NO164458B - PHYSIOLOGICALLY COMPATIBLE, PARAMAGNETIC COMPLEX SALTS AND AGENTS FOR USE IN NMR DIAGNOSTICS. - Google Patents
PHYSIOLOGICALLY COMPATIBLE, PARAMAGNETIC COMPLEX SALTS AND AGENTS FOR USE IN NMR DIAGNOSTICS. Download PDFInfo
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- NO164458B NO164458B NO822546A NO822546A NO164458B NO 164458 B NO164458 B NO 164458B NO 822546 A NO822546 A NO 822546A NO 822546 A NO822546 A NO 822546A NO 164458 B NO164458 B NO 164458B
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- Prior art keywords
- complex
- salt
- methylglucamine
- acid
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- 230000005298 paramagnetic effect Effects 0.000 title claims abstract description 32
- 150000003839 salts Chemical class 0.000 claims abstract description 42
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 claims abstract description 34
- 229960003330 pentetic acid Drugs 0.000 claims abstract description 33
- 150000002500 ions Chemical class 0.000 claims abstract description 15
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 13
- 239000002253 acid Substances 0.000 claims abstract description 9
- 150000007513 acids Chemical class 0.000 claims abstract description 8
- 229910052747 lanthanoid Inorganic materials 0.000 claims abstract description 8
- 150000002602 lanthanoids Chemical class 0.000 claims abstract description 8
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 8
- 150000003624 transition metals Chemical class 0.000 claims abstract description 8
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 6
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 25
- WAEMQWOKJMHJLA-UHFFFAOYSA-N Manganese(2+) Chemical compound [Mn+2] WAEMQWOKJMHJLA-UHFFFAOYSA-N 0.000 claims description 16
- RJOJUSXNYCILHH-UHFFFAOYSA-N gadolinium(3+) Chemical compound [Gd+3] RJOJUSXNYCILHH-UHFFFAOYSA-N 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 11
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 10
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 7
- 239000012266 salt solution Substances 0.000 claims description 7
- 150000007530 organic bases Chemical class 0.000 claims description 6
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 5
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 5
- 239000004472 Lysine Substances 0.000 claims description 5
- IOIFRTZBJMZZFO-UHFFFAOYSA-N dysprosium(3+) Chemical compound [Dy+3] IOIFRTZBJMZZFO-UHFFFAOYSA-N 0.000 claims description 4
- SCKNFLZJSOHWIV-UHFFFAOYSA-N holmium(3+) Chemical compound [Ho+3] SCKNFLZJSOHWIV-UHFFFAOYSA-N 0.000 claims description 4
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 claims description 3
- VEQPNABPJHWNSG-UHFFFAOYSA-N Nickel(2+) Chemical compound [Ni+2] VEQPNABPJHWNSG-UHFFFAOYSA-N 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- 239000007853 buffer solution Substances 0.000 claims description 3
- XLJKHNWPARRRJB-UHFFFAOYSA-N cobalt(2+) Chemical compound [Co+2] XLJKHNWPARRRJB-UHFFFAOYSA-N 0.000 claims description 3
- 239000004094 surface-active agent Substances 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 2
- NVGBPTNZLWRQSY-UWVGGRQHSA-N Lys-Lys Chemical class NCCCC[C@H](N)C(=O)N[C@H](C(O)=O)CCCCN NVGBPTNZLWRQSY-UWVGGRQHSA-N 0.000 claims 2
- 229910052692 Dysprosium Inorganic materials 0.000 claims 1
- 229910052689 Holmium Inorganic materials 0.000 claims 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims 1
- KBQHZAAAGSGFKK-UHFFFAOYSA-N dysprosium atom Chemical compound [Dy] KBQHZAAAGSGFKK-UHFFFAOYSA-N 0.000 claims 1
- KJZYNXUDTRRSPN-UHFFFAOYSA-N holmium atom Chemical compound [Ho] KJZYNXUDTRRSPN-UHFFFAOYSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 13
- JYXGIOKAKDAARW-UHFFFAOYSA-N N-(2-hydroxyethyl)iminodiacetic acid Chemical compound OCCN(CC(O)=O)CC(O)=O JYXGIOKAKDAARW-UHFFFAOYSA-N 0.000 abstract 1
- 125000001183 hydrocarbyl group Chemical group 0.000 abstract 1
- 229920006395 saturated elastomer Polymers 0.000 abstract 1
- 229930195734 saturated hydrocarbon Natural products 0.000 abstract 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 29
- 229960001484 edetic acid Drugs 0.000 description 15
- 229910052739 hydrogen Inorganic materials 0.000 description 14
- 239000011572 manganese Substances 0.000 description 14
- 239000002872 contrast media Substances 0.000 description 11
- 229910052748 manganese Inorganic materials 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 241000700159 Rattus Species 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 238000000921 elemental analysis Methods 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 229910052688 Gadolinium Inorganic materials 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000155 melt Substances 0.000 description 6
- 210000001015 abdomen Anatomy 0.000 description 5
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- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- 238000003384 imaging method Methods 0.000 description 4
- 230000005291 magnetic effect Effects 0.000 description 4
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 4
- 230000037396 body weight Effects 0.000 description 3
- 230000009918 complex formation Effects 0.000 description 3
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- 238000003756 stirring Methods 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 229910021380 Manganese Chloride Inorganic materials 0.000 description 2
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000035508 accumulation Effects 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
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- 229940009662 edetate Drugs 0.000 description 2
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- 230000005865 ionizing radiation Effects 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 235000002867 manganese chloride Nutrition 0.000 description 2
- 239000011565 manganese chloride Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 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 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
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- 230000001488 breeding effect Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
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- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940099607 manganese chloride Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- CTYRPMDGLDAWRQ-UHFFFAOYSA-N phenyl hydrogen sulfate Chemical compound OS(=O)(=O)OC1=CC=CC=C1 CTYRPMDGLDAWRQ-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- -1 polyoxypropylene Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 238000011160 research Methods 0.000 description 1
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- 238000004904 shortening Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
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- 210000004881 tumor cell Anatomy 0.000 description 1
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Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
- G01R33/00—Arrangements or instruments for measuring magnetic variables
- G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
- G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
- G01R33/48—NMR imaging systems
- G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
- G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
- G01R33/5601—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
-
- 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
- C07F9/3839—Polyphosphonic acids
- C07F9/386—Polyphosphonic acids containing hydroxy substituents in the hydrocarbon radicals
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
- G01R33/00—Arrangements or instruments for measuring magnetic variables
- G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
- G01R33/28—Details of apparatus provided for in groups G01R33/44 - G01R33/64
- G01R33/281—Means for the use of in vitro contrast agents
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Radiology & Medical Imaging (AREA)
- General Physics & Mathematics (AREA)
- Condensed Matter Physics & Semiconductors (AREA)
- Biochemistry (AREA)
- High Energy & Nuclear Physics (AREA)
- Signal Processing (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Optics & Photonics (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Oppfinnelsen gjelder fysiologisk forenlige, paramagnetiske komplekssalter for anvendelse ved NMR-diagnostikk, The invention relates to physiologically compatible, paramagnetic complex salts for use in NMR diagnostics,
samt midler for anvendelse i NMR-diagnostikk som minst inneholder ett paramagnetisk, fysiologisk forenlig komplekssalt. Komplekssaltene og midlene har innvirkning på relaksasjons- as well as agents for use in NMR diagnostics which contain at least one paramagnetic, physiologically compatible complex salt. The complex salts and agents have an effect on relaxation
tidene ved NMR-diagnostikken. the times of the NMR diagnostics.
