EP0832150A1 - Polymeres en cascade avec composes aromatiques iodes - Google Patents
Polymeres en cascade avec composes aromatiques iodesInfo
- Publication number
- EP0832150A1 EP0832150A1 EP96921966A EP96921966A EP0832150A1 EP 0832150 A1 EP0832150 A1 EP 0832150A1 EP 96921966 A EP96921966 A EP 96921966A EP 96921966 A EP96921966 A EP 96921966A EP 0832150 A1 EP0832150 A1 EP 0832150A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- coch
- mmol
- iodine
- och
- 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.)
- Withdrawn
Links
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 239000011630 iodine Substances 0.000 title claims abstract description 36
- 229910052740 iodine Inorganic materials 0.000 title claims abstract description 36
- 229920000642 polymer Polymers 0.000 title claims description 37
- 150000001491 aromatic compounds Chemical class 0.000 title 1
- 229910052757 nitrogen Inorganic materials 0.000 claims description 125
- -1 carboxy, sulfo Chemical group 0.000 claims description 96
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 56
- 150000001875 compounds Chemical class 0.000 claims description 46
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 41
- 238000006243 chemical reaction Methods 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
- 150000003254 radicals Chemical class 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 11
- 150000001413 amino acids Chemical class 0.000 claims description 10
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 10
- 230000001850 reproductive effect Effects 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000003277 amino group Chemical group 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 238000003745 diagnosis Methods 0.000 claims description 5
- 239000000654 additive Substances 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 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
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000006832 (C1-C10) alkylene group Chemical group 0.000 claims description 2
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 claims description 2
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001841 imino group Chemical class [H]N=* 0.000 claims description 2
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 2
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 2
- 239000002504 physiological saline solution Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims description 2
- 125000000464 thioxo group Chemical group S=* 0.000 claims description 2
- 208000019553 vascular disease Diseases 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- ZMUADARPXLFDHP-UHFFFAOYSA-N nitrocarbamic acid Chemical group OC(=O)N[N+]([O-])=O ZMUADARPXLFDHP-UHFFFAOYSA-N 0.000 claims 1
- 238000007911 parenteral administration Methods 0.000 claims 1
- 239000000412 dendrimer Substances 0.000 abstract description 3
- 229920000736 dendritic polymer Polymers 0.000 abstract description 3
- 239000000032 diagnostic agent Substances 0.000 abstract description 2
- 229940039227 diagnostic agent Drugs 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 170
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 137
- 239000000243 solution Substances 0.000 description 127
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 121
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 105
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 99
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 82
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 72
- 239000000203 mixture Substances 0.000 description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 64
- 229960000583 acetic acid Drugs 0.000 description 51
- 239000012362 glacial acetic acid Substances 0.000 description 48
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- 239000012528 membrane Substances 0.000 description 36
- 239000002872 contrast media Substances 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- 238000003756 stirring Methods 0.000 description 31
- 239000011734 sodium Substances 0.000 description 30
- 229910052708 sodium Inorganic materials 0.000 description 30
- 239000000047 product Substances 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 239000007787 solid Substances 0.000 description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 24
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 24
- 238000001556 precipitation Methods 0.000 description 24
- 239000000741 silica gel Substances 0.000 description 23
- 229910002027 silica gel Inorganic materials 0.000 description 23
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 22
- 239000000725 suspension Substances 0.000 description 22
- 239000003921 oil Substances 0.000 description 20
- 229920000768 polyamine Polymers 0.000 description 20
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 239000001913 cellulose Substances 0.000 description 18
- 229920002678 cellulose Polymers 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 18
- 239000012510 hollow fiber Substances 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 239000011148 porous material Substances 0.000 description 18
- 238000000108 ultra-filtration Methods 0.000 description 18
- 150000001412 amines Chemical group 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- 239000000470 constituent Substances 0.000 description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 239000012300 argon atmosphere Substances 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- 229940039231 contrast media Drugs 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 238000000746 purification Methods 0.000 description 12
- 210000004369 blood Anatomy 0.000 description 11
- 239000008280 blood Substances 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 238000001704 evaporation Methods 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 8
- UOTMYNBWXDUBNX-UHFFFAOYSA-N 1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxyisoquinolin-2-ium;chloride Chemical compound Cl.C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 UOTMYNBWXDUBNX-UHFFFAOYSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- 239000012317 TBTU Substances 0.000 description 8
- 150000001448 anilines Chemical class 0.000 description 8
- WXWQVSOHWXJBDF-UHFFFAOYSA-N benzene-1,3,5-tricarboxamide Chemical compound NC(=O)C1=CC(C(N)=O)=CC(C(N)=O)=C1 WXWQVSOHWXJBDF-UHFFFAOYSA-N 0.000 description 8
