nitrobenzvl~-malonic acid diamide r21 5.0 g of ester [1] is weighed in in a 500 ml round-bottom flask and dissolved in 200 ml of methanol. In this methanolic solution, ammonia is introduced to saturation, then the catalytic amount of sodium is added and after completion of the gas generation, the flask is closed with a suction piece with balloon and allowed to stand for at least 1 we~k at room temperature.
After several days, a white precipitate precipitates. After all the feedstock is reacted (DC control), the precipitated precipitate is suctioned off and the remaining solution is cooled in the freezer to -20C and again suctioned off. The mother liquor is further concentrated by evaporation on a rotary evaporator and the precipitated precipitate is again suctioned off. The recrystallization of the combined crystal fractions takes place from acetonitrile. The white crystalline product is dried in a vacuum dessicator.
Melting point: 179C
Yield: 91%
H-NMR data in DMSO/TMS
1.2 ppm (s,3H,Me); 3.3 ppm (s,2H,CH2Ar); 7.1 ppm (s(br),4H,CONH2); 7.3 ppm (d,2H,ArH); 8.1 ppm (d,2H,ArH) 2-Methyl-2-(4-nitrobenzvl)-1.3-proPanediamine ~31 Diamide C2] (5.0 g) is suspended with exclusion of atmospheric moisture in 25 ml of abs. tetrahydrofuran in a 250 ml two-necked flask with a reflux condenser and drying tube as well as a septum. The flask is cooled down in an ice bath and then 3 ~ ~ r,~ ,~
the borane solution in THF is added with the help of a 20 or 50-ml one-way syringe by the septum. After the necessary amount of the borane solution (80 ml of a 1 M solution in THF) was added, it was allowed to heat to room temperature. After 30 minutes, the mixture is refluxed for 4 hours. After cooling to room temperature, the excess of borane is hydrolyzed carefully with water (a total of 16 ml of water). After completion of the gas generation, the reaction mixture is converted quantitatively in a 500 ml round-bottom flask and the solvent is drawn off carefully on a rotary evaporator, a white precipitate remains. This precipitate is mixed with 125 ml of 6 N HCl and refluxed for 3 hours. Then, the hydrochloric acid is drawn off slowly on a rotary evaporator. The residue is taken up in the minimum amount of water (about 50-70 ml) and added to a prepared ion exchanger column (strongly basic) and the pure amine is eluted with distilled water. The free diamine is collected (pH control) and the combined fractions are concentrated by evaporation on a rotary evaporator. A pale yellow oil remains as residue.
Melting point (hydrochloride): 270C
Yield: 80%
H-NMR data in DMS0/TMS
1.0 ppm (s,3H,Me); 2.9 ppm (m,4H,CH2NH2); 3.0 ppm (s,2H,CH2Ar); 7.5 ppm (d,2H,ArH); 8.2 ppm (d,2H,ArH); 8.5 ppm (s(br),4H,NH2) 2-Methvl-2-(4~-nitrobenzvl~-N N~-propYlene-bis- r ( 5-sulfo~salicYlidenaminel r4~
A solution of 5.~ g of diamine [3] in 100 ml of 50~ ethanol is adjusted with acetic acid to pH 5-6. 8.6 g of 5-sulfosalicylaldehyde and 1.9 g of sodium cyanoborohydride are added to this solution and stirred overnight~ After cooling to 0C, it is adjusted with semiconcentrat~d hydrochloric acid to pH
2 and concentrated by evaporation. The residue is neutralized with saturated potassium carbonate solution and then freeze-dried. The residue is extracted with DMF/MeOH. After removal of the solvent, a crystalline residue remains which is recrystallized from acetonitrile/water.
Yield: 56%
H-NMR data in DMSO/TMS
0.9 ppm (s,3H,Me); 2.5 ppm (m,4H,CH2NH); 2.8 ppm (s,2H,CH2Ar); 4.1 ppm (m,4H,ArCH2NH); 7.0-7.8 ppm (m,8H,ArH); 8.2 ppm (d,2H,ArH) 2-Methyl-2-(4'-aminobenzyl)-N.N'-ProPYlene-bis-r(5-sulfo)salicylidenamine] r5]
40 mg of 10% Pd/C in 50 ml of MeOH is suspended i~ a 100 ml two-necked flask and saturated with hydrogen. Then, the solution of 595 mg [4] (1 mmol) in 5 ml of methanol and 1.6 ml of 6N
hydrochloric acid is added with a one-way syringe by a septum.
After completion of the absorption of hydrogen, it is separated from the catalyst and the solvent is drawn off in a vacuum.
White crystals remain. The recrystallization takes place from methanol.
Yield: 76%
H-NMR data in DMS0/TMS
1.0 ppm (s,3H,Me); 2.5 ppm tm,4H,CH2NH); 2.8 ppm (s,2H,CH2Ar); 4.2 ppm (m,4H,ArCH2NH); 7.0-7.8 ppm (m,lOH,ArH) 2-Methyl-2-(4-isothiocyanatobenzyl)-N~N'-~roPYlelle-bis- r ( 5-sulfo)salicylidenaminel r61 An 85go solution of thiophosgene in carbon tetrachloride (0.2 ml, 2.23 mmol) is added to the solution of 280 mg [5] (0.5 mmol) in 4 ml of hydrochloric acid (3 M). The reaction mixture is stirred for 3 hours at room temperature and then evaporated to dryness in a vacuum.
Yield: 78%
H-NMR data in DMS0/TMS
1.0 ppm (s,3H,Me); 2.8 ppm (m,4H,CH2NH); 3.0 ppm (s,2H,CH2Ar); 4.2 ppm (m,4H,ArCH2NH); 7.0-7.8 ppm (m,lOH,ArH) Example 2:
2-(4-Nitrobenzy~L-malonic acid diethvl ester r71 21.4 g of lithium diisopropylamide is added to 210 ml of anhydrous tetrahydrofuran under a nitrogen stream in a dry three- `
necked flask with a drying tube and dropping funnel with pressure compensation. Then, 58.0 g of malonic acid diethyl ester in 100 ml of anhydrous tetrahydrofuran is instilled at room temperature within 40 minutes. After 30 minutes, the reaction solution is 23 ~ s3 cooled to -62C and 39.1 g of 4-nitrobenzyl bromide in tetrahydrofuran is instilled slowly with vigorous stirring, it is stirred for another hour at -62C and then the formed precipitate is filtered off cold. The filtrate is concentrated by evaporation on a rotary evaporator, the residue is brought into solution in 300 ml of ethanol at 65C and separated from the insoluble residue. After cooling, 34.7 g of pale yellowish crystals are obtained.
Yield: 65%
H-NMR data in CDC13/TMS
1.2 ppm (t,6H,CH2CH3); 3.3 ppm ~d,2H,CH2Ar); 3.6 ppm (t,lH,CH); 4.1 ppm (q,4H,CH2CH3); 7.4 ppm (d,2H,ArH); 8.1 ppm (d,2H,ArH) 2-(4-Nitrobenzyl)-malonic acid diamide r 8~
This compound is produced corresponding to compound t2].
Yield: 98%
H-NMR data in DMSO/TMS
3.1 ppm (d,2H,CH2Ar); 3.4 ppm (t,lH,CH); 7.1 ppm (s,4H,NH2); 7.4 ppm (d,2H,ArH); 8.2 ppm (d,2H,ArH) 2-(4-Nitrobenzyl)-1~3-ProPanediamine r91 This compound is produced corresponding to compound t3].
Yield: 76%
lH_NMR data in D20 1.3 ppm (t,lH,CH); 3.1 ppm (d,4H,CH2NH2); 3.2 ppm (d,2H,CH2Ar); 7.5 ppm (d,2H,ArH); 8.2 ppm (d,2H,ArH) 2-(4'-Nitrobenzyl)-N,N'-Pro~ylene-bis- r ( 5-sulfo)salicylideniminel r10]
A solution of 9.5 g of 5-sulfosalicylaldehyde in 75 ml of ethanol abs. is instilled in a solution of 5.6 g of diamine t9~
in 75 ml of ethanol abs. with stirring. The resulting solution is slowly discolored intensively yellow. It is stirred for another 3 hours at room temperature, in this way, a more yellow precipitate precipitates, which is filtered off after cooling to -20C.
Yield: 68%
H-NMR data in DMSO/TMS
1.5 ppm (m,lH,CH); 3.2 ppm (d,2H,CH2Ar); 3.5 ppm (m,4H,CH2N=C); 7.1-7.9 ppm (m,8H,ArH); 8.2 ppm (d,2H,ArH); 8.6 ppm (s,2H,CH=N) 2-(4~-Nitrobenzvl)-N.N'-proPylene-bis-~(5-sulfo)salicvlidenamine~
rlll 500 mg of sodium borohydride is added to a solution of 2 g of diimine [10] in 50 ml of 50% ethanol with stirring and stirred for 4 hours at 0C. Then, 20 ml of water is instilled and stirred for 1 hour at room temperature, then the solvent is drawn off on a rotary evaporator and brought to pH 11 with a saturated potassium carbonate solution. The residue is taken up in 2 ~ ~ 2 ~
methanol and filtered by a short column (RP-18~. After drying on sodium sulfate and removal of the solvent, a crystalline residue remains.
Yield: 80%
H-NMR data in DMS0/TMS
1.6 ppm (m,lH,CH); 2.S ppm (m,4H,CH2NH); 2.9 ppm (d,2H,CH2Ar); 4.0 ppm (m,4H,ArCH2NH); 7.1-7.8 ppm (m,8H,ArH); 8.2 ppm (d,2H,ArH) Cu-2-t4'-Nitrobenzvl)-N,N'-propylene-bis- r ( 5-sulfo)salicYlidenaminel L 121 400 mg of copper acetate (2 mmol) in 20 ml of methanol is instilled in a suspension of 1.63 g [11] (2 mmol~ in 50 ml of methanol and stirred at room temperature. After removal of the solvent and drying, a crystalline residue remains.
Yield: 66~
Cu-2-t4'-AminobenzYl)-N,N'-~troPvlene-bis- r f 5~
sulfo)salicvlidenaminel r 13l This compound is produced corresponding to compound [5].
Yield: 78~
cu-2 - [ 4'-Biotincarbamovl)benzyll-N N'-Pro~vlene-bis- r ( 5-sulfo)salicvlidenaminel r141 680 mg of NHS-biotin (2 mmol) is added to a solution of 615 mg [13] (l mmol) in lO ml of DMS0 with stirring and heated for 3 hours to 50C. After cooling to room temperature, it is stirred 26 2 ~ 3 for another 15 hours. Then, the solvent is drawn off in a vacuum and the residue is purified by MPLC (sili~a gel, dichloromethane/ethanol/concentrated ammonia 10:20:1) Yi~ld: 38~
2-r4'-(Biotincarbamoyl~benz~ N N'-~ro~ylene-bis-r(5-sulfo)salicylidenaminel t151 500 mg of potassium cyanide is added to a solution of 500 mg [14] in 70 ml of water at 40C and stirred for another 2 hours.
Then, it is concentrated by evaporation to about 10 ml and the residue is purified by MPLC (silica gel, acetonitrile/concentrated ammonia 40:3).
Yield: 46%
H-NMR data in DMS0/TMS
1.3-1.7 ppm (m,7H,CH2+CH); 2.3 ppm (t,2H,CH2C0); 2.8 ppm (m,2H,CH2S); 3.0 ppm (s,2H,CH2Ar); 3.1 ppm (m,lH,CHS); 4.1 ppm (m,lH,CHNHC0); 4.3 ppm (m,5H,ArCH2NH+CHNHC0); 6.9 ppm-7.8 ppm (m,lOH,ArH).
Example 2a Tc-99m Complex of ~151 5.6 * 10-3 mol of potassium tartrate in 1 ml of H20, 4.8 *
10-8 mol of tin chloride in 1 ml of H2O and 5 mCi of Tc-99m pertechnetate are added to a solution of 1.86 * 10-6 mol ~15] in 1 ml of EtOH/H20 1:9 and incubated for 10 minutes. The corresponding technetium complex is obtained in a ~urity greater than 90%.
Example 3 2-(4'-NitrobenzYl)-N N'-pro~vlene-bis-[(5-carboxy)salicylidenamine] r 16]
This compound is produced corresponding to compound [4].
Yield: 66%
H-NMR data in DMS0/TMS
0.9 ppm (s,3H,Me); 2.5 ppm (m,4H,CH2NH); 2.8 ppm (s,2H,CH2Ar); 4.2 ppm (m,4H,ArCH2NH); 6.9-8.0 ppm (m,8H,ArH); 8.2 ppm (d,2H,ArH) Cu-2-t4'-Nitrobenzyl)-N.N'-Propvlene-bis-[t5-carboxY)salicylidenaminel r171 This compound is produced corresponding to compound [12].
Yield: 74%
Cu-2-t4'-AminobenzYl)-N,N'-proPYlene-bis- r 5-(carboxy)salicylidenaminel r181 This compound is produced corresponding to compound [13].
Yield: 69%
Cu-2- r 4~-tBiotincarbamoyl)benzyll-N~Nr-propylene-bis- r ( 5-carboxv)salicYlidenaminel [191 This compound is produced corresponding to compound [14].