For kompleksdannelsen anvendes bestemte aminopolycarboxylsyrer. De fysiologisk forenlige, paramagnetiske komplekssalter ifølge oppfinnelsen er således kjennetegnet ved at de består av aminopolycarboxylsyrer med formlene I - II Certain aminopolycarboxylic acids are used for the complex formation. The physiologically compatible, paramagnetic complex salts according to the invention are thus characterized by the fact that they consist of aminopolycarboxylic acids with the formulas I - II
N,N,N',N",N"-diethylentriaminpentaeddiksyre (DTPA), N,N,N',N",N"-diethylenetriaminepentaacetic acid (DTPA),
hvor m er 1 - 4, where m is 1 - 4,
og ionene av lanthanid-elementene med atomnumrene 57 70 and the ions of the lanthanide elements with atomic numbers 57 70
eller ionene av overgangsmetallene med atomnumrene 21 - 29, or the ions of the transition metals with atomic numbers 21 - 29,
4 2 og 44, 4 2 and 44,
og en organisk base valgt blant N-methylglucamin, ethanolamin, diethanolamin, morfolin og lysin. and an organic base selected from N-methylglucamine, ethanolamine, diethanolamine, morpholine and lysine.
Oppfinnelsen omfatter videre et middel for anvend- The invention further includes a means for applying
else i NMR-diagnostikk som er kjennetegnet ved at det inneholder minst ett paramagnetisk, fysiologisk forenlig komplekssalt av aminopolycarboxylsyrer med formlene I - II other in NMR diagnostics which is characterized by the fact that it contains at least one paramagnetic, physiologically compatible complex salt of aminopolycarboxylic acids with the formulas I - II
N , N , N ' ,N" ,N"-diethy Lontriaminpentci edd i k sy ro (DTPA), N , N , N ' ,N" ,N"-diethy Lontriaminpentci edd i k sy ro (DTPA),
hvor m er 1 - 4, where m is 1 - 4,
og ionene av lanthanid-elementene med atomnumrene 57 - 70 eller ionene av overgangsmetallene med atomnumrene 21 - 29, 4 2 og 44, and the ions of the lanthanide elements with atomic numbers 57 - 70 or the ions of the transition metals with atomic numbers 21 - 29, 4 2 and 44,
og en organisk base valgt blant N-methylglucamin, ethanolamin, diethanolamin, morfolin og lysin, and an organic base selected from N-methylglucamine, ethanolamine, diethanolamine, morpholine and lysine,
eventuelt sammen med vanlige additiver innen teknikken, som for eksempel fysiologisk forenlige bufferløsninger, tensider og/eller aromastoffer, oppløst eller oppslemmet i vann eller fysiologisk saltoppløsning, idet middelet inneholder 5 - 250 mmol/1, fortrinnsvis 50 - 200 mmol/1, paramagnetisk komplekssalt og har en pH i området 6,5 - 8,0, fortrinnsvis 6,5 - 7,5. possibly together with common additives in the art, such as physiologically compatible buffer solutions, surfactants and/or aromatic substances, dissolved or suspended in water or physiological salt solution, the agent containing 5 - 250 mmol/1, preferably 50 - 200 mmol/1, paramagnetic complex salt and has a pH in the range 6.5 - 8.0, preferably 6.5 - 7.5.
Dessuten omfatter oppfinnelsen et middel for anvendelse i NMR-diagnostikk som er kjennetegnet ved at det inneholder minst ett fysiologisk forenlig, paramagnetisk komplekssalt av aminopolycarboxylsyrer med formlene I - II N,N,N',N",N"-diethylentriaminpentaeddiksyre (DTPA), In addition, the invention includes a means for use in NMR diagnostics which is characterized in that it contains at least one physiologically compatible, paramagnetic complex salt of aminopolycarboxylic acids with the formulas I - II N,N,N',N",N"-diethylenetriaminepentaacetic acid (DTPA),
hvor m er 1 - 4/where m is 1 - 4/
og ionene av lanthanid-olementone med atomnumrene 57 - 70 eller ionene av overgangsmetallen.e med atomnumrene 21 - 29, 4 2 og 4 4, and the ions of the lanthanide elements with atomic numbers 57 - 70 or the ions of the transition metal.e with atomic numbers 21 - 29, 4 2 and 4 4,
og eventuelt en uorganisk base. and optionally an inorganic base.
Som baser anvendes det for saltdannelsen som nevnt en organisk base valgt blant N-methylglucamin, ethanolamin, diethanolamin, morfolin og lysin, idet N-methylglucamin er foretrukket, I komplekssaltene som anvendes i midlene ifølge oppfinnelsen, kan det son nevnt eventuelt være til stede en uorganisk base, idet natriumhydroxyd er foretrukket. As bases, for the salt formation as mentioned, an organic base selected from N-methylglucamine, ethanolamine, diethanolamine, morpholine and lysine is used, with N-methylglucamine being preferred. In the complex salts used in the agents according to the invention, as mentioned, an inorganic base, sodium hydroxide being preferred.
Fremstillingen av de nye midlene foregår på i og for seg kjent måte, idet man løser det paramagnetiske komplekssaltet i vann eller fysiologisk saltløsning, eventuelt The production of the new agents takes place in a manner known per se, by dissolving the paramagnetic complex salt in water or physiological salt solution, possibly
under tilsetning av galenisk vanlige tilsetninger som f. with the addition of galenically common additives such as
eks. fysiologisk tålbare bufferløsninger (f.eks. natrium-dihydrogenfosfatløsning) og steriliserer løsningen. De vandige løsningene kan appliseres oralt, nevralt og spesi-elt intravasalt. Dersom det særlig for den orale avlevering er ønskelig med suspensjoner av de paramagnetiske komplekssaltene i vann eller fysiologisk saltløsning, blandes det paramagnetiske komplekssaltet med ett eller flere av de galenisk vanlige hjelpestoffene og/eller tensidene og/eller aromastoffene for smakskorrigering og suspenderes før den orale anvendelsen i vann eller fysiologisk saltløsning. e.g. physiologically tolerable buffer solutions (e.g. sodium dihydrogen phosphate solution) and sterilize the solution. The aqueous solutions can be applied orally, neurally and especially intravasally. If suspensions of the paramagnetic complex salts in water or physiological salt solution are particularly desirable for the oral delivery, the paramagnetic complex salt is mixed with one or more of the galenically common excipients and/or surfactants and/or flavoring agents for taste correction and suspended before oral use in water or physiological saline solution.
Det anvendes herved fortrinnsvis 3 til 10 g paramagnetisk komplekssalt og 2 til 8 g av ett eller flere hjelpestoffer som f.eks. saccharose, høydisperst siliciumdioxyd, poly-oxylenpolyoxypropylen-polymerer, stivelse, magnesiumstearat, natriumarylsulfat, talkum, lactose eller natriumcarboxy-methylcellulose. Hereby, 3 to 10 g of paramagnetic complex salt and 2 to 8 g of one or more excipients such as e.g. sucrose, highly dispersed silicon dioxide, polyoxylene polyoxypropylene polymers, starch, magnesium stearate, sodium aryl sulfate, talc, lactose or sodium carboxymethylcellulose.
