NZ201372A - Paramagnetic complex salts,and use in nmr-diagnostics - Google Patents
Paramagnetic complex salts,and use in nmr-diagnosticsInfo
- Publication number
- NZ201372A NZ201372A NZ201372A NZ20137282A NZ201372A NZ 201372 A NZ201372 A NZ 201372A NZ 201372 A NZ201372 A NZ 201372A NZ 20137282 A NZ20137282 A NZ 20137282A NZ 201372 A NZ201372 A NZ 201372A
- Authority
- NZ
- New Zealand
- Prior art keywords
- acid
- complex
- salt
- ch2cooh
- methylglucamine
- Prior art date
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 58
- 230000005298 paramagnetic effect Effects 0.000 title claims abstract description 40
- 229960003330 pentetic acid Drugs 0.000 claims abstract description 54
- 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 44
- 238000002360 preparation method Methods 0.000 claims abstract description 36
- 239000002253 acid Substances 0.000 claims abstract description 27
- 150000002500 ions Chemical class 0.000 claims abstract description 21
- 229910052747 lanthanoid Inorganic materials 0.000 claims abstract description 11
- 150000002602 lanthanoids Chemical class 0.000 claims abstract description 11
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 11
- 150000003624 transition metals Chemical class 0.000 claims abstract description 11
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract description 8
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 8
- 229930195734 saturated hydrocarbon Natural products 0.000 claims abstract description 8
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims abstract description 8
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 6
- JYXGIOKAKDAARW-UHFFFAOYSA-N N-(2-hydroxyethyl)iminodiacetic acid Chemical compound OCCN(CC(O)=O)CC(O)=O JYXGIOKAKDAARW-UHFFFAOYSA-N 0.000 claims abstract description 5
- 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 51
- 229960001484 edetic acid Drugs 0.000 claims description 49
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical group CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 39
- 238000003745 diagnosis Methods 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 36
- 239000011572 manganese Substances 0.000 claims description 34
- 229910052748 manganese Inorganic materials 0.000 claims description 33
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 claims description 31
- 229910052688 Gadolinium Inorganic materials 0.000 claims description 27
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 claims description 25
- 239000000463 material Substances 0.000 claims description 24
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 150000007530 organic bases Chemical class 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 12
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 12
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 12
- XQRLCLUYWUNEEH-UHFFFAOYSA-N diphosphonic acid Chemical compound OP(=O)OP(O)=O XQRLCLUYWUNEEH-UHFFFAOYSA-N 0.000 claims description 12
- 239000010949 copper Substances 0.000 claims description 8
- 230000005291 magnetic effect Effects 0.000 claims description 8
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 7
- 229910052692 Dysprosium Inorganic materials 0.000 claims description 7
- 229910052689 Holmium Inorganic materials 0.000 claims description 7
- 229910052802 copper Inorganic materials 0.000 claims description 7
- KBQHZAAAGSGFKK-UHFFFAOYSA-N dysprosium atom Chemical compound [Dy] KBQHZAAAGSGFKK-UHFFFAOYSA-N 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- KJZYNXUDTRRSPN-UHFFFAOYSA-N holmium atom Chemical compound [Ho] KJZYNXUDTRRSPN-UHFFFAOYSA-N 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- 239000004475 Arginine Substances 0.000 claims description 6
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 6
- 239000004472 Lysine Substances 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 6
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- -1 hydroxy , amino Chemical group 0.000 claims description 6
- UCNNJGDEJXIUCC-UHFFFAOYSA-L hydroxy(oxo)iron;iron Chemical compound [Fe].O[Fe]=O.O[Fe]=O UCNNJGDEJXIUCC-UHFFFAOYSA-L 0.000 claims description 6
- 229910052759 nickel Inorganic materials 0.000 claims description 6
- 239000012266 salt solution Substances 0.000 claims description 6
- CUGDYSSBTWBKII-LXGUWJNJSA-N (2r,3r,4r,5s)-6-(dimethylamino)hexane-1,2,3,4,5-pentol Chemical compound CN(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO CUGDYSSBTWBKII-LXGUWJNJSA-N 0.000 claims description 5