Yield: 43~
2 ~ 3 2- r 4'-(Biotincarbamovl)be_zYll--N.N'-propYlene-bis- r ( s-carboxY)salicYlidenaminel l2ol This compound is produced corresponding to compound ~15].
Yield: 49%
H-NMR data in DMS0/TMS
1.3-1.7 ppm (m,7H,CH2~CH); 2.3 ppm (t,2H,CH2C0); 2.8 ppm (m,2H,CH2S); 3.0 ppm ~s,2H,CH2Ar); 3.1 ppm (m,lH,CHS); 4.1 ppm (m,lH,CHNHCO); 4.2 ppm (m,5H,ArCH2NH+CHNHCO); 6.9 ppm-8.1 ppm (m,lOH,ArH).
Example 4 2-Bromomethyl-5-nitrobenzoic acid r 211 20 ml of bromine is slowly instilled in 72 g of 2-methyl-5-nitrobenzoic acid and 100 mg of dibenzoyl peroxide in 250 ml of carbon tetrachloride under irradiation with a 500 W incandescent lamp. The reaction mixture is refluxed for 24 hours, the solvent is drawn off after cooling, taken up in dichloromethane, washed several times with water, dried and concentrated by evaporation.
The resid~e is chromatographically purified (silica gel, dichloromethane).
Yield: 56~
H-NMR data in CDC13/TMS
4.4 ppm (s,2H,CH2); 8.3-8.5 ppm (m,3H,ArH).
(2-CarboxY-4-nitrobenzyl~malondinitrile r 221 The solution of 16.4 g of malondinitrile in 100 ml of anhydrous DMF is instilled in a suspension of 11.9 g of sodium 2 ~
hydride in 100 ml of anhydrous DMF at 0C within 3 hours. Then, 65 g of [21] in 100 ml of anhydrous DMF is instilled within 6 hours and stirred after heating to room temperature for another 12 hours. The reaction mixture is hydrolyzed with ice water, acidified and extracted with chloroform. After drying and concentration by evaporation, a crystalline residue remains, which is recrystallized from methanol.
Yield: 48%
H-NMR data in CDCl3/TMS
3.5 ppm (d,2H,CH2Ar); 3.8 ppm (t,lH,CH); 8.3-8.5 ppm (m,3H,ArH).
2-(2-Carboxv-4-nitrobenzvl)-1 3-propanediamine ~23l 19 g of sodium borohydride is slowly added to a solution of 12 g of [22] (0.05 mol) and 24 g of cobalt chloride hexahydrate (0.1 mol) in 300 ml of 99~ methanol at -15C and then stirred for another 3 hours. After adding lOO ml of 3N hydrochloric acid, the solvent is distilled off for the most part, the remaining aqueous phase is alkalized with saturated potassium carbonate solution and extracted several times with dichloromethane. After drying and concentration by evaporation, a residue remains which is recrystallized from ethanol.
Yield: 59%
H-NMR data in DMSO
1.3 ppm (t,lH,CH2); 3.1 ppm (d,2~,CH2NH2); 3.~ ppm (d,2H,CH2Ar); 8.3-8.5 ppm (m,3H,ArH) ~ ~ ~ 2 ~ ~ 3 2- r 2'-Carboxy-(4'-nitrobenzyl)l-N,N'-pro~ylerle-bis-salicylidenamine [241 This compound is produced corresponding to compound [4].
Yield: 62%
H-NMR data in CDC13/TMS
1.6 ppm (m,lH,CH); 2.5 ppm (m,4H,CH2NH); 3.0 ppm (d,2H,CH2Ar); 3.9 ppm (m,4H,ArCH2NH); 6.9 ppm (m,4H,ArH); 7.1-7.3 ppm (m,4H,ArH); 8.3-8.4 ppm (m,3H,ArH) 2- r 2'-Carboxv-(4'-aminobenzyl)~-N,N'-propvlene-bis-salicvlidenamine r251 This compound is produced corresponding to compound [5].
Yield: 85%
H-NMR data in DMSO/TMS
1.5 ppm (m,lH,CH); 2.5 ppm (m,4H,CH2NH2); 2.9 ppm (t,2H,CH2Ar); 4.1 ppm (m,4H,ArCH2NH); 6.8-7.4 ppm (m,llH,ArH) 2-r2'-Carboxv-(4'-isothiocyanatobenzyl)l-N N'-propylene-bis-salicylidenamine r261 This compound is produced corresponding to compound [6].
Yield: 77%
H-NMR data in DMSO/TMS
1.5 ppm (m,lH,CH); 2.9 ppm (m,5H,CH2NH+CH2Ar); 3.0 ppm (s,2H,CH2Ar); 4.1 ppm (m,4H,ArCH2NH); 6.8-7.4 ppm (m,llH,ArH).
3 1 ~ 2 '.
E~ample 5 6-(2'-Carboxy-4'-nitrobenzyl)-3 3 9,9-tetramethYl-4 8-diazaundecane-2 10-dione-dioxime [271 13 g of diamine [23] is dissolved in 90 ml of methanol and cooled to 0C, then 6.5 g of 2-chloro-2-methyl-3-nitrosobutane is added with stirring. After heating to room temperature, it is stirred for 2 hours, refluxed for another 2 hours, the solvent is drawn off and the remaining solid is dissolved in water. It is neutralized with sodium bicarbonate, concentrated by evaporation, and the remaining residue is recrystallized from ethanol.
Yield: 38%
H-NMR data in DMSO/TMS
1.3 ppm (s,12H,MeCNH); 1.8 ppm (s,6H,MeC=N); 2.4 ppm (m,lH,CH~; 2.5 ppm (m,4H,CH2NH); 2.9 ppm (d,2H,CH2Ar); 8.2-8.4 ppm (m,3H,ArH); 10.8 ppm (s,2H,HON=C) 6-(2'-Carboxy-4'-aminobenzyl)-3 3 9 9-tetramethyl-4.8-diazaundecane-2 10-dione-dioxime r 281 500 mg of nitro compound [27] is dissolved in 50 ml of 50%
methanol (pH 11~ and hydrogenated at room temperature with adding 25 mg of Pd/Alox. After separating the catalyst and concentration by evaporation, a crystalline solid remains.
Yield: 49%
lH_NMR data in D2O
32 2 ~ ~i 2 ~, g L;3 1.2 ppm (s,12H,MeCN~I); 1.7 ppm (s,6H,MeC=N); 1.9 ppm (m,lH,CH); 2.5 ppm ~m,4H,CH2NH); 2.5 ppm (d,2H,CH2Ar); 6.7 ppm (d,lH,ArH); 7.3 ppm (m,2H,~rH) Cu-6-(2'-Carboxy-4'-aminobenzvl)-3,3,9,9-tetramethyl-4.8-diazaundecane-2,10-dione-dioxime ~291 This compound is produced corresponding to compound [12].
Yield: 58%
Cu-6- r 2'-CarboxY-4'-(biotincarbamoyl)benzyll-3,3,9,9-tetramethvl-4 8-diazaundecane-2,10-dione-dioxime t301 This compound is produced corresponding to compound [14].
Yield: 34%
6-(2'-Carboxy-4'-biotincarbamoyl)benzvll-3 3,9 9-tetramethyl-4 8-diazaundecane-2 10-dione dioxime r311 This compound is produced corresponding to compound [15]~
Yield: 41%
Tc-99m Complex of ~311 3.2 * 10-3 mol of potassium tartrate in 1 ml of H2O~ 4 0 *
10-8 mol of tin chloride in 1 ml of H2O and 5 mCi of Tc-99m pertechnetate are added to a solution of 1.86 * 10-6 mol of t31]
in 1 ml of EtOH/H2O 1:4 and incubated for 10 minutes. The corresponding technetium complex is obtained in a purity greater than 90%.
2 ~ 3 ~
Example 6 2-Meth~l-2- r 4'-nitrobenzoyll-malonic acid dimethyl ester [32]
5 ml of carbon tetrachloride is added to the mixture of 24.3 g of magnesium chips (1 mol) in 50 ml of anhydrous ethanol~
Then, a solution of 174 g of methylmalonic acid diethyl ester (1 mol) in 100 ml of ethanol and 400 ml of anhydrous ether is instilled so that the mixture boils vigorously. After dissolution of the magnesium, 185 g of 4-nitrobenzoyl chloride in lO0 ml of anhydrous ether is instillad under ice cooling and stirred for another 12 hours. It is hydrolyzed under ice cooling, the ether phase is separated, extracted several times with ether, washed neutral, dried and concentrated by evaporation. After distillation in a vacuum, the pure product is obtained.
Yield: 78%
H~NMR data in CDCl3/TMS
1.2 ppm (m,9H,Me); 4.1 ppm (q,4H,CH2Me~; 8.1-8.3 ppm (m,4H,ArH) 2-Methyl-2- r 4'-nitrobenzoYl]-malonic acid [33]
41 g of [32] (127 mmol) is dissolved in 200 ml of methanol and a solution of 28.3 g of NaOH (708 mmol) in 50 ml of water is slowly instilled in it. Then, it is heated for 2 hours in a water bath to 50C, the solvent is drawn off on a rotary evaporator and the residue is taken up in water. It is acidified with semiconcentrated hydrochloric acid and the fre'e carboxylic acid is extracted with chloroform, washed and dried.
Yield: 80%
H-NMR data in DMS0/TMS
1.2 ppm (s,3H,Me); 8.1-8.3 ppm (m,4H,ArH) 2-Methyl-2- r 4'-nitrobenzovll-malonic acid chloride r 34l The mixture of 3.40 g of [333 and 8.9 g of thionyl chloride and one drop of DMF is heated to boiling under exclusion of moisture with stirring. After completion of the gas generation, the excess thionyl chloride is drawn off at room temperature in a vacuum and the residue is distilled in a vacuum.
Yield: 91%
N N'-bis r ( 2-(Benzylthio)benzyll-2-methyl-2-(4'-nitrobenzovl)malonic acid diamide ~35l 7.4 g of [34] (24.3 mmol) in 100 ml of dichloromethane is carefully instilled in the mixture of 10.5 g of (2-mercaptobenzyl)benzylamine (48.6 mmol) and 5.06 g of triethylamine (50 mmol) in 100 ml of dichloromethane with exclusion of moisture. It is stirred for another 3 hours at room temperature, then first water is added and extracted several times with chloroform. The organic phase is washed in succession with lN hydrochloric acid, saturated potassium carbonate solution and water and dried on sodium sulfate.
Yield: 64%
H-NMR data in CDCl3/TMS
1.2 ppm (s,3H,Me); 4.1 ppm (sj8H,ArCH2S+ArCH2NH); 7.1-7.6 ppm (m,18H,ArH); 8.3 ppm (m,4H,ArH).
~ 2 ~
N N'-bis~r2-Benzylthio)benzyll-2-meth~1-2- r hvdroxY-(4-nitrophenyl)-methyll-malonic acid diamide r361 5.7 g of sodium borohydride is added to a solution of 66 g (100 mmol) of [35] in 50 ml of ethanol and stirred for 2 hours at room temperature. It is substantially concentrated by evaporation and the residue is mixed with 50 ml of water and neutralized. It is extracted with ether, washed with saturated common salt solution, dried and concentrated by evaporation.
Yield: 77%
H-NMR data in DMSO/TMS
1.4 ppm (s,3H,Me); 4.1 ppm (s,8H,ArCH2S+ArCH2NH); 4.3 ppm ~m,lH,CHOH); 7.1-7.6 ppm (m,20H,ArH); 8.2 ppm (m,2H,ArH).
N,N'-bisr(2-Benzylthio)benzY11-2-methYl-2-~hYdroXV-(4-nitrophenyl)methYl)1-1~3-Propanediamine r 371 This compound is produced corresponding to compound [3].
H-NMR data in CDC13/TMS
1.5 ppm (s,3H,Me); 2.5 ppm (m,4H,CH2NH); 4.1 ppm (s,4H,ArCH2NH); 4.3 ppm (m,lH,CHOH); 7.0-7.5 ppm (m,lOH,ArH); 8.2 ppm (d,lH,ArH).
N~N~-bis(2-Mercaptobenzyl)-2-methyl-2-[hYdroxy-(4-nitrophenyl)methY~ 3-propanediamine r 381 3.5 g of sodium is carefully added to a solution, cooled to -50C, of 4.3 g of [37] in 50 ml of THF and 100 ml of li~uid ammonia and stirred for 4 hours. Excess sodium is carefully 36 ~ 2 /~
destroyed with ammonium chloride and then allowed to heat slowly to room temperature. The residue is taken up in water and extracted several times with dichloromethane, the organic phase is dried and concentrated by evaporation.
Yield: 62%
H--NMR data in CDC13/TMS
1.5 ppm (s,3H,Me); 205 ppm (m,4H,CH2NH); 4.1 ppm (s,4H,ArCH2NH); 4.3 ppm (m,lH,CHOH); 7.0-7.5 ppm (m,lOH,ArH); 8.2 ppm (d,lH,ArH).
N N'-bis(2-Mercaptobenzyl)-2-methyl-2- r hvdroxv-(4-aminopheny-llmethvl)~ 3-propanediamine r 391 This compound is produced corresponding to compound [5].