- PFXWAZGPFWJKBF-UHFFFAOYSA-N benzyl aziridine-1-carboxylate Chemical compound C1CN1C(=O)OCC1=CC=CC=C1 PFXWAZGPFWJKBF-UHFFFAOYSA-N 0.000 description 8
- DWPBEWIGNADCAX-UHFFFAOYSA-N benzyl n-[2-[2-(phenylmethoxycarbonylamino)ethylamino]ethyl]carbamate Chemical compound C=1C=CC=CC=1COC(=O)NCCNCCNC(=O)OCC1=CC=CC=C1 DWPBEWIGNADCAX-UHFFFAOYSA-N 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 229920002521 macromolecule Polymers 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 7
- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical compound C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- WBSCNDJQPKSPII-KKUMJFAQSA-N Lys-Lys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(O)=O WBSCNDJQPKSPII-KKUMJFAQSA-N 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 230000007717 exclusion Effects 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- PIYNUZCGMLCXKJ-UHFFFAOYSA-N 1,4-dioxane-2,6-dione Chemical compound O=C1COCC(=O)O1 PIYNUZCGMLCXKJ-UHFFFAOYSA-N 0.000 description 6
- 229920002307 Dextran Polymers 0.000 description 6
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000005917 acylation reaction Methods 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 230000033228 biological regulation Effects 0.000 description 6
- 210000004204 blood vessel Anatomy 0.000 description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
- 230000010933 acylation Effects 0.000 description 5
- 238000005804 alkylation reaction Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- 230000002792 vascular Effects 0.000 description 5
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 238000002583 angiography Methods 0.000 description 4
- 150000008064 anhydrides Chemical class 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 150000001768 cations Chemical class 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical class C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 235000010299 hexamethylene tetramine Nutrition 0.000 description 4
- 239000004312 hexamethylene tetramine Substances 0.000 description 4
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 150000007529 inorganic bases Chemical class 0.000 description 4
- 239000012948 isocyanate Substances 0.000 description 4
- 150000002513 isocyanates Chemical class 0.000 description 4
- 150000002596 lactones Chemical class 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- 229940087646 methanolamine Drugs 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 230000010412 perfusion Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- BYNKULISCUABSP-UHFFFAOYSA-N 3-amino-5-(2,3-diacetyloxypropylcarbamoyl)-2,4,6-triiodobenzoic acid hydrochloride Chemical compound Cl.CC(=O)OCC(OC(C)=O)CNC(=O)C1=C(I)C(N)=C(I)C(C(O)=O)=C1I BYNKULISCUABSP-UHFFFAOYSA-N 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 3
- FBJVWRITWDYUAC-UHFFFAOYSA-N 5-amino-2,4,6-triiodobenzene-1,3-dicarbonyl chloride Chemical compound NC1=C(I)C(C(Cl)=O)=C(I)C(C(Cl)=O)=C1I FBJVWRITWDYUAC-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 230000036765 blood level Effects 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- MTMNJFGEKOYMIV-UHFFFAOYSA-N carbonyl dichloride;toluene Chemical compound ClC(Cl)=O.CC1=CC=CC=C1 MTMNJFGEKOYMIV-UHFFFAOYSA-N 0.000 description 3
- 150000001805 chlorine compounds Chemical class 0.000 description 3
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 210000001723 extracellular space Anatomy 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- DGAIEPBNLOQYER-UHFFFAOYSA-N iopromide Chemical compound COCC(=O)NC1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)N(C)CC(O)CO)=C1I DGAIEPBNLOQYER-UHFFFAOYSA-N 0.000 description 3
- 208000028867 ischemia Diseases 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 230000020477 pH reduction Effects 0.000 description 3
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 3
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920003228 poly(4-vinyl pyridine) Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- XOJVVFBFDXDTEG-UHFFFAOYSA-N pristane Chemical compound CC(C)CCCC(C)CCCC(C)CCCC(C)C XOJVVFBFDXDTEG-UHFFFAOYSA-N 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000006894 reductive elimination reaction Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- SJMDMGHPMLKLHQ-UHFFFAOYSA-N tert-butyl 2-aminoacetate Chemical compound CC(C)(C)OC(=O)CN SJMDMGHPMLKLHQ-UHFFFAOYSA-N 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- FAGUFWYHJQFNRV-UHFFFAOYSA-N tetraethylenepentamine Chemical compound NCCNCCNCCNCCN FAGUFWYHJQFNRV-UHFFFAOYSA-N 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- RRBYUSWBLVXTQN-VZCHMASFSA-N tricyclene Natural products C([C@@H]12)C3C[C@H]1C2(C)C3(C)C RRBYUSWBLVXTQN-VZCHMASFSA-N 0.000 description 1
- 229960001124 trientine Drugs 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- QMKYBPDZANOJGF-UHFFFAOYSA-N trimesic acid Natural products OC(=O)C1=CC(C(O)=O)=CC(C(O)=O)=C1 QMKYBPDZANOJGF-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0442—Polymeric X-ray contrast-enhancing agent comprising a halogenated group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0215—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu
Definitions
- Articles ie new iodine-containing dendrimeric polymers, agents containing these compounds, the use of the polymeric compounds as contrast agents and methods for producing these compounds and agents.
- X-ray contrast media are indispensable tools for diagnosis
- the X-ray density of a contrast agent depends on it as the only parameter. This is particularly the case in angiography when the contrast agent is injected into blood vessels at high speed via catheters and thus displaces the blood.
- Contrast center also desirable, e.g. if the thinning in the body is otherwise too strong (injection into the heart chambers, the aorta or with intravenous digital subtraction angiography) or with unfavorable
- contrast medium solutions which is linked among other things to the lipophilicity of the molecules, their protein affinity and
- Electron density It manifests itself in clinical use through the occurrence of side effects such as nausea, vomiting, of certain
- Circulatory reactions urticaria, bronchospasm and other symptoms up towards shock and death.
- Pharmacologically, chemotoxic effects can be measured, for example, as LD 50 after intravenous injection; c) the viscosity.