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 5
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 5
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 5
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims description 5
- LBFUKZWYPLNNJC-UHFFFAOYSA-N cobalt(ii,iii) oxide Chemical compound [Co]=O.O=[Co]O[Co]=O LBFUKZWYPLNNJC-UHFFFAOYSA-N 0.000 claims description 5
- 229960003104 ornithine Drugs 0.000 claims description 5
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 4
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 claims description 3
- WAEMQWOKJMHJLA-UHFFFAOYSA-N Manganese(2+) Chemical compound [Mn+2] WAEMQWOKJMHJLA-UHFFFAOYSA-N 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- BDDLHHRCDSJVKV-UHFFFAOYSA-N 7028-40-2 Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O BDDLHHRCDSJVKV-UHFFFAOYSA-N 0.000 claims description 2
- MBKDYNNUVRNNRF-UHFFFAOYSA-N medronic acid Chemical compound OP(O)(=O)CP(O)(O)=O MBKDYNNUVRNNRF-UHFFFAOYSA-N 0.000 claims 4
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims 2
- CUGDYSSBTWBKII-UHFFFAOYSA-N 6-(dimethylamino)hexane-1,2,3,4,5-pentol Chemical compound CN(C)CC(O)C(O)C(O)C(O)CO CUGDYSSBTWBKII-UHFFFAOYSA-N 0.000 claims 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 150000007513 acids Chemical class 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 43
- 229940059947 gadolinium Drugs 0.000 description 13
- 239000000126 substance Substances 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000002872 contrast media Substances 0.000 description 8
- 241000700159 Rattus Species 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 238000012360 testing method Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 239000012620 biological material Substances 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 241000282412 Homo Species 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- 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 2
- 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
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 210000001015 abdomen Anatomy 0.000 description 2
- 230000035508 accumulation Effects 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 235000013681 dietary sucrose Nutrition 0.000 description 2
- 229940043237 diethanolamine Drugs 0.000 description 2
- 229940009662 edetate Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- RJOJUSXNYCILHH-UHFFFAOYSA-N gadolinium(3+) Chemical compound [Gd+3] RJOJUSXNYCILHH-UHFFFAOYSA-N 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 238000011835 investigation Methods 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
- 239000011565 manganese chloride Substances 0.000 description 2
- 235000002867 manganese chloride Nutrition 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000008259 solid foam Substances 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- YGDVXSDNEFDTGV-UHFFFAOYSA-N 2-[6-[bis(carboxymethyl)amino]hexyl-(carboxymethyl)amino]acetic acid Chemical compound OC(=O)CN(CC(O)=O)CCCCCCN(CC(O)=O)CC(O)=O YGDVXSDNEFDTGV-UHFFFAOYSA-N 0.000 description 1
- WYMDDFRYORANCC-UHFFFAOYSA-N 2-[[3-[bis(carboxymethyl)amino]-2-hydroxypropyl]-(carboxymethyl)amino]acetic acid Chemical compound OC(=O)CN(CC(O)=O)CC(O)CN(CC(O)=O)CC(O)=O WYMDDFRYORANCC-UHFFFAOYSA-N 0.000 description 1
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 1
- QFIIYGZAUXVPSZ-UHFFFAOYSA-N 8-(2,4-dihydroxy-6-methylanilino)-2-(2,4-dihydroxy-6-methylphenyl)imino-7-hydroxy-1,9-dimethyldibenzofuran-3-one Chemical compound CC1=CC(=CC(=C1NC2=C(C3=C(C=C2O)OC4=CC(=O)C(=NC5=C(C=C(C=C5C)O)O)C(=C43)C)C)O)O QFIIYGZAUXVPSZ-UHFFFAOYSA-N 0.000 description 1
- 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
- 208000010454 Experimental Liver Neoplasms Diseases 0.000 description 1
- 102400000321 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 229910021577 Iron(II) chloride Inorganic materials 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
- 239000004218 Orcein Substances 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
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000002583 angiography Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000011847 diagnostic investigation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 229940075613 gadolinium oxide Drugs 0.000 description 1
- 229910001938 gadolinium oxide Inorganic materials 0.000 description 1