Yield: 89%
H-NMR data in CDC13/TMS
l.S ppm (s,3H,Me); 4.1 ppm (s,4H,ArCH2NH); 4.3 ppm (m,lH,CHOH); 7.0-7.7 ppm (m,llH,ArH).
N,N'-bis(2-MercaptobenzYl)-2-methyl-2-~hydroxv-(4-isothiocvanatophenvl)methyl~ 3-propanediamine r401 This compound is produced corresponding to compound [6].
Yield: 49%
H-NMR data in CDC13/TMS
1.5 ppm (s,3H,Me); 4.1 ppm (s,4H,ArCH2NH); 4.2 ppm (m,lH,CHOH); 7.0-7.6 ppm (m,llH,ArH).
37 2 ~
Example 7 N N' bis r ( 2-Benzvlthio-3-pyridyl)methyll-2~methvl-2-(4'-nitrobenzyl)malonic acid diamide ~411 This compound is produced corresponding to compound [35].
Yield: 60%
H-NMR data in CDC13/TMS
1.2 ppm (s,3H,Me); 3.5 ppm (s,2H,CH2Ar); 4.1 ppm (s,8H,ArCH2S+ArCH2NH); 7.1-7.5 ppm (m,14H,ArH); 8.3-8.S ppm (m,6H,ArH).
N~N~-bisr(2-Benzylthio-3-pyridyl3methyll-2-methyl-2-(4~-nitrobenzyl)-1 3-propanediamine L4 21 This eompound is produeed eorresponding to eompound [3].
Yield: 57%
H-NMR data in CDC13/TMS
1.0 ppm (s,3H,Me); 2.5 ppm (m,4H,CH2NH); 2.9 ppm (s,2H,CH2Ar); 4.1 ppm (s,8H,ArCH2NH+ArCH2S~; 7.1-7.5 ppm (m,14H,ArH); 8.3-8.5 ppm (m,6H,ArH).
N N'-bis r t2-MereaPto-3-pyridYl)methyll-2-methyl-2-(4 nitrobenzyl)-1~3-Propanediamine r431 This eompound is produeed eorresponding to eompound [38].
Yield: 65%
H-NMR data in CDC13/TMS
1.0 ppm (s,3H,Me); 2.5 ppm (m,4H,CH2NH); 2.9 ppm (s,2H,CH2Ar); 4.1 ppm (s,4H/ArCH2NH); 7.0-7.5 ppm (m,4H,ArH);
But a drawback of the technetium is its complicated and still not completely known complex chemistry. Technetium can be present in a number of oxidation stages (+7 to -1), which can greatly change the pharmacological properties by changing the charge of a complex. It is therefore necessary to synthesize complexes which bind the technetium in a defined oxidation stage and to prevent redox reactions, which could lead to a redistribution of the pharmaceutical agent. A number of such Tc-99m complexing agents are already known and are clinically used. In the case of neutral complexes, systems, in which the Tc-99m is bound between 2-4 nitrogen atoms and 0-2 sulfur atoms (N2S2, N3S and propylenamine oxime complexes), are often involved. But often the 2 ~,?.~ ~ ~
insufficient stability of these Tc-ssm complexes is a significant drawback (Hung, J. C. et al.; J. Nucl. Med. 29: 1568, 1988). In clinical use, therefore, e.g., HMPAO (hexamethyl-propylenamine oxime) has to be administered shor~ly after its labeling with pertechnetate, so that the portion of decomposition products, which reduce the diagnostic informative value, is not too high.
A coupling of these chelates or chelating agents to other substances selectively accumulating in foci of disease is not possible. Therefore, most of said complexes are distributed according to the blood circulation and/or metabolic activity of an organ (e.g., Europ. Patent Appl. 0 194 843), so that, e.g., necrotic or ischemic regions can be represented after infarction or stroke in a scintigram.
But for a successful diagnosis of tumors, neurological diseases or diseases of the cardiovascular system, substances are more promising which can produce molecular changes of diseased tissue, by being bound specifically to these diseased tissues or being infiltrated in their metabolism. The findings of the biological and biochemical basic research allow the selection of a number of substances, which selectively accumulate in foci of disease: various tumors develop increased or reduced surface concentrations on receptors, e.g., for growth factors or steroid hormones (Sledge, G. W.; Adv. Cancer Res. 38: 61-75 [1983]).
Also, in neurological diseases, a change of the concentration of receptors for neutrotransmitters results in specific areas of the brain (Frost, J. J.; Trends Pharmacol. Sci. 7: 490-496 [19873).
Further, diseased, damaged or cells transformed into tumor cells 3 ~ ;3 often show great changes of their metabolism and an oxygen deficiency inside the tumor. The use of such physiological characteristics can be used in in vivo diagnosis, by, e.g., hormones, neurotransmitters or certain metabolic products such as fatty acids, saccharides, peptides or amino acids being coupled to chelating agents for Tc-99m. Also, substances such as misonidazole (a radiosensitizer) or other compounds reacting to radicals in the absence of oxygen can be used for specific accumulation of radioactive isotopes and thus graphic representation of tumors or ischemic regions. Finally, also the coupling to monoclonal antibodies is possible, which because of their high specificity have become a promising instrument in the diagnosis of tumors.
For the production of diagnostic agents according to the described principle, it is necessary that chelating agents for radioactive metal ions, in particular Tc-99m, can be coupled to substances selectively accumulating in diseased tissues.
Since the isotopes of rhenium (Re-188 and Re-186) have chemical properties similar to Tc-99m, the chelating agents can also be used to complex these isotopes. Said Re-isotopes are ~-radiators. Thus, the selectively accumulating substances complexed with rhenium instead of with teçhnetium are also usable in the treatment cf tumors.
The previously known attempts to couple chelating agents to selectively accumulating substances in many cases can be considered as unsatisfactory. If the functional groups of the complexing agent are used to bind the chelating agent to such a 4 2 ~ u 3 molecule, a weakening of the complex stability often results, i.e., a diagnostically intolerable portion of the isotope is released from the conjugate. ~Brechbiel, M. W. et al., Inorg.
Chem. 25: 2772 [1986]). It is therefore necessary to produce bifunctional complexing agents, i.e. complexing agents which carry both functional groups for coordinative bonding of the desired metal ion and a (another) functional group for bonding the selectively accumulating molecule. Such bifunctional ligands make possible a specific, chemically defined bonding of technetium to the most varied biological materials, also then when a so-called prelabeling is performed. Since according to this method, first the labeling with Tc-99m and the isolation of the complexes is performed and this complex is linked only in a second step with a selectively accumulating molecule, the labeled compounds are obtained with a high degree of purity.
Some chelating agents coupled to monoclonal antibodies (e.g., Europ. Patent App. 0 247 866 and 0 188 256) or fatty acids (Europ. Patent Appl. 0 200 492) were described. But as chelating agents, the already mentioned N2S2 systems are used, which are not very suitable because of their low stability. The somewhat more stable N3S chelates showed, coupled to monoclonal antibodies, not so great a loss of Tc-99m from the conjugates (J.
Lister-James; J. Nucl. Med. 30: 793 and Europ. Patent Appl. 0 284 071).
Since both the selectively accumulating substances in their properties and the mechanisms, according to which they are accumulated, are very different, it is further necessary to be 2`~2~i2)~
able to vary the couplable chel.ating agents and match the physiological requirements of the coupling participant with respect to lipophilia and hydrophilia, membrane permeability or impermeability, etc.
For these reasons, there exists an urgent need for stable complex compounds, which are coupled or able to couple to various selectively accumulating compounds.
The object of the invention is thus to make available stahle chelating agents, which contain a functional group for coupling to a selectively accumulating compound or a selectively accumulating compound coupled with the help of this functional group.
According to the invention, this object is achieved by the compounds of general formula I
Rl R2A
R3\ ~ ~ R3 R4 y N N ~ R4 Rs l ~ Rs (I) in which Rl stands for hydrogen or a C1_6 alkyl radical optionally substituted with one or two hydroxyl groups, R2 stands for a Cl_6 alkylene radical optionally substituted with a hydroxyl group, R3 stands for a hydrogen atom, a C1_6 alkyl radical, a carboxymethyl radical or a (Cl-6 alkoxycarbonyl)methyl radical, R4 stands for a hydrogen atom, a C1-6 alkyl radical optionally substituted with a hydroxyl group or for the meaning indicated under RX, R5 stands for a hydrogen atom or a C1-6 alkyl radical optionally substituted with a hydroxyl group, B stands for a pyrrolyl radical, a substituted phenyl radical of formula II or a substituted pyridine radical of formula III
~Z ~ Z
in which Z means a hydroxyl group, amino group or a mercapto group and Y means a hydrogen atom, a carboxy radical or a sulfonyl radical 7 2'~ 2~
or B stands for a nitrosomethyl radical of formula IV
NOH
--C
RX
in which Rx means a Cl_6~alkyl radical or, together with R4,is a trimethylene or tetramethylene group to form a 5- or 6-membered ring.
and A stands for an amino radical, a mercapto radical, a carboxy radical, a C2_6 alkinyl or C2_6 alkenyl radical, an oxiranyl radical, a fluorinated phenoxycarbonyl radical, a succinimidoxycarbonyl radical optionally substituted with a sodium sulfate radical, an aminophenyl radical or isothiocyanatophenyl radical, and the phenyl group optionally can be substituted in addition by a carboxy radical, a chlorosulfonyl radical or a sulfonic acid radical or contains a compound T selectively accumulating in lesions or specific tissues -- optionally bound by a bifunctional linker radical L with the help of said functional group and T stands for monoclonal antibodies or their fragments, hormones, enzymes, ligands for cell membrane receptors, neurotransmitters, lipids, steroids, saccharides, amino acids and oligopeptides, biotin, as well as radiosensitizers, such as, e.g., misonidazole, NOH
and in the case of B = -C, pyrrolyl radical or I X
~3^,32.;~
Y = H, R2 is to stand for a hydroxylated C1_6 alkylene chain or A
is to stand for a substituted aminophenyl or isothiocyanatophenyl radical, as well as their ~omplexes with radioactive metal ions --suitable for diagnosis and treatment of tumors -- as well as their salts with inorganic and organic acids or bases.
According to the invention, those compounds according to claim 1 are preferred in which R4 and R5 mean hydrogen atoms or methyl radicals, as well as those compounds according to claim 1, in which A stands for an amino radical, a mercapto radical, a carboxy radical, a C2_6 alkinyl or C2_6 alkenyl radical, an oxiranyl radical, a fluorinated phenoxycarbonyl radical, a succinimidoxycarbonyl radical optionally substituted with a sodium sulfate radical, an aminophenyl or isothiocyanatophenyl radical, and the phenyl group can be substituted by another carboxyl or sulfonic acid radical, and the selectively accumulating compound T optionally contained in A stands for monoclonal antibodies, their fragments, biotin or misonidazole.
Surprisingly, many of the chelates synthesized and labeled with Tc-99m showed a higher stability than the comparable N2S2, N3S and propylenamine oxime chelates. Thus, no decomposition products were able to be observed after 5 hours, e.g., in a substance according to the invention (example 2), which was coupled by an aminophenyl radical to biotin, while this was the case in the comparable HMPAO known in the literature (Hung, J. ~.
et al.; J. Nucl. Med. 29: 1568, 1988). Also, by competitive tests, it was possible to be determined that the Tc-99m chelates 9 2 ~2 ~ s ~3 described in this invention complex better than the comparable N2S2, N3S and propylenamine oxime chelates. The chelates described in the invention are thus definitely better suitable for diagnostic and therapeutic purposes than the previously known chelates.
The production of the compounds according to claim 1 takes place, by a) a 1,3-propanediamine of general formula v Rl R2A' H2N ~ 2 ~V) in which R1 and R2 have the above-mentioned meanings, and ~' means A or a radical able to be converted to A
being reacted with a compound of general formula VI
B - R4C = 0 ~VI) in which R4 and B have the above-mentioned meanings, in a polar solvent, preferably ethanol, or by using a water separator in a nonpolar solvent, preferably benzene, at temperatures of 25-180C within 6 hours to 3 days, the imino function being reduced in a way known in the art, preferably with sodium borohydride in a polar solvent, preferably a methanol/water mixture, at temperatures of 25-100C within 0.5 to 24 hours, preferably 2 hours, or b) by a propanediamine of general formula V
1 o 2 ~ $ 2 t. i ~3 Rl~R2A' H2N NH2 (V) (V) in which Rl, R2 and A' have the above-mentioned meanings, being reacted with a compound of general formula VII
B - CO-X ~VII), in which B has the above-mentioned meaning, functional groups contained in B optionally are present in protected form and X stands for a halogen atom, preferably for a chlorine atom, or c) by a propanediamine of general formula V
Rl R2A' H2N ~ 2 (V) in which Rl, R2 and A' have the above-mentioned meanings, being reacted with a compound of general formula VIII
B~C-R5 X (VIII) in which R4, R5, B and X have the above-mentioned meanings and functional groups contained in B optionally are present in protected form, or d) substituted malonic actd halides, preferably malonic acid chlorides of general formula IX
?~
R~2A~
XOC COX (IX) in which R1, R2, ~' and X have the above-mentioned meanings and functional groups contained in B optionally are present in protected form, being reacted with an amine of general formula X
NHR3 (X) in whi.ch R4, R5 and B have the above-mentioned meanings, R3 stands for a hydrogen atom or for a Cl_6 al~yl radical and functional groups contained in B optionally are present in protected form, in an aprotic solvent, preferably dichloromethane, at temperatures of 0-180C, preferably at room temperature, within 2 to 24 hours, preferably 4 hours, optionally by adding suitable bases, e.g., triethylamine, the amide function obtained according to process d) being reduced in a way known in the art, preferably with borane in THF
or with lithium aluminum hydride in an aprotic solvent, preferably diethyl ether, at temperatures of 25-150C within 0.5 to 24 hours, preferably 8 hours to the corresponding amino ~unction, the amino groups, in the case that R3 stands for a hydrogen atom, optionally being alkylated in a way known in the art with an alkylating agent introducing R3 and present protecting g~oups being cleaved 12 2 ~
and in the thus obtained compounds, group A' optionally converted to A -- optionally after protecting the free amino groups and functional groups Z with protective ions, e.g., as a Cu complex -- being generated and then optionally the thus obtained compounds being coupled by these functional groups to selectively accumulating compounds T and substituents B
optionally being complexed with the radioactive isotope desired in each case, and protective ions optionally present in the product in advance being removed according to methods known in the literature and the sequence of the steps of complexing with radioactive isotopes and coupling to T being able to be interchanged.