Til NMR-diagnostikk hos mennesker anvendes vandige løsninger eller suspensjoner som inneholder 5 til 250 mmol/1, fortrinnsvis 50 til 200 mmol/1, av et paramagnetisk komplekssalt. De vandige løsningene ligger i pH-området mellom ca. 6,5 og 8,0, fortrinnsvis mellom 6,5 og 7,5. For NMR diagnostics in humans, aqueous solutions or suspensions containing 5 to 250 mmol/1, preferably 50 to 200 mmol/1, of a paramagnetic complex salt are used. The aqueous solutions lie in the pH range between approx. 6.5 and 8.0, preferably between 6.5 and 7.5.
Ved kompleksdannelsen avgiftes de paramagnetiske saltene og det oppnås dessuten at saltene også i det fysio-logiske pH-området i vann er bestandige og godt oppløselige. During the complex formation, the paramagnetic salts are detoxified and it is also achieved that the salts are also stable and well soluble in the physiological pH range in water.
Særlig egnet synes de nye midlene i form av kompleks-saltløsninger å være for bedre avgrensning henholdsvis loka-lisasjon av lesjoner i bukspyttkjertelen og leveren såvel som tumorer og blødninger i det kraniale området. For diagnose av det område; som skal undersøkes appliseres eksempelvis en vandig løsning av paramagnetisk komplekssalt som er isotonisk med blod i en dose fra 1 til 100 umol/ kg intravenøst. Ved en konsentrasjon av komplekssaltet fra 50 til 200 mmol/1 behøves det for en undersøkelse på mennesker ca. 1 til 50 ml løsning. Opptak av det skikt som er interessant skjer ca. 15 til 60 min. etter den intra-venøse applikasjon av den vandige løsningen av det para-m-agnetiske komplekssaltet. The new agents in the form of complex salt solutions appear to be particularly suitable for better demarcation and localization of lesions in the pancreas and liver as well as tumors and bleeding in the cranial area. For diagnosis of that area; to be investigated, an aqueous solution of a paramagnetic complex salt that is isotonic with blood is applied, for example, in a dose of 1 to 100 umol/kg intravenously. At a concentration of the complex salt from 50 to 200 mmol/1, approx. 1 to 50 ml solution. Recording of the layer that is interesting takes place approx. 15 to 60 min. after the intra-venous application of the aqueous solution of the para-m-magnetic complex salt.
De i den medisinske praksis vanlige fysikalske diagnose-fremgangsmåter, som kan utføres uten eller bare med lite operativt inngrep, er eksempelvis gjennomstråling av kroppen med røntgenlys, scintigrafi og sonografi. Alle disse metoder er enten beheftet med sunnhetsrisker eller anvendelsesom-rådet er innskrenket. Således utsettes pasienten ved rønt-genteknikkene og scintigrafien for ioniserende stråling, slik at disse metodene ikke kan anvéndes etter behag eller slett ikke ved risikogrupper, som eksempelvis hos diebarn og svangre. The physical diagnostic procedures common in medical practice, which can be carried out without or with little operative intervention, are, for example, irradiation of the body with X-ray light, scintigraphy and sonography. All these methods are either fraught with health risks or the area of application is restricted. The x-ray techniques and scintigraphy thus expose the patient to ionizing radiation, so that these methods cannot be used at will or not at all in risk groups, such as, for example, nursing infants and pregnant women.
Sonografien har riktignok ikke de nevnte ulempene, men likevel er deres anvendelsesområde meget innskrenket, særlig i det kraniale området. It is true that sonography does not have the aforementioned disadvantages, but nevertheless their area of application is very limited, particularly in the cranial area.
Da det på tross av stort forskningsarbeid hittil ennå ikke er lykkes fullstendig å fjerne de beskrevne ulempene, søker man etter fremgangsmåter som gir bilder, som ikke har ulempene, men gir en sammenlignbar informasjonsgevinst for diagnosen. Since, despite extensive research work, it has not yet succeeded in completely removing the described disadvantages, methods are being sought that provide images that do not have the disadvantages, but provide a comparable gain in information for the diagnosis.
En av disse bildegivende fremgangsmåtene er kjerne-spinntomografien (Spin-Imaging, "Zeugmatographie") som be-ror på den fysikalske effekt av den såkalte kjernespinn-resonans ("Nuclear Magnetic Resonance") denne diagnose-fremgangsmåte gjør det mulig å oppnå snittbilder av den levende kropp og innblikk i stoffskifteprosesser uten anvendelse av ioniserende stråler. Effekten av kjerne-resonansen viser atomkjerner, som, som f.eks. hydrogen, One of these imaging procedures is nuclear spin tomography (Spin-Imaging, "Zeugmatographie") which depends on the physical effect of the so-called nuclear magnetic resonance ("Nuclear Magnetic Resonance"), this diagnostic procedure makes it possible to obtain cross-sectional images of the living body and insight into metabolic processes without the use of ionizing radiation. The effect of the nuclear resonance shows atomic nuclei, which, as e.g. hydrogen,
som i det biologiske vevet i hovedsak finnes som vann, har et magnetisk moment og ved hjelp av. dette retter seg ut i et sterkt ytre magnetfelt. Ved en høyfrekvens-impuls (resonansfrekvens) bringes de ut av sin likevektstilstand, til hvilken de vender tilbake med en karakteristisk hastig-het igjen. Varigheten på tilbakevendelsen til likevekts-tilstanden, den såkalte relaksasjonstid, gir opplysning om ordensgraden til atomet og over deres vekselvirkning med sin omgivelse. which in the biological tissue is mainly found as water, has a magnetic moment and with the help of. this aligns itself in a strong external magnetic field. By a high-frequency impulse (resonant frequency) they are brought out of their equilibrium state, to which they return with a characteristic speed again. The duration of the return to the equilibrium state, the so-called relaxation time, provides information about the degree of order of the atom and about their interaction with their surroundings.
Bildefremstillingen, som oppnås ved måling av protontykkelse henholdsvis relaksasjonstider, er av høy diagnostisk verdi og gir opplysning om antallet og om tilstanden til det undersøkte vevet. Således oppviser tumorvev eksempelvis lengre relaksasjonstider enn sunt sammenligningsvev. The imaging, which is obtained by measuring proton thickness and relaxation times, is of high diagnostic value and provides information on the number and condition of the examined tissue. Thus, for example, tumor tissue exhibits longer relaxation times than healthy comparison tissue.
(A. Ganssen u.a. Computertomographie 1, 1981. s. 2-10; Georg Thieme Verlag, Stuttgart, New York). (A. Ganssen et al. Computertomographie 1, 1981. pp. 2-10; Georg Thieme Verlag, Stuttgart, New York).
Det er nå fastslått, at paramagnetiske ioner, som eksempelvis Mn 2 + (mangan) eller Cu 2 +(kobber), innvirker på relaksasjonstidene og dermed forhøyer informasjonsinnholdet. It has now been established that paramagnetic ions, such as Mn 2 + (manganese) or Cu 2 + (copper), affect the relaxation times and thus increase the information content.