- CMIHHWBVHJVIGI-UHFFFAOYSA-N gadolinium(iii) oxide Chemical compound [O-2].[O-2].[O-2].[Gd+3].[Gd+3] CMIHHWBVHJVIGI-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000011656 manganese carbonate Substances 0.000 description 1
- 235000006748 manganese carbonate Nutrition 0.000 description 1
- 229940099607 manganese chloride Drugs 0.000 description 1
- 229910000016 manganese(II) carbonate Inorganic materials 0.000 description 1
- XMWCXZJXESXBBY-UHFFFAOYSA-L manganese(ii) carbonate Chemical compound [Mn+2].[O-]C([O-])=O XMWCXZJXESXBBY-UHFFFAOYSA-L 0.000 description 1
- 239000000155 melt Substances 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
- 235000019248 orcein Nutrition 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 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
- 230000000704 physical effect Effects 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 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
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
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
Landscapes
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Physics & Mathematics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Condensed Matter Physics & Semiconductors (AREA)
- Radiology & Medical Imaging (AREA)
- Epidemiology (AREA)
- Optics & Photonics (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Signal Processing (AREA)
- High Energy & Nuclear Physics (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
1. The use of at least one physiologically tolerable paramagnetic complex salt made from aminopolycarboxylic acids having the formulae I to IV see diagramm : EP0169299,P6,F1 N-hydroxyethyl-N,N',N'-ethylenediaminetriacetic acid (HEDTA), see diagramm : EP0169299,P6,F2 N,N,N',N",N"-diethylenetriaminepenta-acetic acid (DTPA), HOH2 C-CH2 N(CH2 COOH)2 N-hydroxyethylimino-diacetic acid, see diagramm : EP0169299,P6,F3 wherein m represents the numbers 1 to 4, n the numbers 0 to 2, R**1 a saturated or unsaturated hydrocarbon radical having from 4 to 12 hydrocarbon atoms or the group -CH2 -COOH, and from the ions of the lanthanide elements having the atomic numbers 57 to 70 or from the ions of the transition metals having the atomic numbers 21 to 29, 42 and 44 and, optionally from an inorganic base for the preparation of agents for NMR diagnostics.
Description
80137a
Priority Date(s)c .. P.fi'.
Complete Specification Filed: \
Class: f.°. IF. 3$....
C°l. &9J. fotff.WJflf.1*
q.ot. ma/PX . ML« U/A ?, */£. *9, J*
COTCto.fop. AI0(KJt*[°° I- g y\ug iqoc Publication Date:
P.O. Journal, No: .. J.
NEW ZEALAND Patents Act. 1953
COMPLETE SPECIFICATION
"PARAMAGNETIC COMPLEX SALTS, THEIR PREPARATION, AND THEIR USE IN NMR-DIAGNOSTICS."
We, SCHERING AKTIENGESELLSCHAFT, a body corporate organized according to the laws of Germany, of 170-178 Mullerstrasse, D-1000 Berlin 65, Germany and Waldstrasse 14, 4619 Bergkamen, Germany, do hereby declare the invention, for which we pray that a Patent may be granted to us, and the method t
by which it is to be performed to be particularly described in and by the following statement
; 201372
The present invention relates to new paramagnetic complex salts, to pharmaceutical preparations comprising them, a process for the preparation thereof and to their use as NMR-diagnostics and a preparation for use in NMR-diagnostics. According to one aspect of the present invention there is provided a physiologically compatible paramagnetic complex salt of (a) an aminopolycarboxylic acid of anyone of the formulae I to IV
hoocch- ch cooh
\ /
n-(ch_)_-n (i)
2 2 X
hoh2cch2 ^ ch2cooh
N-Hydroxyethyl-N.N',N'-ethylenediaminetriacetic acid (hedta)
ch—cooh pu paatj hooch.c r 2 ch cooh
2 \ i / 2
^n-(ch2)2-n-(ch2)2-n (ii)
hooch2c ^ ch2cooh n.n.n',n",N"-Diethylenetriaminepentaacetic acid (dtpa)
hoh2c-ch2n(ch2cooh)2 (iii)
N-Hydroxyethyliminodiacetic acid
! ch- ch cooh
8 \ I /
n n-(ch2)i!1-(ch2-n-ch2)n-(ch2)m -n^civ)
hoocch2 ^ ch2cooh
, v. V/
oir wherein m represents an integer from 1 to 4,
7
/ n represents an integer from 0 to 2, and represents a saturated or unsaturated hydrocarbon group with 4 to 12
— j -
<•
carbon atoms or the group -ch2-cooh,
or a. diphosphonic acid of the general formula V
201372
P°3H2 r2-c-r3
P°3H2
(v)
wherein
2
R represents hydrogen, alkyl of 1 to 4 carbon atoms, halogen, or a hydroxy, . amino or -CH2COOH group, and represents hydrogen, alkyl of 1 to 4 carbon atoms, or the -CH2-COOH group.