- Injectables with higher viscosity contrast media also have the disadvantage of poor miscibility with blood (streak formation instead of homogeneous filling of the cardiac cavity or blood vessels) and obstruction of the passage by capillaries, e.g. the lungs; d) osmolality
- contrast media solutions In the case of the application of solutions that are very hypertonic to blood and tissue (the physiological value is 310 m osm / kg), water is driven out of the cells, which among other things Cell membranes are destroyed and the overall electrolyte balance is disturbed.
- contrast agent solutions which allow heat sterilization and a shelf life of at least 24 months.
- X-ray contrast media that are distributed exclusively in the vascular space would be desirable for the display of vessels, ie the volume of distribution of the contrast medium should correspond to the intravascular space.
- the contrast media used hitherto for angiography have the disadvantage that they leave the vasal space very quickly because they are too small and hydrophilic and can be distributed in the extracellular space.
- your Elimination so quickly that usually a local application by means of
- Catheter e.g. in the cranial area
- Catheter e.g. in the cranial area
- blood pool agents perfusion agents
- Infected tissue could also be distinguished from the surrounding healthy or ischemic tissue due to its anemia if a vasal contrast agent was used. This is of particular importance if e.g. is about distinguishing a heart attack from ischemia.
- Another application is in the diagnosis of
- Vascular areas with reduced or increased permeability e.g. can be caused by inflammation or tumors, as well as in the
- X-ray contrast media that can mark the vasal space (blood pool agent). These compounds are said to be well tolerated and to be highly effective (high increase in signal intensity or lower dose) and by the molecules remaining in the vasal space (no extravasation) and by a longer half-life compared to those used for angiography Mark contrast media.
- dextran derivatives a broad molecular weight distribution and associated with an incomplete excretion and an insufficient tolerance.
- iodine-containing polyamines disclosed in international patent application WO 93/10824 are not very readily soluble in water and, moreover, are relatively poorly tolerated.
- iodine-containing dendrimeric polymers which have a nitrogen-containing core and triiodoaromatics and have aliphatic carboxy, sulfo or phosphono-containing imaging residues, are surprisingly outstandingly suitable for producing X-ray diagnostics without having the disadvantages mentioned.
- Dendrimers are branched polymeric molecules such as those e.g. in Angew. Chem. Vol. 104, 1609 (1992).
- the iodine-containing dendrimers (cascade polymers) according to the invention can be described by the general formula I A- ⁇ X- [Y- (Z- ⁇ WD w > z ) y ] x ⁇ a (I), in which
- R 1 and R 2 each independently represent a hydrogen atom, a -CONR 3 R 4 - or -NR 6 COR 5 group, where
- R 3 , R 4 either independently of one another for a hydrogen atom or a straight-chain, branched or cyclic alkyl group with up to 12 C atoms, which are optionally substituted by 1-5 hydroxyl and / or 1-3 C 1 -
- R 3 and R 4 together with the nitrogen atom for a heterocyclic 5- or
- 6-ring which optionally contains an oxygen atom, an SO 2 group or an N-CO-R 7 radical,
- R 7 for a carboxy group or an alkyl group with up to
- R 5 represents a carboxy group or a straight-chain or branched
- C 1 -C 12 alkyl group which is optionally interrupted by an oxygen atom, which may also be an
- R 6 represents a hydrogen atom, or a straight-chain or branched one
- Alkyl group with up to 12 carbon atoms which may be by 1-3 carboxy, sulfo or phosphono group (s) and / or optionally by 1-3 hydroxy group (s) and / or 1-3 C 1 -C 3 - Alkoxy group (s) is substituted
- a stands for the digits 2 to 12, x, y, z independently of one another for the digits 1 to 4 and w stands for the digits 1 to 8, with the proviso that at least two reproductive units are different and that for the product of multiplicities applies
- U stands for a group (CH 2 ) u q for the digits 0 or 1 and u for the digits 1-4 and their salts with physiologically acceptable organic and / or inorganic bases, amino acids or amino acid amides.
- cascade core A The following are suitable as cascade core A:
- M is a C 1 -C 10 alkylene chain which may be 1 to 3
- Oxygen atoms is interrupted and / or optionally with 1 to 2
- the reproduction units X, Y, Z and W contain -NQ 1 Q 2 groups, in which Q 1 is a hydrogen atom or Q 2 is a direct bond.
- the number Q 2 contained in the respective reproduction unit (eg X) corresponds to the multiplicity of reproduction of this unit (eg x in the case of X).
- the product of all multiplicities (axyzw) gives the number of triiodinated benzene residues B bound in the cascade polymer.
- the polymers according to the invention contain at least 16 and at most 128 radicals B in the molecule.
- the reproduction units can be terminated both via NHQ 2 groups (for example by acylation reactions) and via NQ 2 Q 2 groups (for example through
- the cascade polymer complexes according to the invention have a maximum of 10
- Reproduction units X, Y and Z are present in the molecule), but preferably 2 to 4 generations, at least two of the reproduction units in the molecule being different.
- the preferred cascade cores A are those which fall under the general formulas mentioned above, if
- n for the numbers 1 to 3, particularly preferably for the number 1,
- cascade core A the separation of the cascade core and the first reproduction unit can be chosen purely formally and therefore independently of the actual synthetic structure of the desired cascade polymer complexes. So you can e.g.