De tungmetallsaltløsninger som hittil er anvendt på forsøksdyr, er dog uegnet for intravenøs/ applikasjon på mennesker på grunn av deres høye toksisitet. Det letes derfor etter paramagnetiske substanser, som tåles godt og innvirker gunstig på bildegivingen. Det sistnevnte kan eksempelvis foregå derved, at spinn-gitter-relaksasjonstiden T nedsettes sterkt, mens samtidig spinn-spinn-relaksasjonstid T2 holdes i det vesentlige konstant. Det ble nå funnet, at den ønskede avgiftning av de ellers toksiske metallsaltene kan foregå ved en kompleksering, uten at de param.agnetiske egenskapene påvirkes ugunstig. Det siste er overraskende, da herved som kjent fordelingen av d- henholdsvis f-elektroner forandres over d- henholdsvis f-orbitalen. Således kunne det ved forsøk på rotter i av-søker med magnetfelt på 0,15 Tesla ved en innmatet energi på 300 Watt/impuls og en 180°-puls på 720 us ved opptaks-tider på 2 min. stundom 10 min. etter intravenøs injeksjon av .20 umol/kg mangan-edetat som vandig glucaminsaltløsning med en konsentrasjon på 6 mmol/1 observeres en tydelig sterkere forandring av signalet i området for leverparenzymet sammenlignet med 0-opptaket, mens det med en vandig mangan (II) kloridløsning med samme molaritet under de samme forsøksbetingelser bare kunne oppnås en forholdsvis liten kontrastering. På den annen side oppnås ved kompleksdannelsen den ønskede avgiftning av de ellers toksiske paramagnetiske saltene. Således ble det hos rotter etter intravenøs injeksjon av en vandig løsning av N-methylglucaminsaltet av mangan-edetat funnet et LD^g på 4 mmol/kg. Sammenliknet med dette viste manganklorid under identiske betingelser hos rotter en LDj-q på bare 0,5 mmol/kg. However, the heavy metal salt solutions that have so far been used on experimental animals are unsuitable for intravenous/application on humans due to their high toxicity. There is therefore a search for paramagnetic substances, which are well tolerated and have a favorable effect on the imaging. The latter can, for example, take place in that the spin-lattice relaxation time T is greatly reduced, while at the same time the spin-spin relaxation time T2 is kept essentially constant. It was now found that the desired detoxification of the otherwise toxic metal salts can take place by complexation, without the paramagnetic properties being adversely affected. The latter is surprising, as this, as is well known, changes the distribution of d- and f-electrons over the d- and f-orbital respectively. Thus, when testing rats in a detector with a magnetic field of 0.15 Tesla at an input energy of 300 Watt/impulse and a 180° pulse of 720 us with recording times of 2 min. sometimes 10 min. after intravenous injection of .20 umol/kg manganese edetate as an aqueous glucamine salt solution with a concentration of 6 mmol/1, a clearly stronger change in the signal in the area of the liver parenzyme is observed compared to the 0 uptake, while with an aqueous manganese (II) chloride solution with the same molarity under the same experimental conditions only a relatively small contrast could be achieved. On the other hand, the complex formation achieves the desired detoxification of the otherwise toxic paramagnetic salts. Thus, in rats, after intravenous injection of an aqueous solution of the N-methylglucamine salt of manganese edetate, an LD^g of 4 mmol/kg was found. Compared to this, manganese chloride under identical conditions in rats showed an LDj-q of only 0.5 mmol/kg.
Gjennomføringen av en NMR-diagnostisk undersøkelse under anvendelse av komplekssalt skal forklares nærmere ved hjelp av følgende eksempel: Det fremstilles en steril, vandig løsning av N-methylglucaminsaltet av gadolinium-III-komplekset av diethylentriaminpentaeddiksyre med en konsentrasjon på 0,1 mol/l. pH-verdi-en i den klare løsningen var 7,2. The implementation of an NMR diagnostic examination using a complex salt shall be explained in more detail with the help of the following example: A sterile, aqueous solution of the N-methylglucamine salt of the gadolinium-III complex of diethylenetriaminepentaacetic acid with a concentration of 0.1 mol/l is prepared. The pH value of the clear solution was 7.2.
Den for NMR-tomografien benyttede (Siemens AG/Erlangen) hel.kroppavsøkeren arbeider med et magnetfelt på 0,1 T, som tilsvarer en "Larmorprotonfrekvens" på 4,99 MHz. Apparatet ble utstyrt med en høyfrekvens sender- og mottaker-spole av liten dimensjon, for også å kunne avbilde objekter med liten størrelse med tilfredsstillende oppløsning. Under-søkelsene ble gjennomført etter en spinn- ekko-fremgangsmåte. Tiden for et opptak oppgikk til mellom 1 og 3 min. The (Siemens AG/Erlangen) whole-body scanner used for the NMR tomography works with a magnetic field of 0.1 T, which corresponds to a "Larmor proton frequency" of 4.99 MHz. The device was equipped with a high-frequency transmitter and receiver coil of small dimensions, in order to also be able to image objects of small size with satisfactory resolution. The examinations were carried out using a spin echo method. The time for a recording amounted to between 1 and 3 min.
Forsøkene gjennomføres med hannrotter av oppdrett (Wistar-Han-Schering (SPF)) med en kroppsvekt på 250 g. 8 dager før undersøkelsen mottok dyrene en Novikoff-Hepa-tom -tumor-cellesuspensjon intraperitonealt (0,5 ml med The experiments are carried out with breeding male rats (Wistar-Han-Schering (SPF)) with a body weight of 250 g. 8 days before the examination, the animals received a Novikoff-Hepa-tom tumor cell suspension intraperitoneally (0.5 ml with
1 x IO<6> celler). 1 x IO<6> cells).
Dyrene narkotiseres med en intraperitoneal injeksjon av pentobarbital-natrium (60 mg/kg kropsvekt). Deretter fikk dyrene innlagt en vingekanyle i en av halevenene. The animals are anesthetized with an intraperitoneal injection of pentobarbital sodium (60 mg/kg body weight). The animals then had a wing cannula inserted into one of the tail veins.
Før applikasjon av kontrastmidlet lages det opptak Before application of the contrast agent, a recording is made
i kroppsstammens sagittale og horisontale plan (illustrasjon 1, 2) . in the sagittal and horizontal planes of the body trunk (illustration 1, 2) .
Kontrastmidlet appliseres intravenøst i løpet av 1 min. i en dose på 1 mmol/kg. I illustrasjon 3 oq 4 som er mellom 22 og 25 min. etter peritoneal applikasjon, kan det fastslås en sterk uklarhetsøkning i abdomen. Etter intravenøs inngivelse kommer kontrastmidlet inn i de pato-logiske væskeansamlingene og bevirker her en sterk for-kortning av spinn-gitter-relaksasjonstiden (T^) som fører til en stigning av signalintensiteten. Først etter applikasjon av kontrastmidlet er den tumorøse væskeansamling og en forbedret avgrensning av organene erkjennbar. Uten tilsetning av kontrastmiddel kan det knapt erkjennes strukturer i abdomen, da organene bare oppviser små forskjeller i protontykkelse og relaksasjonstider. The contrast agent is applied intravenously within 1 min. in a dose of 1 mmol/kg. In illustration 3 oq 4 which is between 22 and 25 min. after peritoneal application, a strong increase in opacity can be determined in the abdomen. After intravenous administration, the contrast agent enters the pathological fluid accumulations and here causes a strong shortening of the spin-lattice relaxation time (T^), which leads to an increase in the signal intensity. Only after application of the contrast agent is the tumorous fluid accumulation and an improved delineation of the organs recognisable. Without the addition of contrast medium, structures in the abdomen can hardly be recognized, as the organs only show small differences in proton thickness and relaxation times.