As hydroxy protecting groups, e.g., the benzyl, 4-methoxybenzyl, 4-nitrobenzyl, trityl, diphenylmethyl, trimethylsilyl, dimethyl-t-butylsilyl and diphenyl-t-butylsilyl groups are suitable. In the case of polyols, the hydroxy groups can also be protected in the form of ketals with, e.g., acetone, acetaldehyde, cyclohexanone or benzaldehyde. Further, the hydroxy groups can also be present, e.g., as THP-ether, ~-alkoxyethyl ether, MEM ether or as esters with aromatic or aliphatic carboxylic acids, such as, e.g., acetic acid or benzoic acid. The hydroxy protecting groups can be released according to methods in the literature known to one skilled in the art, e.g., by hydrogenolysis, reductive cleavage with lithium/ammonia, acid treatment of the ethers and ketals or alkali treatment of the esters ~s~e, e.g., "Protective Groups in Organic Synthesis," T.
W. Greene, John Wiley and Sons 1981).
13 2 ~3 ~
As amino protecting groups, e.g., trifluoroacetyl, t-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzoxycarbonyl and acetyl groups are suitable. The amino protecting groups can be cleaved according to methods known in the literature, e.g., by basic or acid hydrolysis, reductive cleavage with zinc in acetic acid or hydrogenolysis.
As mercapto protecting groups, Cl_6 alkyl radicals or benzylthioether are suitable. The cleavage of the mercapto protecting groups takes place selectively with alkali alkylthiolates, alkali alcoholates or alkali metals, preferably with sodium methylthiolate in a polar solvent, preferably in HMPT, DMF or dimethylacetamide or by reductive cleavage with sodium/ammonia.
The functional group in radical A is suitable for producing a stable compound to proteins or other selectively accumulating molecules. By the corresponding selection of the functional group in radical A, the coupling is possible under gentle reaction conditions, which do not influence the biological function and/or selectivity.
The coupling to the desired compounds also takes place according to methods known in the art (e.g., Fritzberg et al.; J.
Nucl. Med.: 26, 7 [1987]~, for example, by reaction of the corresponding functional groups in radical A with nucleophilic groups of the selectively accumulating molecule or, if a nucleophile is involved in the corresponding functional group in radical A itself, with activated groups of the selectively accumulating molecule.
The functional group in radical A represents every substituent which on the one hand allows a coupling to a selectively accumulating molecule under mild conditions (e.g., by acylation or amidation) as well as every activated group, which can react with nucleophilic groups of proteins, antibodies, hormones or other biomolecules, such as the amino, phenol, sulfhydryl, formyl or imidazole group. By activated group is to be understood a function which is capable of reacting with the formation of a conjugate with a nucleophilic substituent of a selectively accumulating molecule or of the complex ligand itself in aqueous solution within a suitably short time, under reaetion conditions which entail neither denaturation nor loss of the biologieal activity. Examples in this respect are imide esters, alkylimide esters, amidoalkylimide esters, succinimide esters, acylsuccinimides, phenol esters, substituted phenol esters, tetrafluorophenol esters, anhydrides, and Michael acceptors. The functional group in radical A is preferably an activated ester (sueh as phenol or imide ester), a mereaptan or isothioeyanate, in particular for the eoupling with nucleophilic groups of amino aeids or an aliphatic or aromatie primary amine for the eoupling to earbohydrate radieals of proteins.
If a nucleophile is involved in the functional group in radieal A itself, it ean reaet with aetivated groups of a seleetively aceumulating moleeule, and groups of the molecule reaeted with so-called "crosslinking reagents" are also enelosed, such as homobifunctional imido esters, homobifunetional N-hydroxysueeinimide esters (NHS) and heterobifunctional ~ ~ ~ 2 ~
"crosslinkers," which contain various functional groups, such as NHS esters, pyridyl disulfides and activated halogens, such as ~-keto halides. Such crosslinkers are commercially available.
As coupling participants (= compound T), i.a., various biomolecules are provided: ligands, which bind to specific receptors and thus can detect a tissue changed in its receptor density; they include, i.a., peptide and steroid hormones and neurotransmitters. With ligands for steroid hormone receptors, the possibility of an improved diagnosis of breast and p~ostate carcinomas was demonstrated (S. J. Brandes & J. A.
Katzenellenbogen, Nucl. Med. Biol. 15: 53, 1988~. Often, ligands labeled with positron-emitting isotopes for neuroreceptors were able to be used for diagnosis of various brain diseases (J. J.
Forst, Trends in Pharmacol. Sci. 7: 490, 1987). Other biomolecules are metabolites able to infiltrate the metabolism of the cells, which make a changed metabolism recognizable; they include, for example, fatty acids, saccharides, peptides and amino acids. Fatty acids coupled to the more unstable N2S2 chelating agents were described in EPA 0 200 492. Other metabolism products such as saccharides (dexoxyglucose), lactate, pyruvate and amino acids (leucine, methylmethionine, glycine) were used with the help of the PET technique for graphic representation of changed metabolic processes (R. Weinreich, Swiss Med. 8, 10, 1986). Also, nonbiological substances such as misonidazole and its derivatives, which in tissues or tissue parts with reduced oxygen concentration bind irreversibly to cell ' components, can be used for specific accumulation of radioactive 16 2~ 3 isotopes and thus graphic representation of tumors or ischemic regions (M. E. Shelton, J. Nucl. Med. 30: 351, 1989). Finally, the coupling of the bifunctional chelating agents to monoclonal antibodies or their fragments is also possible. The compounds according to the invention containing biotin make possible the bonding of the radioactive conjugates to substances containing avidin or streptavidin. This can be used to accumulate antibody-streptavidin conjugates on the tumor and only later to administer the radioactive biotin-containing components, which results in a reduced exposure of the patient to radioactive radiation (D. J.
Hnatowich et al., J. Nucl. Med. 28: 1294, 1987). By complexing the conjugates with Tc-99m or rhenium isotopes, a diagnosis and treatment of tumors can be made possible.
It is unimportant whether a labeling of the chelating agents with Tc-99m or a rhenium isotope is performed before or after the coupling to the selectively accumulating molecule. But for a coupling to the selectively accumulating molecule after a complexing, it is a prerequisite that the reaction of the radioactive complex with the accumulating compound occurs quickly, under gentle conditions and almost quantitatively, and no subsequent purification is necessary.
The production of the pharmaceutical agents according to the invention takes place in a way known in the art, by the complexing agents according to the invention being dissolved while adding a reducing agent, preferably tin ~II) salts such as tin chloride or tin tartrate -- and optionally by adding the 17 ~ 3 additives usual in galenicals -- in aqueous medium and then being sterilized by filtration.
Suitable additives are, for example, physiologically harmless buffers (e.g., tromethamine), small additions of electrolytes (e.g., sodium chloxide), stabilizers ~e.g., gluconate, phosphates or phosphonates). The pharmaceutical agent according to the invention is present in the form of a solution or in freeze-dried form and is mixed shortly before the administration with a solution of Tc-99m pertechnetate, eluted from commercially available generators, or a perrhenate solution.
In the nuclear medical in vivo use, the agents according to the invention are provided in amounts of 1 10-5 to 5 104 nmol/kg of body weight, preferably in amounts between 1 10-3 and 5-102 nmol/kg of body weight. Starting from an average body weight or 70 kg, the amount of radioactivity for diagnostic uses is between 0.05 and 50 mCi, preferably 5 to 30 mCi per administration. For therapeutic uses, between 5 and 500 mCi, preferably 10-350 mCi is administered. The administration is normally performed by intravenous, intraarterial, peritoneal or intratumoral injection of 0.1 to 2 ml of a solution of the agent according to the invention. The intravenous administration is preferred.
The following examples are used to explain the object of the invention in more detail.
18 ;~ ?.'~1 r~
Example 1:
2-Methvl-2-(4-nitrobenzyl)-malonic acid dimethvl ester ~1l 11.5 g (0.5 mol) of sodium under a nitrogen stream is added in a dry three-necked flask holding 1000 ml with a reflux condenser and drying tube as well as a dropping funnel with pressure compensation. Then, 350 ml of methanol is carefully instilled and stirred until the sodium is completely dissolved.
In the still warm sodium methanolate solution, the methanolic solution of 87 g (0.5 mol) of methylmalonic acid diethyl ester is instilled very slowly. After completion of the addition, it is stirred for another 30 minutes and then the 4-nitrobenzyl bromide is added in portions with the help of a powder funnel. After everything has dissolved, it is first refluxed for 2 hours and then stirred overnight at room temperature. The solvent is drawn off on a rotary evaporator, the residue is mixed with water and extracted several times with ethyl acetate (250 ml each time).
The combined organic extracts are washed with saturated common salt solution and dried on sodium sulfate. After removal of the solvent, pale yellow crystals remain. The recrystallization takes place from dimethylformamide (DMF)/water.
Melting point: 94.5 - 95.0C
Yield: 74~
H-NMR data in DMSO/TMS
1.4 ppm (s,3H,Me); 3.5 ppm (s,2H,CH2Ar); 3.8 ppm (s,6H,MeOOC); 7.2 ppm (d,2H,ArH); 8.2 ppm (d,2H,ArH) 19 2~S~2~ 3 2-Methyl-2-(4-nitrobenzvl~-malonic acid diamide r21 5.0 g of ester [1] is weighed in in a 500 ml round-bottom flask and dissolved in 200 ml of methanol. In this methanolic solution, ammonia is introduced to saturation, then the catalytic amount of sodium is added and after completion of the gas generation, the flask is closed with a suction piece with balloon and allowed to stand for at least 1 we~k at room temperature.
After several days, a white precipitate precipitates. After all the feedstock is reacted (DC control), the precipitated precipitate is suctioned off and the remaining solution is cooled in the freezer to -20C and again suctioned off. The mother liquor is further concentrated by evaporation on a rotary evaporator and the precipitated precipitate is again suctioned off. The recrystallization of the combined crystal fractions takes place from acetonitrile. The white crystalline product is dried in a vacuum dessicator.
Melting point: 179C
Yield: 91%
H-NMR data in DMSO/TMS
1.2 ppm (s,3H,Me); 3.3 ppm (s,2H,CH2Ar); 7.1 ppm (s(br),4H,CONH2); 7.3 ppm (d,2H,ArH); 8.1 ppm (d,2H,ArH) 2-Methyl-2-(4-nitrobenzvl)-1.3-proPanediamine ~31 Diamide C2] (5.0 g) is suspended with exclusion of atmospheric moisture in 25 ml of abs. tetrahydrofuran in a 250 ml two-necked flask with a reflux condenser and drying tube as well as a septum. The flask is cooled down in an ice bath and then 3 ~ ~ r,~ ,~
the borane solution in THF is added with the help of a 20 or 50-ml one-way syringe by the septum. After the necessary amount of the borane solution (80 ml of a 1 M solution in THF) was added, it was allowed to heat to room temperature. After 30 minutes, the mixture is refluxed for 4 hours. After cooling to room temperature, the excess of borane is hydrolyzed carefully with water (a total of 16 ml of water). After completion of the gas generation, the reaction mixture is converted quantitatively in a 500 ml round-bottom flask and the solvent is drawn off carefully on a rotary evaporator, a white precipitate remains. This precipitate is mixed with 125 ml of 6 N HCl and refluxed for 3 hours. Then, the hydrochloric acid is drawn off slowly on a rotary evaporator. The residue is taken up in the minimum amount of water (about 50-70 ml) and added to a prepared ion exchanger column (strongly basic) and the pure amine is eluted with distilled water. The free diamine is collected (pH control) and the combined fractions are concentrated by evaporation on a rotary evaporator. A pale yellow oil remains as residue.