- the cascade reproduction units X, Y, Z and Q are run independently
- Oxygen atoms and / or 1 to 2 -N (CO) q -R 2 -, 1 to 2 phenylene and / or 1 to 2 phenyleneoxy radicals is interrupted and / or optionally by 1 to 2 oxo, thioxo, carboxy, C 1 -C 5 alkylcarboxy, C 1 -C 5 alkoxy, hydroxy, C 1 -C 5 alkyl groups is substituted, wherein
- R 2 represents a hydrogen atom, a methyl or an ethyl radical which is optionally substituted by 1-2 hydroxyl or 1 carboxy group (s),
- L represents a hydrogen atom or the group
- V stands for the methine group if U 4 is a direct one
- Binding or the group M means and U 5 one of the meanings of
- Preferred cascade reproduction units X, Y, Z and W are those in the above general formulas
- radical U 4 stands for a direct bond or for -CH 2 CO-
- the cascade reproduction units X, Y, Z and W are given as examples:
- alkyl groups R 3 , R 4 and R 7 contained in the R 1 or R 2 substituent of the triiodoaromatic B are straight-chain or branched-chain or cyclic
- Examples include methyl, hydroxymethyl, ethyl, 2-hydroxyethyl, 2-hydroxy-1- (hydroxymethyl) ethyl, 1- (hydroxymethyl) ethyl, propyl, isopropyl, 2-hydroxypropyl -, 3-hydroxypropyl, 2,3-dihydroxypropyl, 1,2,3-trihydroxypropyl, butyl, isobutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-, 3- and 4-hydroxy-2-methylbutyl, 2- and 3-hydroxyisobutyl, 2,3,4-trihydroxybutyl, 1, 2,4-trihydroxybutyl, pentyl, cyclopentyl, cyclohexyl, 2,3,4, 5,6-pentahydroxyhexyl, 2-methoxyethyl, carboxymethyl, 2-sulfoethyl, phosphonomethyl, 2-carboxyethyl, 10-hydroxydecyl, carboxy, 3-sulfopropyl,
- the heterocyclic 5- or 6-ring optionally formed by R 3 and R 4 including the amide nitrogen can optionally be a
- radicals R 5 and R 6 contained in the R 1 or R 2 substituent of the triiodoaromatic B are, in addition to the corresponding radicals listed for R 3 , R 4 , R 7 , the following:
- the alkyl, aryl or aralkyl radical or alkylene, arylene or aralkylene radical which represents R 8 and R 9 or V can be straight-chain or branched and contain up to 20, preferably up to 12, carbon atoms.
- the R 8 and R 9 substituent can be substituted by 1 to 4, preferably 1 to 2, hydroxyl group (s), the chain for V (optionally additionally) interrupted by 1 to 4, preferably 1 to 2, oxygen atoms.
- the following groups are mentioned as examples:
- the alkylene chain representing U can have up to 6, preferably up to 2, carbon atoms and may be interrupted by 1-2 oxygen atoms and / or optionally by 1-4, preferably 1-2, hydroxyl groups and / or 1 - 2 carboxy group (s) may be substituted.
- the acidic hydrogen atoms of the acid groups contained in the polymer can be replaced in whole or in part by cations of inorganic and / or organic bases, amino acids or amino acid amides.
- Suitable cations of inorganic bases are, for example, lithium, potassium, calcium, magnesium, zinc and in particular that
- Suitable cations of organic bases include those of primary, secondary or tertiary amines, e.g. Ethanolamine,
- Suitable cations of amino acids are, for example, those of lysine, arginine and ornithine and the amides of otherwise acidic or neutral amino acids.
- the compounds according to the invention have the desired properties described at the outset. They contain the number of triiodoaromatics required for their use as X-ray contrast media. They are only distributed in the vasal space and can therefore be marked using X-ray diagnostics.
- the iodine content of the compounds according to the invention exceeds
- Macromolecules such as the dextran derivatives described in WO 88/06162 (approx. 2 to 35%) - in some cases many times over.
- the invention
- Example 18 190 [mosmol / kg] at 37 ° C, 130 mg iodine / ml).
- the osmolality of the compounds according to the invention is also significantly lower than that of the dextran compounds described in WO 88/06162 (440 mosmol / kg at 90 mg iodine / ml).
- Example 18 2.8 mPas at 37 ° C and 100 mg iodine / ml;
- Example 10 of WO 88/06162 26 mPas at 37 ° C and 90 mg iodine / ml).
- Example 12 of WO 94/21600 has a significantly lower solubility and at the same time a significantly higher viscosity than the compounds according to the invention.
- Dextran compounds may be between 5 and 10% of the total.
- dextran molecules of this size become no longer filtered glomerularly, and the renal clearance of these molecules is therefore almost zero.
- EP 0206551, EP 0436316 and in the Examples 1, 2 and 3 of the compounds described in WO 93/10824 cannot be complete because of their high molecular weight components after iv administration
- Perfusion agents suitable With the compounds according to the invention, it has surprisingly been possible to provide iodine-containing polymers which only leave the vasal space slowly, but at the same time still pass through the capillaries of the kidney and are therefore completely eliminated.
- the invention therefore relates to the compounds described by the formula I.
- the compounds according to the invention show a blood concentration in the first 10 minutes after intravenous administration, which is about four times higher than with the extracellular X-ray contrast agents such as e.g. Ultravist®.
- the cascade polymers are only in the body
- Vasal space i.e. the volume of distribution is approximately 0.05 l / kg. This makes it possible to produce macromolecular contrast media with triiodoaromatics to suit the body.
- the cascade polymers according to the invention serve as contrast agents for
- the dose can be reduced fourfold; because the macromolecules are distributed in a fourfold smaller space, namely only in the vasal space, ie a quarter of the dose is sufficient to achieve equal concentrations in the blood.