Også etter oral inngivelse av kontrastmidlet forbedres avgrensningen av strukturene. I denne hensikt gis 5 ml av N-methylglucaminløsningen av gadoliniumkomplekset av diethylentriaminpentaeddiksyren i en konsentrasjon på 1 mmol/1 ved hjelp av en sonde med en narkotisert hannrotte (kroppsvekt 250 g) . Først etter inngivelse av kontrastmidlet /(illustrasjonene 5, 6, 7) er en klar avgrensning av maven henholdsvis tarmkanalen fra de resterende organene synlig. Also after oral administration of the contrast agent, the delineation of the structures is improved. For this purpose, 5 ml of the N-methylglucamine solution of the gadolinium complex of the diethylenetriaminepentaacetic acid in a concentration of 1 mmol/l is given by means of a probe with an anesthetized male rat (body weight 250 g). Only after administration of the contrast medium / (illustrations 5, 6, 7) is a clear demarcation of the stomach or the intestinal tract from the remaining organs visible.
Egne farmakokinetiske undersøkelser hos rotter har vist at N-methylglucaminløsningen av gadoliniumkomplekset av diethylentriaminpentaeddiksyre etter intravenøs og sub-kutan inngivelse for det meste elimineres renalt i løpet av 2 4 timer. Gadoliniumkomplekset utskilles ved glomerulær filtrasjon med en halvtid på ca. 20 min. fra rotten. Den andel som elimineres med feces er mindre enn 5% av den appliserte dose. Own pharmacokinetic studies in rats have shown that the N-methylglucamine solution of the gadolinium complex of diethylenetriaminepentaacetic acid after intravenous and subcutaneous administration is mostly eliminated renally within 24 hours. The gadolinium complex is excreted by glomerular filtration with a half-time of approx. 20 min. from the rat. The proportion that is eliminated with faeces is less than 5% of the applied dose.
Etter oral irngivelse observeres ingen resorpsjon av substansen. Det farmakokinetiske forhold ligner forholdet til de klassiske røntgenkontrastmidlene for uroangiografien. After oral administration, no resorption of the substance is observed. The pharmacokinetic relationship is similar to that of the classical X-ray contrast agents for uroangiography.
Illust. 1: Opptak i sagittalplanet til en levende rotte, som 8 dager før undersøkelsen fikk transplantert et Novikoff-nepatom. Illust. 3: Opptak i sagittalplanet 2 2 min. etter intravenøs inngivelse 1 mmol/kg av N-methylglucaminsaltet av gadoliniumkomplekset av diethylentriaminpentaeddiksyre. Tydelig kan det merkes den sterke oppklaring av ascites-væsken . Illust. 2; Opptak i horisontalplanet av det samme dyret i høyde med abdomen. I llust. 4: Opptak i horisontalplanet av samme dyr i høyde med abdomen. illust. 5: Opptak av en levende rotte før inngivelse av et kontrastmiddel.Illust. 6: Opptak av det samme dyret 10 min. etter oral inngivelse av 5 ml av en løsning (1 mmol/1) av N-methylglucaminsaltet av gadoliniumkomplekset av diethylentriaminpentaeddiksyren. Illust. 1: Recording in the sagittal plane of a living rat, which had a Novikoff nepatoma transplanted 8 days before the examination. Illust. 3: Recording in the sagittal plane 2 2 min. after intravenous administration of 1 mmol/kg of the N-methylglucamine salt of the gadolinium complex of diethylenetriaminepentaacetic acid. The strong clarification of the ascites fluid can be clearly felt. Illust. 2; Recording in the horizontal plane of the same animal at the height of the abdomen. In llust. 4: Recording in the horizontal plane of the same animal at the height of the abdomen. illus. 5: Recording of a living rat before administration of a contrast agent. Illust. 6: Recording of the same animal 10 min. after oral administration of 5 ml of a solution (1 mmol/1) of the N-methylglucamine salt of the gadolinium complex of diethylenetriaminepentaacetic acid.
Illust. 7; Horisontalsnitt gjennom abdomen av samme dyr i høyde med magen 30 min. etter oral inngivelse av kontrastmidlet. Magen er tydelig avgrens-bar ved hjelp av kontrastmidlet. Illust. 7; Horizontal section through the abdomen of the same animal at the level of the stomach 30 min. after oral administration of the contrast agent. The stomach is clearly delineable with the help of the contrast agent.
Fremstillingen av de paramagnetiske komplekssaltene The preparation of the paramagnetic complex salts
foregår ifølge fremgangsmåter som er kjente for fagmannen, idet det paramagnetiske metallsaltet av lanthanidelementene med atomnumrene 57 til 70 eller overgangsmetallene med atomnumrene 21 til 29, 42 og 44 oppløses i vann og/eller alkohol og tilsettes en løsning av de ekvivalente mengdene av kompleksdannerne i vann og/eller alkohol og omrøres, om nødvendig under oppvarming til 50°C til 120°C til omset- takes place according to methods known to those skilled in the art, whereby the paramagnetic metal salt of the lanthanide elements with atomic numbers 57 to 70 or the transition metals with atomic numbers 21 to 29, 42 and 44 is dissolved in water and/or alcohol and a solution of the equivalent amounts of the complex formers in water is added and/or alcohol and stirred, if necessary while heating to 50°C to 120°C until the
ningen er avsluttet. Dersom det anvendes alkohol som løs-ningsmiddel, anvendes methanol eller ethanol. Når det dannede kompleks er uløselig i det anvendte løsningsmiddel, krystalliserer det og kan avfiltreres. Er det løselig, ning has ended. If alcohol is used as solvent, methanol or ethanol is used. When the complex formed is insoluble in the solvent used, it crystallizes and can be filtered off. Is it soluble,
kan det isoleres ved inndampning av løsningen til tørrhet. can be isolated by evaporating the solution to dryness.
Fremgangsmåten skal forklares nærmere ved hjelp av The procedure shall be explained in more detail by means of
følgende arbeidsforskrifter: the following work regulations:
Fremstilling av mangan-II-komplekset av ethylendiamin-t etraeddiksyre : Preparation of the manganese-II complex from ethylenediamine-tetraacetic acid:
Suspensjonen av 6,17 g mangan-II-carbonat i 500 ml The suspension of 6.17 g of manganese II carbonate in 500 ml
vann tilsettes 14,6 g ethylendiamintetraeddiksyre og opp- water, 14.6 g of ethylenediaminetetraacetic acid is added and up-
varmes under omrøring på dampbad, hvorved det opptrer en gassutvikling. Den til å begynne med rosa fargen forsvinner etter ca. 20 min. og alt unntatt en liten rest går i opp- is heated while stirring in a steam bath, whereby a gas evolution occurs. The initially pink color disappears after approx. 20 min. and all but a small remnant goes up-
løsning. Etter 1 times omrøring ved 110°C avfiltreres det uløste og filtratet avkjøles. Etter 15 timers henstand avsuges krystallisatet og tørkes: = 14,1 g (molvekt 345,17) smp. 256°/258-259°C. Fremstilling av gadolinium- III- komplekset av diethylentriamin- pentaeddiksyre: Fremstilling av suspensjonen av _435 g gladoliniumoxyd (Gd20.j) og 944 g diethylentriamin-penta-eddiksyre i 12 1 vann oppvarmes under omrøring ved 90°C til 100°C og omrøres i 48 timer ved denne temperatur. Så frafiltreres det uløste og filtratet inndampes til tørrhet. Den amorfe rest pulveriseres. solution. After stirring for 1 hour at 110°C, the undissolved material is filtered off and the filtrate is cooled. After standing for 15 hours, the crystallisate is suctioned off and dried: = 14.1 g (mol weight 345.17) m.p. 256°/258-259°C. Preparation of the gadolinium-III complex of diethylenetriamine-pentaacetic acid: Preparation of the suspension of _435 g of gladolinium oxide (Gd20.j) and 944 g of diethylenetriamine-penta-acetic acid in 12 1 of water is heated with stirring at 90°C to 100°C and stirred in 48 hours at this temperature. The undissolved material is then filtered off and the filtrate is evaporated to dryness. The amorphous residue is pulverized.