Melting point (hydrochloride): 270C
Yield: 80%
H-NMR data in DMS0/TMS
1.0 ppm (s,3H,Me); 2.9 ppm (m,4H,CH2NH2); 3.0 ppm (s,2H,CH2Ar); 7.5 ppm (d,2H,ArH); 8.2 ppm (d,2H,ArH); 8.5 ppm (s(br),4H,NH2) 2-Methvl-2-(4~-nitrobenzvl~-N N~-propYlene-bis- r ( 5-sulfo~salicYlidenaminel r4~
A solution of 5.~ g of diamine [3] in 100 ml of 50~ ethanol is adjusted with acetic acid to pH 5-6. 8.6 g of 5-sulfosalicylaldehyde and 1.9 g of sodium cyanoborohydride are added to this solution and stirred overnight~ After cooling to 0C, it is adjusted with semiconcentrat~d hydrochloric acid to pH
2 and concentrated by evaporation. The residue is neutralized with saturated potassium carbonate solution and then freeze-dried. The residue is extracted with DMF/MeOH. After removal of the solvent, a crystalline residue remains which is recrystallized from acetonitrile/water.
Yield: 56%
H-NMR data in DMSO/TMS
0.9 ppm (s,3H,Me); 2.5 ppm (m,4H,CH2NH); 2.8 ppm (s,2H,CH2Ar); 4.1 ppm (m,4H,ArCH2NH); 7.0-7.8 ppm (m,8H,ArH); 8.2 ppm (d,2H,ArH) 2-Methyl-2-(4'-aminobenzyl)-N.N'-ProPYlene-bis-r(5-sulfo)salicylidenamine] r5]
40 mg of 10% Pd/C in 50 ml of MeOH is suspended i~ a 100 ml two-necked flask and saturated with hydrogen. Then, the solution of 595 mg [4] (1 mmol) in 5 ml of methanol and 1.6 ml of 6N
hydrochloric acid is added with a one-way syringe by a septum.
After completion of the absorption of hydrogen, it is separated from the catalyst and the solvent is drawn off in a vacuum.
White crystals remain. The recrystallization takes place from methanol.
Yield: 76%
H-NMR data in DMS0/TMS
1.0 ppm (s,3H,Me); 2.5 ppm tm,4H,CH2NH); 2.8 ppm (s,2H,CH2Ar); 4.2 ppm (m,4H,ArCH2NH); 7.0-7.8 ppm (m,lOH,ArH) 2-Methyl-2-(4-isothiocyanatobenzyl)-N~N'-~roPYlelle-bis- r ( 5-sulfo)salicylidenaminel r61 An 85go solution of thiophosgene in carbon tetrachloride (0.2 ml, 2.23 mmol) is added to the solution of 280 mg [5] (0.5 mmol) in 4 ml of hydrochloric acid (3 M). The reaction mixture is stirred for 3 hours at room temperature and then evaporated to dryness in a vacuum.
Yield: 78%
H-NMR data in DMS0/TMS
1.0 ppm (s,3H,Me); 2.8 ppm (m,4H,CH2NH); 3.0 ppm (s,2H,CH2Ar); 4.2 ppm (m,4H,ArCH2NH); 7.0-7.8 ppm (m,lOH,ArH) Example 2:
2-(4-Nitrobenzy~L-malonic acid diethvl ester r71 21.4 g of lithium diisopropylamide is added to 210 ml of anhydrous tetrahydrofuran under a nitrogen stream in a dry three- `
necked flask with a drying tube and dropping funnel with pressure compensation. Then, 58.0 g of malonic acid diethyl ester in 100 ml of anhydrous tetrahydrofuran is instilled at room temperature within 40 minutes. After 30 minutes, the reaction solution is 23 ~ s3 cooled to -62C and 39.1 g of 4-nitrobenzyl bromide in tetrahydrofuran is instilled slowly with vigorous stirring, it is stirred for another hour at -62C and then the formed precipitate is filtered off cold. The filtrate is concentrated by evaporation on a rotary evaporator, the residue is brought into solution in 300 ml of ethanol at 65C and separated from the insoluble residue. After cooling, 34.7 g of pale yellowish crystals are obtained.
Yield: 65%
H-NMR data in CDC13/TMS
1.2 ppm (t,6H,CH2CH3); 3.3 ppm ~d,2H,CH2Ar); 3.6 ppm (t,lH,CH); 4.1 ppm (q,4H,CH2CH3); 7.4 ppm (d,2H,ArH); 8.1 ppm (d,2H,ArH) 2-(4-Nitrobenzyl)-malonic acid diamide r 8~
This compound is produced corresponding to compound t2].
Yield: 98%
H-NMR data in DMSO/TMS
3.1 ppm (d,2H,CH2Ar); 3.4 ppm (t,lH,CH); 7.1 ppm (s,4H,NH2); 7.4 ppm (d,2H,ArH); 8.2 ppm (d,2H,ArH) 2-(4-Nitrobenzyl)-1~3-ProPanediamine r91 This compound is produced corresponding to compound t3].
Yield: 76%
lH_NMR data in D20 1.3 ppm (t,lH,CH); 3.1 ppm (d,4H,CH2NH2); 3.2 ppm (d,2H,CH2Ar); 7.5 ppm (d,2H,ArH); 8.2 ppm (d,2H,ArH) 2-(4'-Nitrobenzyl)-N,N'-Pro~ylene-bis- r ( 5-sulfo)salicylideniminel r10]
A solution of 9.5 g of 5-sulfosalicylaldehyde in 75 ml of ethanol abs. is instilled in a solution of 5.6 g of diamine t9~
in 75 ml of ethanol abs. with stirring. The resulting solution is slowly discolored intensively yellow. It is stirred for another 3 hours at room temperature, in this way, a more yellow precipitate precipitates, which is filtered off after cooling to -20C.
Yield: 68%
H-NMR data in DMSO/TMS
1.5 ppm (m,lH,CH); 3.2 ppm (d,2H,CH2Ar); 3.5 ppm (m,4H,CH2N=C); 7.1-7.9 ppm (m,8H,ArH); 8.2 ppm (d,2H,ArH); 8.6 ppm (s,2H,CH=N) 2-(4~-Nitrobenzvl)-N.N'-proPylene-bis-~(5-sulfo)salicvlidenamine~
rlll 500 mg of sodium borohydride is added to a solution of 2 g of diimine [10] in 50 ml of 50% ethanol with stirring and stirred for 4 hours at 0C. Then, 20 ml of water is instilled and stirred for 1 hour at room temperature, then the solvent is drawn off on a rotary evaporator and brought to pH 11 with a saturated potassium carbonate solution. The residue is taken up in 2 ~ ~ 2 ~
methanol and filtered by a short column (RP-18~. After drying on sodium sulfate and removal of the solvent, a crystalline residue remains.
Yield: 80%
H-NMR data in DMS0/TMS
1.6 ppm (m,lH,CH); 2.S ppm (m,4H,CH2NH); 2.9 ppm (d,2H,CH2Ar); 4.0 ppm (m,4H,ArCH2NH); 7.1-7.8 ppm (m,8H,ArH); 8.2 ppm (d,2H,ArH) Cu-2-t4'-Nitrobenzvl)-N,N'-propylene-bis- r ( 5-sulfo)salicYlidenaminel L 121 400 mg of copper acetate (2 mmol) in 20 ml of methanol is instilled in a suspension of 1.63 g [11] (2 mmol~ in 50 ml of methanol and stirred at room temperature. After removal of the solvent and drying, a crystalline residue remains.
Yield: 66~
Cu-2-t4'-AminobenzYl)-N,N'-~troPvlene-bis- r f 5~
sulfo)salicvlidenaminel r 13l This compound is produced corresponding to compound [5].
Yield: 78~
cu-2 - [ 4'-Biotincarbamovl)benzyll-N N'-Pro~vlene-bis- r ( 5-sulfo)salicvlidenaminel r141 680 mg of NHS-biotin (2 mmol) is added to a solution of 615 mg [13] (l mmol) in lO ml of DMS0 with stirring and heated for 3 hours to 50C. After cooling to room temperature, it is stirred 26 2 ~ 3 for another 15 hours. Then, the solvent is drawn off in a vacuum and the residue is purified by MPLC (sili~a gel, dichloromethane/ethanol/concentrated ammonia 10:20:1) Yi~ld: 38~
2-r4'-(Biotincarbamoyl~benz~ N N'-~ro~ylene-bis-r(5-sulfo)salicylidenaminel t151 500 mg of potassium cyanide is added to a solution of 500 mg [14] in 70 ml of water at 40C and stirred for another 2 hours.
Then, it is concentrated by evaporation to about 10 ml and the residue is purified by MPLC (silica gel, acetonitrile/concentrated ammonia 40:3).
Yield: 46%
H-NMR data in DMS0/TMS
1.3-1.7 ppm (m,7H,CH2+CH); 2.3 ppm (t,2H,CH2C0); 2.8 ppm (m,2H,CH2S); 3.0 ppm (s,2H,CH2Ar); 3.1 ppm (m,lH,CHS); 4.1 ppm (m,lH,CHNHC0); 4.3 ppm (m,5H,ArCH2NH+CHNHC0); 6.9 ppm-7.8 ppm (m,lOH,ArH).
Example 2a Tc-99m Complex of ~151 5.6 * 10-3 mol of potassium tartrate in 1 ml of H20, 4.8 *
10-8 mol of tin chloride in 1 ml of H2O and 5 mCi of Tc-99m pertechnetate are added to a solution of 1.86 * 10-6 mol ~15] in 1 ml of EtOH/H20 1:9 and incubated for 10 minutes. The corresponding technetium complex is obtained in a ~urity greater than 90%.
Example 3 2-(4'-NitrobenzYl)-N N'-pro~vlene-bis-[(5-carboxy)salicylidenamine] r 16]
This compound is produced corresponding to compound [4].
Yield: 66%
H-NMR data in DMS0/TMS
0.9 ppm (s,3H,Me); 2.5 ppm (m,4H,CH2NH); 2.8 ppm (s,2H,CH2Ar); 4.2 ppm (m,4H,ArCH2NH); 6.9-8.0 ppm (m,8H,ArH); 8.2 ppm (d,2H,ArH) Cu-2-t4'-Nitrobenzyl)-N.N'-Propvlene-bis-[t5-carboxY)salicylidenaminel r171 This compound is produced corresponding to compound [12].
Yield: 74%
Cu-2-t4'-AminobenzYl)-N,N'-proPYlene-bis- r 5-(carboxy)salicylidenaminel r181 This compound is produced corresponding to compound [13].
Yield: 69%
Cu-2- r 4~-tBiotincarbamoyl)benzyll-N~Nr-propylene-bis- r ( 5-carboxv)salicYlidenaminel [191 This compound is produced corresponding to compound [14].
Yield: 43~
2 ~ 3 2- r 4'-(Biotincarbamovl)be_zYll--N.N'-propYlene-bis- r ( s-carboxY)salicYlidenaminel l2ol This compound is produced corresponding to compound ~15].
Yield: 49%
H-NMR data in DMS0/TMS
1.3-1.7 ppm (m,7H,CH2~CH); 2.3 ppm (t,2H,CH2C0); 2.8 ppm (m,2H,CH2S); 3.0 ppm ~s,2H,CH2Ar); 3.1 ppm (m,lH,CHS); 4.1 ppm (m,lH,CHNHCO); 4.2 ppm (m,5H,ArCH2NH+CHNHCO); 6.9 ppm-8.1 ppm (m,lOH,ArH).
Example 4 2-Bromomethyl-5-nitrobenzoic acid r 211 20 ml of bromine is slowly instilled in 72 g of 2-methyl-5-nitrobenzoic acid and 100 mg of dibenzoyl peroxide in 250 ml of carbon tetrachloride under irradiation with a 500 W incandescent lamp. The reaction mixture is refluxed for 24 hours, the solvent is drawn off after cooling, taken up in dichloromethane, washed several times with water, dried and concentrated by evaporation.
The resid~e is chromatographically purified (silica gel, dichloromethane).
Yield: 56~
H-NMR data in CDC13/TMS
4.4 ppm (s,2H,CH2); 8.3-8.5 ppm (m,3H,ArH).
(2-CarboxY-4-nitrobenzyl~malondinitrile r 221 The solution of 16.4 g of malondinitrile in 100 ml of anhydrous DMF is instilled in a suspension of 11.9 g of sodium 2 ~
hydride in 100 ml of anhydrous DMF at 0C within 3 hours. Then, 65 g of [21] in 100 ml of anhydrous DMF is instilled within 6 hours and stirred after heating to room temperature for another 12 hours. The reaction mixture is hydrolyzed with ice water, acidified and extracted with chloroform. After drying and concentration by evaporation, a crystalline residue remains, which is recrystallized from methanol.
Yield: 48%
H-NMR data in CDCl3/TMS
3.5 ppm (d,2H,CH2Ar); 3.8 ppm (t,lH,CH); 8.3-8.5 ppm (m,3H,ArH).
2-(2-Carboxv-4-nitrobenzvl)-1 3-propanediamine ~23l 19 g of sodium borohydride is slowly added to a solution of 12 g of [22] (0.05 mol) and 24 g of cobalt chloride hexahydrate (0.1 mol) in 300 ml of 99~ methanol at -15C and then stirred for another 3 hours. After adding lOO ml of 3N hydrochloric acid, the solvent is distilled off for the most part, the remaining aqueous phase is alkalized with saturated potassium carbonate solution and extracted several times with dichloromethane. After drying and concentration by evaporation, a residue remains which is recrystallized from ethanol.