- the compounds according to the invention can be used to carry out perfusion measurements, for example on the myocardium, which was only possible to a limited extent with the low molecular weight compounds such as Ultravist®, since these molecules rapidly "leak” into the interstitial space. The "leakage" into the interstitium often led to a blurring of the image in the case of the low molecular weight compounds, which can be avoided by the compounds according to the invention.
- the measurement time can be greatly extended compared to the low molecular weight compounds.
- Macromolecules with different lipophilic or hydrophilic triiodaryl residues have become accessible. This enables the compatibility and pharmacokinetics of these cascade polymers to be controlled by differently substituted triiodaryl radicals.
- the invention therefore also relates to the use of
- the iodine-containing dendrimeric polymers according to the invention are prepared by dendrimeric polymers of the general formula I '
- x, y, z independently of one another represent the digits 1 to 4,
- R has the meaning of a hydrogen atom or a methyl group
- B ' has the meaning given for B of a triiodoaromatic, but carboxy and hydroxyl groups contained in B are in protected
- u stands for the digits 1-4.
- An example of an activated carbonyl group in the radicals T of the starting materials of the general formula II are anhydride, p-nitrophenyl ester, lactone and
- Lower alkyl, aryl and aralkyl groups for example the methyl, ethyl, propyl, n-butyl, t-butyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl, bis (p-nitrophenyi ) methyl group, and trialkylsilyl groups in question.
- the protective groups are split off according to those known to the person skilled in the art
- hydroxyl protective groups are the benzyl, 4-methoxybenzyl, 4-nitrobenzyl, trityl, diphenylmethyl, trimethylsilyl, dimethyl-t-butylsilyl,
- the hydroxyl groups can also be present, for example, as THP ether, ⁇ -alkoxyethyl ether, MEM ether or as an ester with aromatic or aliphatic carboxylic acids, such as acetic acid or benzoic acid.
- the hydroxy groups can also be protected in the form of ketals with, for example, acetone, acetaldehyde, cyclohexanone or benzaldehyde. If carboxyl groups are present at the same time, hydroxyl groups can also be protected by intramolecular esterification to give the corresponding lactones.
- the hydroxyl protecting groups can be prepared according to the literature methods known to the skilled person, e.g. are released by hydrogenolysis, reductive cleavage with lithium / ammonia, acid treatment of the ethers and ketaie or alkali treatment of the esters
- (Carboxymethyl) amine or amide substituted triiodoaromatics in liquid reaction media such as water, dipolar aprotic solvents such as diethyl ether, tetrahydrofuran, dioxane, acetonitrile, N-methylpyrrolidone, dimethylformamide, dimethylacetamide and the like or mixtures thereof with the addition of amines such as e.g. Triethylamine, N-ethyldiisopropylamine,
- reaction temperatures are between about -80 ° C and 160 ° C, with temperatures of 20 ° C to 80 ° C are preferred.
- reaction times are between 0.5 hours and 7 days, preferably between 1 hour and 48 hours.
- the acid anhydrides can be prepared by known processes, for example by the process described in US Pat. No. 3,660,388 or in DE 16 95 050 with acetic anhydride in pyridine. In certain cases, however, it is advantageous to carry out the elimination of water with carbodiimides in a suitable solvent, such as, for example, dimethylformamide or dimethyl acetamide.
- the isocyanate- or isothiocyanate-substituted triiodoaromatics are reacted by methods known from the literature (DOS 26 10 500, EP 0 431 838), for example in aprotic solvents such as DMSO, DMF, DMA or in water or water-containing solvent mixtures at temperatures of 0 - 120 ° C, preferably 20 - 75 ° C.
- the reaction times are generally between 1-48 hours, preferably 3-24 hours.
- acylations of the terminal amino groups of the polymers of the general formula I 'with triiodoaromatics which contain an acid chloride substituent are carried out by the processes known to the person skilled in the art, e.g. made analogously to the regulation in EP 0015867.
- the reaction is generally carried out in polar aprotic solvents such as e.g. DMF, DMA, or in mixtures of polar aprotic solvents with water, in the presence of an acid scavenger, e.g. tertiary amine (e.g.
- triethylamine trimethylamine
- N, N-dimethylaminopyridine 1, 5-diazabicyclo [4.3.0] nonen-5 (DBN), 1,5-diazabicyclo [5.4.0] undecen-5 (DBU)
- DBU 1,5-diazabicyclo [5.4.0] undecen-5
- alkali or alkaline earth carbonate hydrogen carbonate or hydroxide (e.g.
- the neutralization of the acid groups can be carried out with the aid of inorganic bases (e.g. hydroxides, carbonates or bicarbonates) of, for example, sodium, potassium, Lithium, magnesium or calcium and / or organic bases such as, inter alia, primary, secondary and tertiary amines, such as, for example, ethanolamine, morpholine, glucamine, N-methyl- and N, N-dimethylglucamine, and basic amino acids, such as, for example, lysine, arginine and ornithine or amides of originally neutral or acidic amino acids.
- inorganic bases e.g. hydroxides, carbonates or bicarbonates
- inorganic bases e.g. hydroxides, carbonates or bicarbonates
- organic bases such as, inter alia, primary, secondary and tertiary amines, such as, for example, ethanolamine, morpholine, glucamine, N-methyl- and N, N-dimethylglucamine,
- cascade core A and reproductive units is purely formal. It can be synthetically advantageous that the formal cascade starter A (H) a is not used, but that the nitrogen atoms, which by definition belong to the cascade core, are only introduced together with the first generation. For example, for the synthesis of the compound described in Example 1b) it is more advantageous than the formal one
- Cascade core trimesic acid triamide with e.g. Benzyloxycarbonyl aziridine
- the amine protecting groups are the benzyloxycarbonyl, tertiary-butoxycarbonyl, trifluoroacetyl, fluorenylmethoxycarbonyl, benzyl and formyl group [Th. W. Greene, P.G.M Wuts, Protective Groups in Organic
- next desired generation can be in the molecule be introduced.