Utbytte 144 g: (molekylvekt 547,58) Yield 144 g: (molecular weight 547.58)
Smeltepunkt: smelter fra 235° og blir uspaltet opptil 320°C. Melting point: melts from 235° and remains undecomposed up to 320°C.
Dersom den oppnådde paramagnetiske kompleksforbindelse fortsatt inneholder en eller flere sure eller basiske grupper, så kan den oppnådde kompleksforbindelse om ønsket deretter løses eller suspenderes i vann og tilsettes den uorganiske eller organiske base henholdsvis syre, inntil nøytralpunktet er oppnådd. Etter frafiltrering av uløste deler inndampes løsningen og det ønskede komplekssalt oppnås som rest. If the obtained paramagnetic complex compound still contains one or more acidic or basic groups, then the obtained complex compound can, if desired, then be dissolved or suspended in water and added to the inorganic or organic base or acid, until the neutral point is reached. After filtering off undissolved parts, the solution is evaporated and the desired complex salt is obtained as a residue.
Disse forbindelsene er nye. These connections are new.
Følgende eksempler skal forklare oppfinnelsen nærmere. The following examples shall explain the invention in more detail.
Eksempel 1 Example 1
Fremstilling av di-N-methylglucaminsaltet av mangan(II)-komplekset av ethylendiamin-tetraeddiksyr<e,><C>2^<H>^<gN>^0^gMn. Preparation of the di-N-methylglucamine salt of the manganese(II) complex of ethylenediamine-tetraacetic acid<e,><C>2^<H>^<gN>^0^gMn.
7,4 g (= 20 mmol) av mangan(II)-komplekset av ethylendiamin-tetraeddiksyre (vanninnhold 6,9%) suspenderes i 30 ml vann og oppløses ved tilsetning av omtrent 7,8 g (= 40 7.4 g (= 20 mmol) of the manganese(II) complex of ethylenediamine-tetraacetic acid (water content 6.9%) are suspended in 30 ml of water and dissolved by the addition of approximately 7.8 g (= 40
mmol) N-methylglucamin ved pH 7,5. Etter frafiltrering av litt uløselig stoff inndampes løsningen til tørrhet i vakuum. Det oppstår et fast skum i kvantitativt utbytte, som smelter fra 95°C og som blir seigtflytende ved 170°C. mmol) N-methylglucamine at pH 7.5. After filtering off some insoluble material, the solution is evaporated to dryness in a vacuum. A solid foam is formed in quantitative yield, which melts from 95°C and becomes viscous at 170°C.
Analyse: Beregnet tørrsubstans C 39,19% H 6,58% N 7,61% Analysis: Calculated dry substance C 39.19% H 6.58% N 7.61%
Mn 7,47% Mn 7.47%
Funnet; C 39,23 H 7,10% N 7,26% Found; C 39.23 H 7.10% N 7.26%
Mn 7,53% H20 3,26% Ekvivaléntvekt beregnet 367,8 Mn 7.53% H20 3.26% Equivalent weight calculated 367.8
funnet 369 (filtrering med tetramethyl-ammoniumhydroxyd i vandig aceton ) . found 369 (filtration with tetramethylammonium hydroxide in aqueous acetone).
Ved oppløsning i varm methanol og inndamping i vakuum til tørrhet oppnås substansen som hvitt, hygroskop-isk pulver. By dissolving in hot methanol and evaporating in a vacuum to dryness, the substance is obtained as a white, hygroscopic powder.
På analog måte oppnås: Analogously, this is achieved:
Di-N-methylglucaminsalt av nikkel(II)-komplekset av ethylendiamintetraeddiksyre, C24H4gN40lgNi, som blått pulver med dekomponeringspunkt ved 220-223°C. Di-N-methylglucamine salt of the nickel(II) complex of ethylenediaminetetraacetic acid, C24H4gN40lgNi, as a blue powder with a decomposition point at 220-223°C.
Elementæranalyse (beregnet på tørrstoff): Elemental analysis (calculated on dry matter):
Di-ethanolaminsalt av kobolt(II)-komplekset av ethylendiamintetraeddiksyre, C^H^N^jO^Co, som rosafarvet pulver som sintrer ved 105°C og smelter ved 180-185°C. Elementæranalyse (beregnet på tørrstoff): C 35,67% H 5,98% N 11,88% Co 12,50% (beregnet) Di-ethanolamine salt of the cobalt(II) complex of ethylenediaminetetraacetic acid, C^H^N^jO^Co, as pink powder which sinters at 105°C and melts at 180-185°C. Elemental analysis (calculated on dry matter): C 35.67% H 5.98% N 11.88% Co 12.50% (calculated)
C 35,78% H 6,03% N 11,70%' Co 12,40% (funnet) C 35.78% H 6.03% N 11.70%' Co 12.40% (found)
Dimorfolinsalt av mangan(II)-komplekset av ethylendiamintetraeddiksyre, ClgH32N401C)Mn, som hvitt pulver med dekomponeringspunkt 270-275 C. Dimorpholine salt of the manganese(II) complex of ethylenediaminetetraacetic acid, ClgH32N401C)Mn, as white powder with decomposition point 270-275 C.
Elementæranalyse (beregnet på tørrstoff): Elemental analysis (calculated on dry matter):
C 41,62% H 6,21% N 10,78% Mn 10,57% (beregnet) C 41.62% H 6.21% N 10.78% Mn 10.57% (calculated)
C 41,52% H 6,40% N 10,58% Mn 10,32% (funnet) C 41.52% H 6.40% N 10.58% Mn 10.32% (found)
Di-diethanolaminsalt av kobber(II)-komplekset av ethylendiamintetraeddiksyre, ci8H36N4°12Cu' som klått Pulver med dekomponeringspunkt ved 212-215°C. Di-diethanolamine salt of the copper(II) complex of ethylenediaminetetraacetic acid, ci8H36N4°12Cu' as clinched Powder with decomposition point at 212-215°C.