Yield: 59%
H-NMR data in DMSO
1.3 ppm (t,lH,CH2); 3.1 ppm (d,2~,CH2NH2); 3.~ ppm (d,2H,CH2Ar); 8.3-8.5 ppm (m,3H,ArH) ~ ~ ~ 2 ~ ~ 3 2- r 2'-Carboxy-(4'-nitrobenzyl)l-N,N'-pro~ylerle-bis-salicylidenamine [241 This compound is produced corresponding to compound [4].
Yield: 62%
H-NMR data in CDC13/TMS
1.6 ppm (m,lH,CH); 2.5 ppm (m,4H,CH2NH); 3.0 ppm (d,2H,CH2Ar); 3.9 ppm (m,4H,ArCH2NH); 6.9 ppm (m,4H,ArH); 7.1-7.3 ppm (m,4H,ArH); 8.3-8.4 ppm (m,3H,ArH) 2- r 2'-Carboxv-(4'-aminobenzyl)~-N,N'-propvlene-bis-salicvlidenamine r251 This compound is produced corresponding to compound [5].
Yield: 85%
H-NMR data in DMSO/TMS
1.5 ppm (m,lH,CH); 2.5 ppm (m,4H,CH2NH2); 2.9 ppm (t,2H,CH2Ar); 4.1 ppm (m,4H,ArCH2NH); 6.8-7.4 ppm (m,llH,ArH) 2-r2'-Carboxv-(4'-isothiocyanatobenzyl)l-N N'-propylene-bis-salicylidenamine r261 This compound is produced corresponding to compound [6].
Yield: 77%
H-NMR data in DMSO/TMS
1.5 ppm (m,lH,CH); 2.9 ppm (m,5H,CH2NH+CH2Ar); 3.0 ppm (s,2H,CH2Ar); 4.1 ppm (m,4H,ArCH2NH); 6.8-7.4 ppm (m,llH,ArH).
3 1 ~ 2 '.
E~ample 5 6-(2'-Carboxy-4'-nitrobenzyl)-3 3 9,9-tetramethYl-4 8-diazaundecane-2 10-dione-dioxime [271 13 g of diamine [23] is dissolved in 90 ml of methanol and cooled to 0C, then 6.5 g of 2-chloro-2-methyl-3-nitrosobutane is added with stirring. After heating to room temperature, it is stirred for 2 hours, refluxed for another 2 hours, the solvent is drawn off and the remaining solid is dissolved in water. It is neutralized with sodium bicarbonate, concentrated by evaporation, and the remaining residue is recrystallized from ethanol.
Yield: 38%
H-NMR data in DMSO/TMS
1.3 ppm (s,12H,MeCNH); 1.8 ppm (s,6H,MeC=N); 2.4 ppm (m,lH,CH~; 2.5 ppm (m,4H,CH2NH); 2.9 ppm (d,2H,CH2Ar); 8.2-8.4 ppm (m,3H,ArH); 10.8 ppm (s,2H,HON=C) 6-(2'-Carboxy-4'-aminobenzyl)-3 3 9 9-tetramethyl-4.8-diazaundecane-2 10-dione-dioxime r 281 500 mg of nitro compound [27] is dissolved in 50 ml of 50%
methanol (pH 11~ and hydrogenated at room temperature with adding 25 mg of Pd/Alox. After separating the catalyst and concentration by evaporation, a crystalline solid remains.
Yield: 49%
lH_NMR data in D2O
32 2 ~ ~i 2 ~, g L;3 1.2 ppm (s,12H,MeCN~I); 1.7 ppm (s,6H,MeC=N); 1.9 ppm (m,lH,CH); 2.5 ppm ~m,4H,CH2NH); 2.5 ppm (d,2H,CH2Ar); 6.7 ppm (d,lH,ArH); 7.3 ppm (m,2H,~rH) Cu-6-(2'-Carboxy-4'-aminobenzvl)-3,3,9,9-tetramethyl-4.8-diazaundecane-2,10-dione-dioxime ~291 This compound is produced corresponding to compound [12].
Yield: 58%
Cu-6- r 2'-CarboxY-4'-(biotincarbamoyl)benzyll-3,3,9,9-tetramethvl-4 8-diazaundecane-2,10-dione-dioxime t301 This compound is produced corresponding to compound [14].
Yield: 34%
6-(2'-Carboxy-4'-biotincarbamoyl)benzvll-3 3,9 9-tetramethyl-4 8-diazaundecane-2 10-dione dioxime r311 This compound is produced corresponding to compound [15]~
Yield: 41%
Tc-99m Complex of ~311 3.2 * 10-3 mol of potassium tartrate in 1 ml of H2O~ 4 0 *
10-8 mol of tin chloride in 1 ml of H2O and 5 mCi of Tc-99m pertechnetate are added to a solution of 1.86 * 10-6 mol of t31]
in 1 ml of EtOH/H2O 1:4 and incubated for 10 minutes. The corresponding technetium complex is obtained in a purity greater than 90%.
2 ~ 3 ~
Example 6 2-Meth~l-2- r 4'-nitrobenzoyll-malonic acid dimethyl ester [32]
5 ml of carbon tetrachloride is added to the mixture of 24.3 g of magnesium chips (1 mol) in 50 ml of anhydrous ethanol~
Then, a solution of 174 g of methylmalonic acid diethyl ester (1 mol) in 100 ml of ethanol and 400 ml of anhydrous ether is instilled so that the mixture boils vigorously. After dissolution of the magnesium, 185 g of 4-nitrobenzoyl chloride in lO0 ml of anhydrous ether is instillad under ice cooling and stirred for another 12 hours. It is hydrolyzed under ice cooling, the ether phase is separated, extracted several times with ether, washed neutral, dried and concentrated by evaporation. After distillation in a vacuum, the pure product is obtained.
Yield: 78%
H~NMR data in CDCl3/TMS
1.2 ppm (m,9H,Me); 4.1 ppm (q,4H,CH2Me~; 8.1-8.3 ppm (m,4H,ArH) 2-Methyl-2- r 4'-nitrobenzoYl]-malonic acid [33]
41 g of [32] (127 mmol) is dissolved in 200 ml of methanol and a solution of 28.3 g of NaOH (708 mmol) in 50 ml of water is slowly instilled in it. Then, it is heated for 2 hours in a water bath to 50C, the solvent is drawn off on a rotary evaporator and the residue is taken up in water. It is acidified with semiconcentrated hydrochloric acid and the fre'e carboxylic acid is extracted with chloroform, washed and dried.
Yield: 80%
H-NMR data in DMS0/TMS
1.2 ppm (s,3H,Me); 8.1-8.3 ppm (m,4H,ArH) 2-Methyl-2- r 4'-nitrobenzovll-malonic acid chloride r 34l The mixture of 3.40 g of [333 and 8.9 g of thionyl chloride and one drop of DMF is heated to boiling under exclusion of moisture with stirring. After completion of the gas generation, the excess thionyl chloride is drawn off at room temperature in a vacuum and the residue is distilled in a vacuum.
Yield: 91%
N N'-bis r ( 2-(Benzylthio)benzyll-2-methyl-2-(4'-nitrobenzovl)malonic acid diamide ~35l 7.4 g of [34] (24.3 mmol) in 100 ml of dichloromethane is carefully instilled in the mixture of 10.5 g of (2-mercaptobenzyl)benzylamine (48.6 mmol) and 5.06 g of triethylamine (50 mmol) in 100 ml of dichloromethane with exclusion of moisture. It is stirred for another 3 hours at room temperature, then first water is added and extracted several times with chloroform. The organic phase is washed in succession with lN hydrochloric acid, saturated potassium carbonate solution and water and dried on sodium sulfate.
Yield: 64%
H-NMR data in CDCl3/TMS
1.2 ppm (s,3H,Me); 4.1 ppm (sj8H,ArCH2S+ArCH2NH); 7.1-7.6 ppm (m,18H,ArH); 8.3 ppm (m,4H,ArH).
~ 2 ~
N N'-bis~r2-Benzylthio)benzyll-2-meth~1-2- r hvdroxY-(4-nitrophenyl)-methyll-malonic acid diamide r361 5.7 g of sodium borohydride is added to a solution of 66 g (100 mmol) of [35] in 50 ml of ethanol and stirred for 2 hours at room temperature. It is substantially concentrated by evaporation and the residue is mixed with 50 ml of water and neutralized. It is extracted with ether, washed with saturated common salt solution, dried and concentrated by evaporation.
Yield: 77%
H-NMR data in DMSO/TMS
1.4 ppm (s,3H,Me); 4.1 ppm (s,8H,ArCH2S+ArCH2NH); 4.3 ppm ~m,lH,CHOH); 7.1-7.6 ppm (m,20H,ArH); 8.2 ppm (m,2H,ArH).
N,N'-bisr(2-Benzylthio)benzY11-2-methYl-2-~hYdroXV-(4-nitrophenyl)methYl)1-1~3-Propanediamine r 371 This compound is produced corresponding to compound [3].
H-NMR data in CDC13/TMS
1.5 ppm (s,3H,Me); 2.5 ppm (m,4H,CH2NH); 4.1 ppm (s,4H,ArCH2NH); 4.3 ppm (m,lH,CHOH); 7.0-7.5 ppm (m,lOH,ArH); 8.2 ppm (d,lH,ArH).
N~N~-bis(2-Mercaptobenzyl)-2-methyl-2-[hYdroxy-(4-nitrophenyl)methY~ 3-propanediamine r 381 3.5 g of sodium is carefully added to a solution, cooled to -50C, of 4.3 g of [37] in 50 ml of THF and 100 ml of li~uid ammonia and stirred for 4 hours. Excess sodium is carefully 36 ~ 2 /~
destroyed with ammonium chloride and then allowed to heat slowly to room temperature. The residue is taken up in water and extracted several times with dichloromethane, the organic phase is dried and concentrated by evaporation.
Yield: 62%
H--NMR data in CDC13/TMS
1.5 ppm (s,3H,Me); 205 ppm (m,4H,CH2NH); 4.1 ppm (s,4H,ArCH2NH); 4.3 ppm (m,lH,CHOH); 7.0-7.5 ppm (m,lOH,ArH); 8.2 ppm (d,lH,ArH).
N N'-bis(2-Mercaptobenzyl)-2-methyl-2- r hvdroxv-(4-aminopheny-llmethvl)~ 3-propanediamine r 391 This compound is produced corresponding to compound [5].
Yield: 89%
H-NMR data in CDC13/TMS
l.S ppm (s,3H,Me); 4.1 ppm (s,4H,ArCH2NH); 4.3 ppm (m,lH,CHOH); 7.0-7.7 ppm (m,llH,ArH).
N,N'-bis(2-MercaptobenzYl)-2-methyl-2-~hydroxv-(4-isothiocvanatophenvl)methyl~ 3-propanediamine r401 This compound is produced corresponding to compound [6].
Yield: 49%
H-NMR data in CDC13/TMS
1.5 ppm (s,3H,Me); 4.1 ppm (s,4H,ArCH2NH); 4.2 ppm (m,lH,CHOH); 7.0-7.6 ppm (m,llH,ArH).
37 2 ~
Example 7 N N' bis r ( 2-Benzvlthio-3-pyridyl)methyll-2~methvl-2-(4'-nitrobenzyl)malonic acid diamide ~411 This compound is produced corresponding to compound [35].
Yield: 60%
H-NMR data in CDC13/TMS
1.2 ppm (s,3H,Me); 3.5 ppm (s,2H,CH2Ar); 4.1 ppm (s,8H,ArCH2S+ArCH2NH); 7.1-7.5 ppm (m,14H,ArH); 8.3-8.S ppm (m,6H,ArH).
N~N~-bisr(2-Benzylthio-3-pyridyl3methyll-2-methyl-2-(4~-nitrobenzyl)-1 3-propanediamine L4 21 This eompound is produeed eorresponding to eompound [3].
Yield: 57%
H-NMR data in CDC13/TMS
1.0 ppm (s,3H,Me); 2.5 ppm (m,4H,CH2NH); 2.9 ppm (s,2H,CH2Ar); 4.1 ppm (s,8H,ArCH2NH+ArCH2S~; 7.1-7.5 ppm (m,14H,ArH); 8.3-8.5 ppm (m,6H,ArH).
N N'-bis r t2-MereaPto-3-pyridYl)methyll-2-methyl-2-(4 nitrobenzyl)-1~3-Propanediamine r431 This eompound is produeed eorresponding to eompound [38].
Yield: 65%
H-NMR data in CDC13/TMS
1.0 ppm (s,3H,Me); 2.5 ppm (m,4H,CH2NH); 2.9 ppm (s,2H,CH2Ar); 4.1 ppm (s,4H/ArCH2NH); 7.0-7.5 ppm (m,4H,ArH);
8.2-8.5 ppm (m,6H,ArH).
38 ~ 3 N N'-bis[~2-Mercapto-3-pyridyl ! methyll-2-methyl-2-(4-aminobenzyl~-1 3-propanediamine r 441 This compound is produced corresponding to compound [S].