- the simultaneous introduction of two e.g. X- [Y] x , or several generations, e.g. X- [Y- ( Z) y ] x , possible.
- These multi-generation units are constructed by alkylation or acylation of unprotected amines (“reproductive amine”) having the structures of the desired reproductive units with a second reproductive amine, the amine groups of which are in protected form.
- Examples include: tris (aminoethyl) amine [e.g. Fluka Chemie AG, Switzerland; Aldrich chemistry,
- Tris (aminopropyl) amine e.g. C. Woerner et al., Angew. Chem. Int. Ed. Engl.
- Triethylene tetramine e.g. Fluka; Aldrich
- Tetraethylene pentamine e.g. Fluka; Aldrich
- Trimesic acid triamide e.g. H. Kurihara; Jpn. Kokai Tokkyo Koho JP 04077481; CA 117, 162453];
- Tris (aminopropyl) nitromethane e.g. G.R. Newkome et al., Angew. Chem. 103. 1205 (1991) analogous to R.C. Larock, Comprehensive Organic Transformations, VCH Publishers,
- N-Benzyloxycarbonyl-aziridine see instructions for Example 13a) N-Benzyloxycarbonyl-glycine commercially available from Bachern California, for example to be produced according to CJ Cavallito et al., J. Amer. Chem. Soc. 1943, 65, 2140, by replacing benzyl chloride with N-CO-O-CH 2 C 6 H 5 - (2-bromoethyl) amine [AR Jacobson et al., J. Med. Chem. (1991), 34, 2816] goes out.
- the iodinated aromatics used in the various processes are known or can easily be generated from known ones.
- DE 29 09439 describes iodinated aromatics which can easily be mixed with e.g. Thionyl chloride can be converted to the corresponding aromatics containing acid chloride groups.
- Isocyanate- or isothiocyanate-substituted triiodoaromatics can by
- a triiodoaromatic containing lactone residue can be obtained, for example, by reacting a triiodobenzoyl chloride derivative with 2-amino-4-butyrolactone hydrochloride.
- An implementation of this type is e.g. by J. Brennan and
- Other aromatic residues are as in M. Sovak; Radiocontrast agents,
- the invention further relates to pharmaceutical compositions which contain at least one of the compounds according to the invention.
- the invention further relates to a process for the preparation of these agents, which is characterized in that the shading substance with the additives and stabilizers customary in galenics in a for enteral or
- parenteral application is brought into a suitable form.
- the pharmaceutical preparation can generally be adapted to the specific needs of the user.
- X-ray contrast medium in an aqueous medium is based entirely on the X-ray diagnostic method.
- the iodine content of the solutions is usually in the range between 50 to 450 mg / ml, preferably 70 to 200 mg / ml.
- the resulting agents are then heat sterilized if desired. They are used depending on the iodine content and the
- X-ray diagnostic method or question usually applied in a dose of 30 mg iodine / kg to 2000 mg iodine / kg.
- the aqueous X-ray contrast medium solution can be applied enterally or parenterally, thus orally, rectally, intravenously, intraarterially, intravascularly, intracutaneously, subcutaneously (lymphography), subarachnoidally (myelography).
- Suitable additives are, for example, physiologically harmless buffers (such as tromethamine, bicarbonate, phosphate, citrate), stabilizers (such as DTPA, sodium edetate, calcium disodium edetate) or - if necessary - electrolytes (such as sodium chloride) or - if necessary - Antioxidants (e.g., tromethamine, bicarbonate, phosphate, citrate), stabilizers (such as DTPA, sodium edetate, calcium disodium edetate) or - if necessary - electrolytes (such as sodium chloride) or - if necessary - Antioxidants (e.g.
- physiologically harmless buffers such as tromethamine, bicarbonate, phosphate, citrate
- stabilizers such as DTPA, sodium edetate, calcium disodium edetate
- electrolytes such as sodium chloride
- Antioxidants e.g.
- Ascorbic acid or substances to adjust the osmolality (such as mannitol, glucose).
- suspensions or solutions of the agents according to the invention in water or physiological saline are desired for enteral administration or other purposes, they are combined with one or more adjuvants customary in galenics (for example methyl cellulose, lactose, mannitol) and / or surfactants (e.g. lecithins, Tweens®, Myrj® and / or flavoring agents for flavor correction (e.g. essential oils) mixed.
- adjuvants customary in galenics
- surfactants e.g. lecithins, Tweens®, Myrj® and / or flavoring agents for flavor correction (e.g. essential oils) mixed.
- Tetracosakis ⁇ 3- (3-sodium carboxylatopropionylamino) -5- (2,3-dihydoxypropylcarbamoyl) -2,4,6-triiodobenzoyl ⁇ derivative of the N, N, N ', N', N ", N" - hexakis [2- (trilysylamino) ethyl] trimesic acid triamide a) bis [2- (benzyloxycarbonylamino) ethyl] amine
- Succinic acid monoethyl ester added at room temperature. The. Batch is refluxed for several hours until loud
- Example 1 c 7.0 g (7.5 mmol) of the N ⁇ , N ⁇ - bis (N, N'-dibenzyloxycarbonyl-lysyl) -lysine (protected "tri-lysine") described in Example 1 c are obtained in a manner analogous to Example 1d TBTU and N-hydroxybenzotriazole activated and in an analogous manner with 1.02 g (1 mmol) of the above-described N, N, N-tris [2- (lysylamino) ethyl] amine hexahydrobromide and 5.16 ml (30 mmol) N-Ethyldiisopropylamine implemented and worked up in the same manner as described there.