Elementæranalyse (beregnet på tørrstoff): Elemental analysis (calculated on dry matter):
C 38,33% H 6,43% N 9,93% Cu 11,26% (beregnet) C 38.33% H 6.43% N 9.93% Cu 11.26% (calculated)
C 38,50% H 6,55% N 9,83% Cu 11,10% (funnet) C 38.50% H 6.55% N 9.83% Cu 11.10% (found)
Tri-diethanolaminsalt av mangan(II)-komplekset av diethylentriaminpentaeddiksyr<e,> C-jgHj-^NgO-^Mn, som gult pulver som sintrer ved 90°C og smelter ved 185-188°C. Elementæranalyse (beregnet på tørrstoff): C 41,00% H 7,14% N 11,03% Mn 7,21% (beregnet) Tri-diethanolamine salt of the manganese(II) complex of diethylenetriaminepentaacetic acid<e,> C-jgHj-^NgO-^Mn, as a yellow powder which sinters at 90°C and melts at 185-188°C. Elemental analysis (calculated on dry matter): C 41.00% H 7.14% N 11.03% Mn 7.21% (calculated)
C 41,18% H 7,30% N 11,15% Mn 7,33S (funnet) C 41.18% H 7.30% N 11.15% Mn 7.33S (found)
Tri-N-methylglucaminsalt av mangan(II)-komplekset av diethylentriaminpentaeddiksyr<e,> C^H^Ng^S*11' som hvitt pulver som sintrer ved 92°C og smelter ved 202-205°C. Elementæranalyse (beregnet på tørrstoff): ;C 40,73% H 7,03% N 8,14% Mn 5,32% (beregnet) ;C 40,55% H 7,22% N 8,32% Mn 5,11% (funnet) ;Eksempel 2 ;Fremstilling av N-methylglucaminsaltet av gadolinium (III)-komplekset av ethylendiamin-tetraeddiksyre, ;<C>17<H>30<N>3°13<Gd>- ;4,58 g (= 10 mmol) av gadolinium (III)-komplekset av ethylendiamin-tetraeddiksyre (vanninnhold 2,7%) suspenderes i 15 ml vann og oppløses ved tilsetning av 1,95 g (= 10 mmol) N-methylglucamin ved pH 7,4. Løsningen filtreres og inndampes deretter til tørrhet i vakuum, hvorved det oppstår et fast skum. Utbyttet er idet det tas hensyn til vann-innholdet på 8,5% praktisk talt kvantitativt. Substansen sintrer fra 90°C, fra 140°C inntil skumutvikling. ;Analyse: Beregnet C 26,90% H 2,44% N 6,27% Gd 35,22% Funnet i tørrsub- ;stans: C 26,78% H 2,96% N 5,77% Gd 34,99% ;Ekvivalentvekt beregnet 6 41,7 ;Funnet 634 (titrering med tetramethylammon-iumhydroxyd i vandig aceton). ;Ved oppløsning i varm ethanol og inndamping i vakuum til tørrhet oppnås substansen som hvitt pulver. ;På analog måte oppnås: ;N-methylglucaminsalt av dysprosium(III)-komplekset ;av ethylendiamintetraeddiksyre, C-^H^^O-^Dy, som hvitt pulver med smeltepunkt ved 180-185°C. ;Elementæranalyse (beregnet på tørrstoff): ;;Di-N-methylglucaminsalt av holmium(III)-komplekset av diethylentriaminpentaeddiksyr<e,> C"2gH54N5020Ho, som hvitt pulver som sintrer ved 88°C og smelter ved 187-190°C. Elementæranalyse (beregnet på tørrstoff): ;Di-lysinsalt av gadolinium(III)-komplekset av diethylentriamin-pentaeddiksyre, C — H, oN-,0, .Gd: ;Z o ho I 14 Elementæranalyse: ;Di-N-methylglucaminsalt av gadolinium(III)komplekset av diethylentriamin-pentaeddiksyre, C28<H>5<4>N5<0>2QGd. Elementæranalyse: ;Eksempel 3 ;Fremstilling av en løsning av di-N-methylglucaminsaltet av mangan (II)-komplekset av ethylendiamin-tetraeddiksyre. ;3,68 g (= 5 mmol) av den i eksempel 1 beskrevne substans oppløses i 70 ml vann pro injectione (p.i.) og opp-løsningen tilsettes 0.4 g natriumklorid. Deretter oppfylles til 100 ml med vann p.i. og oppløsningen fylles i ampuller gjennom et sterilfilter. Løsningen er isoton med 280 mOsm. ;Eksempel 4 ;Fremstilling av en løsning av N-methylglucaminsaltet ;av gadolinium (III)-komplekset av ethylen-diamintetraeddik-syre. ;9,6 3 g (= 15 mmol) av den i eksempel 2 beskrevne substans oppløses i 100 ml vann o.i. den tilnærmet blodisotone løs-ning fylles i ampuller over et sterilfilter. ;Eksempel 5 ;Fremstilling av en løsning av di-N-methylglucaminsaltet av gadolinium (III)-komplekset av diethylentriaminpentaeddiksyre. ;5,35 g (= 9 mmol) av gadolinium (III)-komplekset av diethylentriaminpentaeddiksyre (vanninnhold 8%) oppløses i 50 ml vann p.i. og nøytraliseres ved tilsetning av ca. 3,2 g ;(tilsvarer ca. 18 mmol) N-methylglucamin til pH 7,5. Deretter fylles løsningen opp til 100 ml med vann p.i., fylles på ampuller og varmesteriliseres. Konsentrasjonen av løs-ningen innstilles på blodisotoni (ca. 280 mOsm). ;Eksempel 6 ;Fremstilling av en løsning av di-N-methylglucaminsaltet av dysprosium (III)-komplekset av diethylentriaminpentaeddiksyre^^ ;8,0 g (= 15 mmol) av dysprosium (III)-komplekset av diethylentriaminpentaeddiksyre oppløses i 80 ml vann p.i. under tilsetning av ca. 5,3 g (tilsvarer ca. 30 mmol) N-methylglucamin ved pH 7,5. Deretter fylles løsningen opp til 170 ml med vann p.i. Den tilnærmet blodisotone løs-ning fylles på ampuller og varmesteriliseres. ;Eksempel 7 ;Fremstilling av en løsning av di-N-methylglucaminsaltet av holmium (III)-komplekset av av diethylentriaminpentaeddiksyre . ;8,02 g (= 15 mmol) av holmium (III)-komplekset av diethylentriaminpentaeddiksyre op<p>løses i 80 ml vann p.i. under tilsetning av ca. 5,3 g(tilsvarer ca. 30 mmol) N-methylglucamin ved pH 7,2. Deretter oppfylles løsningen med vann p.i. til 170 ml. Den tilnærmede blodisotone løsning fylles på ampuller og varmesteriliseres. ;Løsningen kan også fremstilles ved oppløsning av det ifølge eksempel 2 isolerte komplekssalt. i vann p.i. ;Eksempel 8 ;Fremstilling av en løsning av di-natriumsaltet av mangan (II)- komplekset av ethylendiamin-tetraeddiksyre. ;5,55 g (15 mmol) av mangan (II)-komplekset av ethylendiamintetraeddiksyre (vanninnhold: 6,9%) oppløses i 80 ml vann p.i. under tilsetning av fortynnet natronlut ved pH 7,5. Deretter fylles løsningen opp med vann p.i. til 170 ml, filtreres i ampuller og varmesteriliseres. *Tri-N-methylglucamine salt of the manganese(II) complex of diethylenetriaminepentaacetic acid<e,> C^H^Ng^S*11' as a white powder which sinters at 92°C and melts at 202-205°C. Elemental analysis (calculated on dry matter): ;C 40.73% H 7.03% N 8.14% Mn 5.32% (calculated) ;C 40.55% H 7.22% N 8.32% Mn 5, 11% (found) ;Example 2 ;Preparation of the N-methylglucamine salt of the gadolinium (III) complex from ethylenediamine-tetraacetic acid, ;<C>17<H>30<N>3°13<Gd>- ;4.58 g (= 10 mmol) of the gadolinium (III) complex of ethylenediamine-tetraacetic acid (water content 2.7%) is suspended in 15 ml of water and dissolved by the addition of 1.95 g (= 10 mmol) of N-methylglucamine at pH 7.4 . The solution is filtered and then evaporated to dryness in a vacuum, whereby a solid foam is formed. Taking into account the water content of 8.5%, the yield is practically quantitative. The substance sinters from 90°C, from 140°C until foam develops. ;Analysis: Calculated C 26.90% H 2.44% N 6.27% Gd 35.22% Found in dry substance: C 26.78% H 2.96% N 5.77% Gd 34.99 % ;Equivalent