Yield: 89%
EI-NMR data in CDC13/TMS
1.0 ppm (s,3H,Me~; 2.5 ppm (m,4H,CH2NH); 2.8 ppm (s,2H,CH2Ar); 4.1 ppm (s,4H,ArCH2NH); 7.0-7.7 ppm (m,6H,ArH);
8.3-8.5 ppm (m,4H,ArH).
N,N'-bis~(2-Mercaptopyridyl)methyll-2-methyl-2-(4-isothiocyanatobenzvl)-1,3-propanediamine r451 This compound is produced corresponding to compound t6].
Yield: 46%
H-NMR data in CDC13/TMS
1.0 ppm (s,3H,Me); 2.5 ppm (m,4H,CH2NH); 2.8 ppm (s,2H,CH2Ar); 4.1 ppm (s,4H,ArCH2NH); 7.0-7.7 ppm (m,6H,ArH);
8.3-8.5 ppm (m,4H,ArH).
Example 8 Couplinq and labelinq of a chelatinq aqent containing isothiocyanate to proteins The coupling of Tc-chelating agents containing isothiocyanate of compound [6] to proteins is to be described by the example of F(ab)2 fragments of monoclonal antibody 17-lA.
Instead of antibody fragments, any other protein or a substance containing amino groups can be used. ~
39 c~ 2~,s~
Monoclona] antibody 17-lA is obtained according to methods known in the literature after administration of 107 of the corresponding hybridoma cells in the abdominal space of a BALB/c-mouse and aspiration of ascitic liquid after 7-10 days. The purification takes place also according to methods known in the literature by precipitation of ammonium sulfate and affinity chromatography by protein A-Sepharose. The purified antibody (10 mg/ml) is treated at pH 3.5 for 2 hours with 25 micrograms/ml of pepsin and then isolated by FPLC. Before the coupling with the chelating agent, the fragments are dialyzed at 4C for 12-24 hours from 0.1 M of KH2PO4/0.1 M NaHC03, pH 8.5 The protein concentration is adjusted to 10 mg/ml. A 5-fold molar excess of the chelating agent containing NCS [example l] is dissolved in as little as possible of the same buffer and added to the protein solution. For conjugate formation, the mixture is incubated for 3 hours at 37C. Then, the conjugate is dialyzed for 24-48 hours with repeated buffer change from PBS (phosphate-buffered saline) and the protein concentration is then, if necessary, adjusted again to 10 mg/ml. Until labeling with Tc-9gm, the conjugate can be stored after sterilization by filtration at 4C in acid-purified glass vessels.
The labeling of 1 mg of the antibody fragment with Tc-99m coupled with chelating agent [~] takes place by adding 10 mCi of pertechnetate solution (= 1-2 ml) and 100 micrograms of tin(II) chloride in an argon-flushed Na-pyrophosphate solution (1 mg/ml) or by ligand exchange, e.g., by adding the solution of a 4 o 7~ ~ ~ 2 ~ ~ ~
commercially available glucoheptonate kit mixed with pertechnetate.
38 ~ 3 N N'-bis[~2-Mercapto-3-pyridyl ! methyll-2-methyl-2-(4-aminobenzyl~-1 3-propanediamine r 441 This compound is produced corresponding to compound [S].
Yield: 89%
EI-NMR data in CDC13/TMS
1.0 ppm (s,3H,Me~; 2.5 ppm (m,4H,CH2NH); 2.8 ppm (s,2H,CH2Ar); 4.1 ppm (s,4H,ArCH2NH); 7.0-7.7 ppm (m,6H,ArH);
8.3-8.5 ppm (m,4H,ArH).
N,N'-bis~(2-Mercaptopyridyl)methyll-2-methyl-2-(4-isothiocyanatobenzvl)-1,3-propanediamine r451 This compound is produced corresponding to compound t6].
Yield: 46%
H-NMR data in CDC13/TMS
1.0 ppm (s,3H,Me); 2.5 ppm (m,4H,CH2NH); 2.8 ppm (s,2H,CH2Ar); 4.1 ppm (s,4H,ArCH2NH); 7.0-7.7 ppm (m,6H,ArH);
8.3-8.5 ppm (m,4H,ArH).
Example 8 Couplinq and labelinq of a chelatinq aqent containing isothiocyanate to proteins The coupling of Tc-chelating agents containing isothiocyanate of compound [6] to proteins is to be described by the example of F(ab)2 fragments of monoclonal antibody 17-lA.
Instead of antibody fragments, any other protein or a substance containing amino groups can be used. ~
39 c~ 2~,s~
Monoclona] antibody 17-lA is obtained according to methods known in the literature after administration of 107 of the corresponding hybridoma cells in the abdominal space of a BALB/c-mouse and aspiration of ascitic liquid after 7-10 days. The purification takes place also according to methods known in the literature by precipitation of ammonium sulfate and affinity chromatography by protein A-Sepharose. The purified antibody (10 mg/ml) is treated at pH 3.5 for 2 hours with 25 micrograms/ml of pepsin and then isolated by FPLC. Before the coupling with the chelating agent, the fragments are dialyzed at 4C for 12-24 hours from 0.1 M of KH2PO4/0.1 M NaHC03, pH 8.5 The protein concentration is adjusted to 10 mg/ml. A 5-fold molar excess of the chelating agent containing NCS [example l] is dissolved in as little as possible of the same buffer and added to the protein solution. For conjugate formation, the mixture is incubated for 3 hours at 37C. Then, the conjugate is dialyzed for 24-48 hours with repeated buffer change from PBS (phosphate-buffered saline) and the protein concentration is then, if necessary, adjusted again to 10 mg/ml. Until labeling with Tc-9gm, the conjugate can be stored after sterilization by filtration at 4C in acid-purified glass vessels.
The labeling of 1 mg of the antibody fragment with Tc-99m coupled with chelating agent [~] takes place by adding 10 mCi of pertechnetate solution (= 1-2 ml) and 100 micrograms of tin(II) chloride in an argon-flushed Na-pyrophosphate solution (1 mg/ml) or by ligand exchange, e.g., by adding the solution of a 4 o 7~ ~ ~ 2 ~ ~ ~
commercially available glucoheptonate kit mixed with pertechnetate.
Claims (7)
1. Compounds of general formula I
(I) in which R1 stands for hydrogen or a C1-6 alkyl radical optionally substituted with one or two hydroxyl groups, R2 stands for a C1-6 alkylene radical optionally substituted with a hydroxyl group, R3 stands for a hydrogen atom, a C1-6 alkyl radical, a carboxymethyl radical or a (C1-6 alkoxycarbonyl)methyl radical, R4 stands for a hydrogen atom, a C1-6 alkyl radical optionally substituted with a hydroxyl group or for the meaning indicated under Rx, R5 stands for a hydrogen atom or a C1-6 alkyl radical optionally substituted with a hydroxyl group, B stands for a pyrrolyl radical, a substituted phenyl radical of formula II or a substituted pyridine radical of formula III
(II) (III) in which Z means a hydroxyl group, amino group or a mercapto group and Y means a hydrogen atom, a carboxy radical or a sulfonyl radical or B stands for a nitrosomethyl radical of formula IV
in which Rx means a C1-6-alkyl radical or, cyclized together with R4, is a trimethylene or tetramethylene group to form a 5- or 6-membered ring.
and A stands for an amino radical, a mercapto radical, a carboxy radical, a C2-6 alkinyl or C2-6 alkenyl radical, an oxiranyl radical, a fluorinated phenoxycarbonyl radical, a succinimidoxycarbonyl radical optionally substituted with a sodium sulfate radical, an aminophenyl radical or isothiocyanatophenyl radical, and the phenyl group optionally can be substituted in addition by a carboxy radical, a chlorosulfonyl radical or a sulfonic acid radical or contains a compound T selectively accumulating in lesions or specific tissues -- optionally bound by a bifunctional linker radical L with the help of said functional group and T stands for monoclonal antibodies or their fragments, hormones, enzymes, ligands for cell membrane receptors, neurotransmitters, lipids, steroids, saccharides, amino acids and oligopeptides, biotin, as well as radiosensitizers, such as, e.g., misonidazole, and in the case of , pyrrolyl radical or Y = H, R2 is to stand for a hydroxylated C1-6 alkylene chain or A
is to stand for a substituted aminophenyl or isothiocyanatophenyl radical, as well as their complexes with radioactive metal ions --suitable for diagnosis and treatment of tumors -- as well as their salts with inorganic and organic acids or bases.
(I) in which R1 stands for hydrogen or a C1-6 alkyl radical optionally substituted with one or two hydroxyl groups, R2 stands for a C1-6 alkylene radical optionally substituted with a hydroxyl group, R3 stands for a hydrogen atom, a C1-6 alkyl radical, a carboxymethyl radical or a (C1-6 alkoxycarbonyl)methyl radical, R4 stands for a hydrogen atom, a C1-6 alkyl radical optionally substituted with a hydroxyl group or for the meaning indicated under Rx, R5 stands for a hydrogen atom or a C1-6 alkyl radical optionally substituted with a hydroxyl group, B stands for a pyrrolyl radical, a substituted phenyl radical of formula II or a substituted pyridine radical of formula III
(II) (III) in which Z means a hydroxyl group, amino group or a mercapto group and Y means a hydrogen atom, a carboxy radical or a sulfonyl radical or B stands for a nitrosomethyl radical of formula IV
in which Rx means a C1-6-alkyl radical or, cyclized together with R4, is a trimethylene or tetramethylene group to form a 5- or 6-membered ring.
and A stands for an amino radical, a mercapto radical, a carboxy radical, a C2-6 alkinyl or C2-6 alkenyl radical, an oxiranyl radical, a fluorinated phenoxycarbonyl radical, a succinimidoxycarbonyl radical optionally substituted with a sodium sulfate radical, an aminophenyl radical or isothiocyanatophenyl radical, and the phenyl group optionally can be substituted in addition by a carboxy radical, a chlorosulfonyl radical or a sulfonic acid radical or contains a compound T selectively accumulating in lesions or specific tissues -- optionally bound by a bifunctional linker radical L with the help of said functional group and T stands for monoclonal antibodies or their fragments, hormones, enzymes, ligands for cell membrane receptors, neurotransmitters, lipids, steroids, saccharides, amino acids and oligopeptides, biotin, as well as radiosensitizers, such as, e.g., misonidazole, and in the case of , pyrrolyl radical or Y = H, R2 is to stand for a hydroxylated C1-6 alkylene chain or A
is to stand for a substituted aminophenyl or isothiocyanatophenyl radical, as well as their complexes with radioactive metal ions --suitable for diagnosis and treatment of tumors -- as well as their salts with inorganic and organic acids or bases.
2. Compounds according to claim 1, wherein radical L
optionally contained in A has been produced from bifunctional linkers such as, e.g.,
optionally contained in A has been produced from bifunctional linkers such as, e.g.,
3. Compounds according to claim 1, wherein T stands for monoclonal antibodies, their fragments, biotin or misonidazole.
4. Metal chelates according to claim 1 with coordinatively bound, radioactive ions of Tc, Re, Cu, Co, Ga, Y and In, preferably Tc and Re.
5. Use of the chelates according to claim 4 for in vivo diagnosis and treatment of tumors.
6. Pharmaceutical agents containing at least one chelate according to claim 1, optionally with the additives usual in galenicals.