- Tetracosakis ⁇ 3- (4-sodium carboxylatomethoxyacetylamino) -5- (2,3-dihydroxy-propylcarbamoyl) -2,4,6-triiodobenzoyl ⁇ derivative of the
- Tetracosakis ⁇ 3- [N, N-bis (sodium carboxylatomethyl) carbamoyl)] - 5-methoxyacetylamino-2,4,6-triiodobenzoyl ⁇ derivative of the N, N, N ', N', N ", N" -Hexakis- [2- (trilysyl-amino) -ethyl] -trimesinklatriamids a) 5-methoxyacetylamino-2,4,6-triiodisophthalic acid-N, N-bis (methoxycarbonylmethyl) amide chloride
- Example 1f 3.00 g (0.50 mmol) of the poly-benzyloxycarbonylamine prepared according to Example 1d are described in Example 1f
- the aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 mm, Sartorius) and freeze-dried.
- the product is precipitated by adding hexane, decanted from the solvent and again from THF / hexane and then reprecipitated from THF / toluene. After drying in vacuo, 2.78 g (68% of theory) of a pale yellow solid are obtained.
- the anhydride formed is precipitated by dropwise addition of anhydrous diethyl ether, filtered off and dried in vacuo.
- the solid is added to a solution of 17.1 g (24 mmol) of the anhydride prepared under Example 7h and 5.5 ml (40 mmol) of triethylamine in 100 ml of N, N-dimethylformamide, which is mechanically stirred at room temperature.
- the mixture is stirred for 2 days at room temperature and evaporated in vacuo.
- the residue is neutralized with 2N sodium hydroxide solution, filtered and subjected to ultrafiltration, with low-molecular constituents being separated off by means of a hollow fiber membrane (H1 P3-20, Amicon).
- the aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 mm, Sartorius) and
- Methoxyacetyl chloride added at room temperature. The mixture is boiled under reflux for several hours until thin layer chromatography no longer detects any starting material, then the mixture is evaporated, the residue is taken up in dichloromethane and extracted with saturated aqueous sodium hydrogen carbonate solution. After drying over anhydrous magnesium sulfate, the organic phase is evaporated and the residue is recrystallized from ethyl acetate / tert-butyl methyl ether.
- the residue is taken up in water and subjected to ultrafiltration, with low-molecular constituents being separated off by means of a hollow fiber membrane (H1 P3-20, Amicon).
- the aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 mm, Sartorius) and freeze-dried.
- the product is then precipitated by adding diethyl ether and stirred once more with ether and finally with water. The precipitate is filtered off and dried.
- the solid becomes a solution of 17.8 g (24.0 mmol) of the isothiocyanate and 2.0 described in Example 9g, which is mechanically stirred at room temperature (14 mmol) triethylamine in 120 ml of dimethyl sulfoxide was added dropwise. The mixture is stirred for 2 days at room temperature, then mixed with 30 ml of 2N sodium hydroxide solution and stirred at 50 ° C. for two hours. The solution is opened after cooling
- Triethylamine in 120 ml of N, N-dimethylformamide added 120 ml of N, N-dimethylformamide added. The mixture is stirred for 2 days at room temperature, then mixed with 50 ml of 2N sodium hydroxide solution and stirred at 50 ° C. for 1.5 hours. The solution is left on after cooling
- the product solution is filtered through a cellulose membrane filter (pore size 0.45 ⁇ m, Sartorius) and freeze-dried.
- Tetrahydrofuran (THF) and 2.47 g (10 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ; Fluka) were added and the mixture was stirred overnight.
- the solution is evaporated to dryness in vacuo and chromatographed on silica gel in ethyl acetate / methanol (10: 1).
- Triethylamine added. A suspension is formed which is stirred overnight under argon at room temperature. The mixture is then evaporated and the residue is chromatographed on silica gel 60 (Merck) with dichloromethane / ethyl acetate. After evaporation of the product fractions, a colorless solid is obtained, which is dried in vacuo.
- Triethylamine in 25 ml of anhydrous N, N-dimethylformamide added. The mixture is stirred for 3 days at room temperature, then mixed with 14 ml of 2N sodium hydroxide solution and stirred at 50 ° C. for 2 hours. After evaporation in vacuo, a yellowish oil is obtained which is dissolved in water.
- the aqueous solution is adjusted to pH 7.3, filtered and the filtrate is subjected to an ultrafiltration, whereby low molecular weight components through a hollow fiber membrane (H1 P3-20, Amicon) be separated.
- the aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 mm, Sartorius) and freeze-dried. Yield: 3.79 g (92.2% of theory) of yellowish lyophilisate.
- aqueous solution is adjusted to pH 7.3, filtered and the filtrate is subjected to ultrafiltration, with low-molecular constituents being separated off by means of a hollow fiber membrane (H1 P3-20, Amicon).
- the aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 mm, Sartorius) and
- aqueous solution is adjusted to pH 7.3, filtered and the filtrate is subjected to ultrafiltration, with low-molecular constituents being separated off by means of a hollow fiber membrane (H1 P3-20, Amicon).