weight calculated 6 41.7 ;Found 634 (titration with tetramethylammonium hydroxide in aqueous acetone). By dissolving in hot ethanol and evaporating in a vacuum to dryness, the substance is obtained as a white powder. ;In an analogous way, the following is obtained: ;N-methylglucamine salt of the dysprosium(III) complex ;of ethylenediaminetetraacetic acid, C-^H^^O-^Dy, as a white powder with a melting point at 180-185°C. ;Elementary analysis (calculated on dry matter): ;;Di-N-methylglucamine salt of the holmium(III) complex of diethylenetriaminepentaacetic acid<e,> C"2gH54N5020Ho, as white powder which sinters at 88°C and melts at 187-190°C. Elemental analysis (calculated on dry matter): ;Di-lysine salt of the gadolinium(III) complex of diethylenetriamine-pentaacetic acid, C — H, oN-,0, .Gd: ;Z o ho I 14 Elemental analysis: ;Di-N-methylglucamine salt of the gadolinium(III) complex of diethylenetriamine-pentaacetic acid, C28<H>5<4>N5<0>2QGd.Elementary analysis: ;Example 3 ;Preparation of a solution of the di-N-methylglucamine salt of the manganese (II) complex of ethylenediamine- tetraacetic acid. ; 3.68 g (= 5 mmol) of the substance described in example 1 is dissolved in 70 ml of water pro injectione (p.i.) and the solution is added to 0.4 g of sodium chloride. It is then filled to 100 ml with water p.i. and the solution is filled in ampoules through a sterile filter. The solution is isotonic at 280 mOsm. ;Example 4 ;Preparation of a solution of the N-methylglucamine salt ;of g the adolinium (III) complex of ethylenediaminetetraacetic acid. ;9.6 3 g (= 15 mmol) of the substance described in example 2 is dissolved in 100 ml of water o.i. the nearly blood isotonic solution is filled into ampoules over a sterile filter. ;Example 5 ;Preparation of a solution of the di-N-methylglucamine salt of the gadolinium (III) complex of diethylenetriaminepentaacetic acid. ;5.35 g (= 9 mmol) of the gadolinium (III) complex of diethylenetriaminepentaacetic acid (water content 8%) is dissolved in 50 ml of water p.i. and neutralized by adding approx. 3.2 g (equivalent to approx. 18 mmol) N-methylglucamine to pH 7.5. The solution is then filled up to 100 ml with water p.i., filled into ampoules and heat sterilized. The concentration of the solution is set to blood isotonicity (approx. 280 mOsm). ;Example 6 ;Preparation of a solution of the di-N-methylglucamine salt of the dysprosium (III) complex of diethylenetriaminepentaacetic acid^^ ;8.0 g (= 15 mmol) of the dysprosium (III) complex of diethylenetriaminepentaacetic acid are dissolved in 80 ml of water p.i. while adding approx. 5.3 g (equivalent to approx. 30 mmol) N-methylglucamine at pH 7.5. The solution is then filled up to 170 ml with water p.i. The nearly blood isotonic solution is filled into ampoules and heat sterilized. ;Example 7 ;Preparation of a solution of the di-N-methylglucamine salt of the holmium (III) complex of diethylenetriaminepentaacetic acid. ;8.02 g (= 15 mmol) of the holmium (III) complex of diethylenetriaminepentaacetic acid are dissolved in 80 ml of water p.i. while adding approx. 5.3 g (equivalent to approx. 30 mmol) N-methylglucamine at pH 7.2. The solution is then filled with water p.i. to 170 ml. The approximate blood isotonic solution is filled into ampoules and heat sterilized. The solution can also be prepared by dissolving the complex salt isolated according to example 2. in water p.i. ;Example 8 ;Preparation of a solution of the disodium salt of the manganese (II) complex of ethylenediamine-tetraacetic acid. ;5.55 g (15 mmol) of the manganese (II) complex of ethylenediaminetetraacetic acid (water content: 6.9%) is dissolved in 80 ml of water p.i. while adding dilute caustic soda at pH 7.5. The solution is then filled up with water p.i. to 170 ml, filter into ampoules and heat sterilize. *
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NO1994031C NO1994031I1 (en) | 1981-07-24 | 1994-12-30 | The dimeglumine salt of gadopentetic acid / (di-N-methylglucamine salt of gadolinium (III) complex of diethylenetriaminepentaacetic acid |
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- 1982-07-19 AT AT85102713T patent/ATE52247T1/en not_active IP Right Cessation
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- 1982-07-19 AT AT82730097T patent/ATE18719T1/en active
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- 1982-07-19 EP EP82730097A patent/EP0071564B1/en not_active Expired
- 1982-07-19 DE DE8585102713T patent/DE3280157D1/en not_active Expired - Lifetime
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- 1982-07-23 ZA ZA825313A patent/ZA825313B/en unknown
- 1982-07-23 IE IE1766/82A patent/IE53639B1/en not_active IP Right Cessation
- 1982-07-23 NO NO822546A patent/NO164458C/en not_active IP Right Cessation
- 1982-07-23 CA CA000407923A patent/CA1218597A/en not_active Expired
- 1982-07-23 JP JP57127810A patent/JPS5829718A/en active Granted
-
1985
- 1985-07-31 CA CA000487858A patent/CA1240679A/en not_active Expired
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1986
- 1986-01-24 JP JP61012237A patent/JPH0768193B2/en not_active Expired - Lifetime
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1990
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1993
- 1993-06-09 LU LU88291C patent/LU88291I2/en unknown
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1994
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NL930072I1 (en) | 1993-09-01 |
EP0169299A2 (en) | 1986-01-29 |
JPH0768193B2 (en) | 1995-07-26 |
EP0169299B1 (en) | 1990-04-25 |
DE3129906A1 (en) | 1983-02-10 |
DE3129906C3 (en) | 1996-12-19 |
JPH0339045B2 (en) | 1991-06-12 |
ATE52247T1 (en) | 1990-05-15 |
NO1994031I1 (en) | 1994-12-30 |
AU8633082A (en) | 1983-01-27 |
DE3280157D1 (en) | 1990-05-31 |
NL930072I2 (en) | 1994-01-17 |
AU601916B2 (en) | 1990-09-20 |
EP0071564B1 (en) | 1986-03-26 |
AU566007B2 (en) | 1987-10-08 |
IE53639B1 (en) | 1989-01-04 |
JPS62123159A (en) | 1987-06-04 |
ATE18719T1 (en) | 1986-04-15 |
EP0071564A1 (en) | 1983-02-09 |
NO822546L (en) | 1983-01-25 |
ZA825313B (en) | 1983-05-25 |
AU1018688A (en) | 1988-04-28 |
JPH03209389A (en) | 1991-09-12 |
DE3270097D1 (en) | 1986-04-30 |
NO164458C (en) | 1992-11-23 |
IE821766L (en) | 1983-01-24 |
EP0169299A3 (en) | 1986-12-03 |
CA1218597A (en) | 1987-03-03 |
NZ201372A (en) | 1986-08-08 |
LU88291I2 (en) | 1994-05-04 |
CA1240679A (en) | 1988-08-16 |
JP2548436B2 (en) | 1996-10-30 |
DE3129906C2 (en) | 1990-05-17 |
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