7. Process for the production of compounds of general formula I
(I) in which R1 stands for hydrogen or a C1-6 alkyl radical optionally substituted with one or two hydroxyl groups, R2 stands for a C1-6 alkylene radical optionally substituted with a hydroxyl group, R3 stands for a hydrogen atom, a C1-6 alkyl radical, a carboxymethyl radical or a (C1-6 alkoxycarbonyl)methyl radical, R4 stands for a hydrogen atom, a C1-6 alkyl radical optionally substituted with a hydroxyl group or for the meaning indicated under Rx, R5 stands for a hydrogen atom or a C1-6 alkyl radical optionally substituted with a hydroxyl group, B stands for a pyrrolyl radical, a substituted phenyl radical of formula II or a substituted pyridine radical of formula III
(II) (III) in which Z means a hydroxyl group, amino group or a mercapto group and Y means a hydrogen atom, a carboxy radical or a sulfonyl radical or B stands for a nitrosomethyl radical of formula IV
(IV) in which Rx means a C1-6 alkyl radical, which optionally is cyclized together with R4 by a trimethylene or tetramethylene group to a 5- or 6-ring and A stands for an amino radical, a mercapto radical, a carboxy radical, a C2-6 alkinyl or C2-6 alkenyl radical, an oxiranyl radical, a fluorinated phenoxycarbonyl radical, a succinimidoxycarbonyl radical optionally substituted with a sodium sulfate radical, an aminophenyl radical or isothiocyanatophenyl radical, and the phenyl group optionally can be substituted in addition by a carboxy radical, a chlorosulfonyl radical or a sulfonic acid radical or contains a compound T selectively accumulating in lesions or specific tissues -- optionally bound by a bifunctional linker radical L with the help of said functional group and T stands for monoclonal antibodies or their fragments, hormones, enzymes, ligands for cell membrane receptors, neurotransmitters, lipids, steroids, saccharides, amino acids and oligopeptides, biotin, as well as radiosensitizers, such as, e.g., misonidazole, and in the case of , pyrrolyl radical or Y = H, R2 is to stand for a hydroxylated C1-6 alkylene chain or A
is to stand for a substituted aminophenyl or isothiocyanatophenyl radical, as well as their complexes with radioactive metal ions --suitable for diagnosis and treatment of tumors -- as well as their salts with inorganic and organic acids, wherein a) a 1,3-propanediamine of general formula V
(V) in which R1 and R2 have the above-mentioned meanings, and A' means A or a radical able to be converted to A
is reacted with a compound of general formula VI
B - R4C = 0 (VI) in which R4 and B have the above-mentioned meanings, in a polar solvent, preferably ethanol, or by using a water separator in a nonpolar solvent, preferably benzene, at temperatures of 25-180°C within 6 hours to 3 days, the imino function is reduced in a way known in the art, preferably with sodium borohydride in a polar solvent, preferably a methanol/water mixture, at temperatures of 25-100°C within 0.5 to 24 hours, preferably 2 hours, or b) by a propanediamine of general formula V
(V) in which R1, R2 and A' have the above-mentioned meanings, being reacted with a compound of general formula VII
B - CO-X (VII), in which B has the above-mentioned meaning, functional groups contained in B optionally are present in protected form and X stands for a halogen atom, preferably for a chlorine atom, or c) by a propanediamine of general formula V
(V) in which R1, R2 and A' have the above-mentioned meanings, being reacted with a compound of general formula VIII
(VIII) in which R4, R5, B and X have the above-mentioned meanings and functional groups contained in B optionally are present in protected form, or d) substituted malonic acid halides, preferably malonic acid chlorides of general formula IX
(IX) in which R1, R2, A' and X have the above-mentioned meanings and functional groups contained in B optionally are present in protected form, being reacted with an amine of general formula X
(X) in which R4, R5 and B have the above-mentioned meanings, R3' stands for a hydrogen atom or for a C1-6 alkyl radical and functional groups contained in B optionally are present in protected form, in an aprotic solvent, preferably dichloromethane, at temperatures of 0-180°C, preferably at room temperature, within 2 to 24 hours, preferably 4 hours, optionally by adding suitable bases, e.g., triethylamine, the amide function obtained according to process d) being reduced in a way known in the art, preferably with borane in THF
or with lithium aluminum hydride in an aprotic solvent, preferably diethyl ether, at temperatures of 25-150°C within 0.5 to 24 hours, preferably 8 hours to the corresponding amino function, the amino groups, in the case that R3' stands for a hydrogen atom, optionally being alkylated in a way known in the art with an alkylating agent introducing R3 and present protecting groups being cleaved and in the thus obtained compounds, group A' optionally converted to A -- optionally after protecting the free amino groups and functional groups Z with protective ions, e.g., as a Cu complex -- being generated and then optionally the thus obtained compounds being coupled by this functional group to selectively accumulating compounds T and substituents B
optionally being complexed with the radioactive isotope desired in each case, and protective ions optionally present in the product in advance being removed according to methods known in the literature and the sequence of the steps of complexing with radioactive isotopes and coupling to T being able to be interchanged.
(I) in which R1 stands for hydrogen or a C1-6 alkyl radical optionally substituted with one or two hydroxyl groups, R2 stands for a C1-6 alkylene radical optionally substituted with a hydroxyl group, R3 stands for a hydrogen atom, a C1-6 alkyl radical, a carboxymethyl radical or a (C1-6 alkoxycarbonyl)methyl radical, R4 stands for a hydrogen atom, a C1-6 alkyl radical optionally substituted with a hydroxyl group or for the meaning indicated under Rx, R5 stands for a hydrogen atom or a C1-6 alkyl radical optionally substituted with a hydroxyl group, B stands for a pyrrolyl radical, a substituted phenyl radical of formula II or a substituted pyridine radical of formula III
(II) (III) in which Z means a hydroxyl group, amino group or a mercapto group and Y means a hydrogen atom, a carboxy radical or a sulfonyl radical or B stands for a nitrosomethyl radical of formula IV
(IV) in which Rx means a C1-6 alkyl radical, which optionally is cyclized together with R4 by a trimethylene or tetramethylene group to a 5- or 6-ring and A stands for an amino radical, a mercapto radical, a carboxy radical, a C2-6 alkinyl or C2-6 alkenyl radical, an oxiranyl radical, a fluorinated phenoxycarbonyl radical, a succinimidoxycarbonyl radical optionally substituted with a sodium sulfate radical, an aminophenyl radical or isothiocyanatophenyl radical, and the phenyl group optionally can be substituted in addition by a carboxy radical, a chlorosulfonyl radical or a sulfonic acid radical or contains a compound T selectively accumulating in lesions or specific tissues -- optionally bound by a bifunctional linker radical L with the help of said functional group and T stands for monoclonal antibodies or their fragments, hormones, enzymes, ligands for cell membrane receptors, neurotransmitters, lipids, steroids, saccharides, amino acids and oligopeptides, biotin, as well as radiosensitizers, such as, e.g., misonidazole, and in the case of , pyrrolyl radical or Y = H, R2 is to stand for a hydroxylated C1-6 alkylene chain or A
is to stand for a substituted aminophenyl or isothiocyanatophenyl radical, as well as their complexes with radioactive metal ions --suitable for diagnosis and treatment of tumors -- as well as their salts with inorganic and organic acids, wherein a) a 1,3-propanediamine of general formula V
(V) in which R1 and R2 have the above-mentioned meanings, and A' means A or a radical able to be converted to A
is reacted with a compound of general formula VI
B - R4C = 0 (VI) in which R4 and B have the above-mentioned meanings, in a polar solvent, preferably ethanol, or by using a water separator in a nonpolar solvent, preferably benzene, at temperatures of 25-180°C within 6 hours to 3 days, the imino function is reduced in a way known in the art, preferably with sodium borohydride in a polar solvent, preferably a methanol/water mixture, at temperatures of 25-100°C within 0.5 to 24 hours, preferably 2 hours, or b) by a propanediamine of general formula V
(V) in which R1, R2 and A' have the above-mentioned meanings, being reacted with a compound of general formula VII
B - CO-X (VII), in which B has the above-mentioned meaning, functional groups contained in B optionally are present in protected form and X stands for a halogen atom, preferably for a chlorine atom, or c) by a propanediamine of general formula V
(V) in which R1, R2 and A' have the above-mentioned meanings, being reacted with a compound of general formula VIII
(VIII) in which R4, R5, B and X have the above-mentioned meanings and functional groups contained in B optionally are present in protected form, or d) substituted malonic acid halides, preferably malonic acid chlorides of general formula IX
(IX) in which R1, R2, A' and X have the above-mentioned meanings and functional groups contained in B optionally are present in protected form, being reacted with an amine of general formula X
(X) in which R4, R5 and B have the above-mentioned meanings, R3' stands for a hydrogen atom or for a C1-6 alkyl radical and functional groups contained in B optionally are present in protected form, in an aprotic solvent, preferably dichloromethane, at temperatures of 0-180°C, preferably at room temperature, within 2 to 24 hours, preferably 4 hours, optionally by adding suitable bases, e.g., triethylamine, the amide function obtained according to process d) being reduced in a way known in the art, preferably with borane in THF
or with lithium aluminum hydride in an aprotic solvent, preferably diethyl ether, at temperatures of 25-150°C within 0.5 to 24 hours, preferably 8 hours to the corresponding amino function, the amino groups, in the case that R3' stands for a hydrogen atom, optionally being alkylated in a way known in the art with an alkylating agent introducing R3 and present protecting groups being cleaved and in the thus obtained compounds, group A' optionally converted to A -- optionally after protecting the free amino groups and functional groups Z with protective ions, e.g., as a Cu complex -- being generated and then optionally the thus obtained compounds being coupled by this functional group to selectively accumulating compounds T and substituents B
optionally being complexed with the radioactive isotope desired in each case, and protective ions optionally present in the product in advance being removed according to methods known in the literature and the sequence of the steps of complexing with radioactive isotopes and coupling to T being able to be interchanged.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE4107570A DE4107570A1 (en) | 1991-03-07 | 1991-03-07 | CHELATES, THEIR METAL COMPLEXES AND THEIR USE IN DIAGNOSTICS AND THERAPY |
DEP4107570.6 | 1991-03-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2062483A1 true CA2062483A1 (en) | 1992-09-08 |
Family
ID=6426849
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002062483A Abandoned CA2062483A1 (en) | 1991-03-07 | 1992-03-06 | Chelates, their metal complexes as well as their use in diagnosis and treatment |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP0502594A1 (en) |
JP (1) | JPH0624972A (en) |
AU (1) | AU1214792A (en) |
CA (1) | CA2062483A1 (en) |
DE (1) | DE4107570A1 (en) |
IE (1) | IE920762A1 (en) |
ZA (1) | ZA921717B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102612511A (en) * | 2009-09-28 | 2012-07-25 | 肯塔基大学研究基金会 | Thiol-containing compounds for the removal of elements from contaminated milieu and methods of use |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
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US5672334A (en) * | 1991-01-16 | 1997-09-30 | Access Pharmaceuticals, Inc. | Invivo agents comprising cationic metal chelators with acidic saccharides and glycosaminoglycans |
US6359120B1 (en) | 1991-10-29 | 2002-03-19 | Bracco International B.V. | Rhenium and technetium complexes containing a hypoxia-localizing moiety |
US5808091A (en) * | 1991-10-29 | 1998-09-15 | Bracco International B.V. | Rhenium and technetium complexes containing a hypoxia localizing moiety |
US5608110A (en) * | 1993-06-15 | 1997-03-04 | Bracco International B.V. | Heteroatom-bearing ligands and metal complexes thereof |
CA2156605A1 (en) | 1994-01-12 | 1995-07-20 | David Nowotnik | Ligands and metal complexes thereof |
DE19507820A1 (en) * | 1995-02-21 | 1996-08-22 | Schering Ag | Novel substituted DTPA derivatives, their metal complexes, pharmaceutical compositions containing these complexes, their use in diagnostics, and methods for producing the complexes and compositions |
NZ511705A (en) * | 2001-05-14 | 2004-03-26 | Horticulture & Food Res Inst | Methods and rapid immunoassay device for detecting progesterone and other steroids |
JP2010065019A (en) * | 2008-08-11 | 2010-03-25 | Univ Of Tokyo | Oxime-type cyclic metal complex |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4615876A (en) * | 1983-04-25 | 1986-10-07 | Curators Of The University Of Missouri | Macrocyclic complexes of technetium-99m for use as diagnostic radionuclides |
AU4635885A (en) * | 1984-07-19 | 1986-02-25 | University Of Florida | Compounds for site-enhanced delivery of radionuclides and uses thereof |
CA1243329A (en) * | 1985-03-11 | 1988-10-18 | Amersham Int Plc | Complexes of technetium-99m with propylene amine oximes |
US4746505A (en) * | 1985-04-26 | 1988-05-24 | President And Fellows Of Harvard College | Technetium radiodiagnostic fatty acids derived from bisamide bisthiol ligands |
US4935518A (en) * | 1987-05-08 | 1990-06-19 | Salutar, Inc. | Manganese(II), chelate contrast agents derived from N,N'-bis-(pyridoxal ethylene diamine-N,N')-diacetic acid and derivatives thereof |
AR246956A1 (en) * | 1987-05-08 | 1994-10-31 | Salutar Inc | Dipyridoxyl phosphate nuclear magnetic resonance imagery contrast agents |
US4889931A (en) * | 1988-09-27 | 1989-12-26 | Salutar, Inc. | Manganese (II) chelate manufacture |
DE3930674A1 (en) * | 1989-09-11 | 1991-03-21 | Diagnostikforschung Inst | BIFUNCTIONAL CHELATE FORMERS FOR COMPLEXING TC AND RE-ISOTOPES, METHOD FOR THE PRODUCTION AND DISPLAY OF CONJUGATES THEREOF AND THEIR USE IN DIAGNOSTICS AND THERAPY |
-
1991
- 1991-03-07 DE DE4107570A patent/DE4107570A1/en not_active Withdrawn
-
1992
- 1992-03-05 JP JP4048720A patent/JPH0624972A/en active Pending
- 1992-03-05 EP EP92250051A patent/EP0502594A1/en not_active Withdrawn
- 1992-03-06 CA CA002062483A patent/CA2062483A1/en not_active Abandoned
- 1992-03-06 AU AU12147/92A patent/AU1214792A/en not_active Abandoned
- 1992-03-06 ZA ZA921717A patent/ZA921717B/en unknown
- 1992-03-09 IE IE076292A patent/IE920762A1/en not_active Application Discontinuation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102612511A (en) * | 2009-09-28 | 2012-07-25 | 肯塔基大学研究基金会 | Thiol-containing compounds for the removal of elements from contaminated milieu and methods of use |
Also Published As
Publication number | Publication date |
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EP0502594A1 (en) | 1992-09-09 |
AU1214792A (en) | 1992-09-10 |
IE920762A1 (en) | 1992-09-09 |
DE4107570A1 (en) | 1992-11-19 |
ZA921717B (en) | 1992-11-25 |
JPH0624972A (en) | 1994-02-01 |
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