- the aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 mm, Sartorius) and
- Example 16 a) Meso-2,3-bis (benzyloxycarbonylamino) succinic acid 14.81 g (100 mmol) diaminosuccinic acid (meso form) are suspended in 300 ml tetrahydrofuran and adjusted to pH 9 with 2N sodium hydroxide solution. 42.65 g (250 mmol) are added dropwise at 0 ° C. with vigorous stirring
- aqueous solution is adjusted to pH 7.3, filtered and the filtrate is subjected to ultrafiltration, with low-molecular constituents being separated off by means of a hollow fiber membrane (H1 P3-20, Amicon).
- the aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 mm, Sartorius) and
- Example 17 a) 1,4,7,10,13,16-Hexakis [benzyloxycarbonylglycyl] -1,4,7,10,13,16-hexaazacyclooctadecane
- Hexacyden in toluene is a solution of 3.14 g (15 mmol) of benzyloxycarbonylglycine (Fluka) in tetrahydrofuran (THF) and 3.71 g (15 mmol) of 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline at room temperature (EEDQ; Fluka) added and stirred overnight. After the reaction has ended, the product is precipitated by adding hexane and the precipitate is chromatographed on silica gel using dichloromethane / hexane / isopropanol (20: 10: 1).
- the methylene chloride phase is dried over magnesium sulfate and evaporated.
- aqueous solution is adjusted to pH 7.3, filtered and the filtrate is subjected to ultrafiltration, with low-molecular constituents being separated off by means of a hollow fiber membrane (H1 P3-20, Amicon).
- the aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 mm, Sartorius) and
- the residue is taken up in water and subjected to ultrafiltration, with low-molecular constituents being separated off by means of a hollow fiber membrane (H1 P3-20, Amicon).
- the aqueous product solution is filtered through a cellulose membrane filter (pore size 0.45 ⁇ m, Sartorius) and freeze-dried.
- Concentration-time course (blood level) in the blood of the rat after a single intravenous administration of 400 mg iodine / kg of the macromolecular substance according to Example No. 18 in comparison to the monomeric nonionic lopromide.
- the data were collected from three animals each and represent the mean.
- Contrast medium according to Example No. 18 in comparison to lopromide is due to the fact that the distribution of the substance according to Example No. 18 is predominantly restricted to the vascular space, whereas lopromide is distributed throughout the extracellular space, which leads to a smaller one
- Vascular space is restricted, whereas lopromide is distributed throughout the extracellular space, which leads to a lower concentration in the blood space.
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Abstract
L'invention concerne des polymères dendritiques iodés, utiles comme agents de diagnostic par rayons X.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19521945 | 1995-06-12 | ||
DE1995121945 DE19521945A1 (de) | 1995-06-12 | 1995-06-12 | Kaskadenpolymere mit Iodaromaten |
PCT/EP1996/002517 WO1996041830A1 (fr) | 1995-06-12 | 1996-06-11 | Polymeres en cascade avec composes aromatiques iodes |
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Publication Number | Publication Date |
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EP0832150A1 true EP0832150A1 (fr) | 1998-04-01 |
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EP96921966A Withdrawn EP0832150A1 (fr) | 1995-06-12 | 1996-06-11 | Polymeres en cascade avec composes aromatiques iodes |
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EP (1) | EP0832150A1 (fr) |
DE (1) | DE19521945A1 (fr) |
WO (1) | WO1996041830A1 (fr) |
Families Citing this family (5)
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DE19729013A1 (de) * | 1997-07-03 | 1999-02-04 | Schering Ag | Oligomere, perfluoralkylhaltige Verbindungen, Verfahren zu deren Herstellung und ihre Verwendung in der NMR-Diagnostik |
DE19740403C2 (de) * | 1997-09-09 | 1999-11-11 | Schering Ag | Neue Kontrastmittel |
CN1626246A (zh) | 1999-07-29 | 2005-06-15 | 埃匹克斯医药品股份有限公司 | 通过多位点结合的寻靶多体造影剂 |
TWI221406B (en) | 2001-07-30 | 2004-10-01 | Epix Medical Inc | Systems and methods for targeted magnetic resonance imaging of the vascular system |
DE10214217A1 (de) * | 2002-03-22 | 2003-10-09 | Schering Ag | Kaskadenpolymere mit hydrophilen lodaromaten |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
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FR2610935B1 (fr) * | 1987-02-13 | 1989-09-01 | Guerbet Sa | Polymeres iodes, leurs procedes de preparation et leurs applications comme produits de contraste |
DE3938992A1 (de) * | 1989-11-21 | 1991-05-23 | Schering Ag | Kaskadenpolymer-gebundene komplexbildner, deren komplexe und konjugate, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische mittel |
CA2125188A1 (fr) * | 1991-12-04 | 1993-06-10 | Dominique Meyer | Nouveau compose macromoleculaire polyamine iode, son procede de preparation et son utilisation comme agent de contraste |
-
1995
- 1995-06-12 DE DE1995121945 patent/DE19521945A1/de not_active Withdrawn
-
1996
- 1996-06-11 EP EP96921966A patent/EP0832150A1/fr not_active Withdrawn
- 1996-06-11 WO PCT/EP1996/002517 patent/WO1996041830A1/fr not_active Application Discontinuation
Non-Patent Citations (1)
Title |
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See references of WO9641830A1 * |
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DE19521945A1 (de) | 1996-12-19 |
WO1996041830A1 (fr) | 1996-12-27 |
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