(b) an ion of any one of the lanthanide elements of numbers 57 to 70 or an ion of any one of the transition metals of numbers 21 to 29. 42 and 44
and
(c)
a baoo which ic oithor an inorganio baooj—for eutamplc oodium hydroaiidoi er an organic base, for example,
primary, secondary or tertiary amines, especially glucamine, N-methylglucamine, N,N-dimethylglucamine, ethanolamine, diethanolamine or morpholine, or a basic amino acid, for example lysine, o^^iithine or arginine.
According to another aspect of the present invention there is provided a pharmaceutical preparation for use in NMR diagnosis which comprises a physiologically acceptable carrier and at least one physiologically compatible paramagnetic complex salt of (a) an aminopolycarboxylic acid of any one of the formulae I to IV
201372
~ 4 -
HOOCCH- CH-COOH
\ /
N-(CH2)j-N (i)
hoh2cch2 ^ CH2COOH
N-Kydroxyethyl-N.N",N'-ethylenediaminetriacetic acid (HEDTA)^
HOOCH C CH2COOB CH-COOH
\ i / 2
N-(CH2)2-N-(CH2)2-N^ (I1,
HOOCH2C CH2COOH
N.N.N',N",N"-Diethylenetriaminepentaacetic acid (DTPA)
HOH2C-CH2N(CH2COOH)2 (in)
N-Hydroxyethyliminodiacetic acid,
pi CH- CH-COOH
\ I /
.N-(CH2)B-(CH2-N-CH2>n-«CB2)« "N s<IV>
HOOCCH2 CH-COOH
wherein in represents an integer from 1 to 4,
n represents an integer from 0 to 2, and R1 represents a saturated or unsaturated hydrocarbon group with 4 to 12 carbon atoms or the group -CH2-COOHj
201372
or a diphosphonicacid of the general formula V
f°3H2
R2-C-R3 (V)
I
P°3H2
wherein
2
R represents hydrogen, alkyl of 1 to 4 carbon atoms, halogen, or a hydroxy, amino or -CH2COOH group, and
3
R represents hydrogen, alkyl of 1 to 4 carbon atoms, or the -CH2-COOH group, and • —
(b) an ion of any one of the lanthanide elements of numbers 57 to
70 or an ion of any one of the transition metals of numbers 21
ai\ orcein 1 c or-
to 29. 42 and 44,^ and if desired,l-eni inorganic base.
Preferred complexing agents are N,N,N', N'-ethylene-diamine-tetra-acetic acid (EDTA), N,N,N', N", N"-diethyl-
enetriamine-penta-acetic acid (DPTA), ethane-1-hydroxy-l,
.<
1-diphosphonic acid, metharie-diphosphonic acid and ethane-1-
amino-l, 1-diphosphonic acid.
-
v
201372
- 6 ~
i15 JAN1986
If desired, it is also possible to bind the physiologically tolerable complex salts of the invention to bio-molecules in order in this way to enable the 10 complex salt to be conveyed to a particular area of the living body.
Bio-molecules which may be used are, for example, immunoglobulins, hormones such, for example, as insulin, glucagon, prostaglandins, steroidal hormones, proteins, 15 peptides, amino-sugars and lipids.
The coupling of the paramagnetic complex salts to the desired bio-molecules may be effected by means of methods which are known per se. for example by reacting the nucleophilic group of a bio-molecule such as the 20 amino, phenol, mercapto or imidazole group with an activated derivative of the complex compound.
The activated derivatives which may be considered are for example acid chlorides, mixed anhydrides (which can be prepared from the carboxyl derivative of 25 the complex compound with chlorocarbonic acid ester), activated esters, nitrenes or isothiocyanates.
It is also possible to react an activated derivative of the biomolecule with a nucleophilic
t
301372
derivative of the complex compound.
As inorganic bases for salt formation there may be used, for-example, sodium iiy^-rwi, an<i as organic bases, there may be used, for example, primary, secondary or tertiary amines, especially glucamine, N-methyl-glucamine, N,N-dimethyl glue amine, ethanolamine, diethan-olamine, morpholine, etc., N-methylglucamine being preferred. Basic amino-acids are also suitable for salt formation, for example lysine, ornithine, arginine, etc..
The new preparations of the invention may be made up in a manner known per se by dissolving the paramagnetic complex salt in water or physiological salt solution, if desired with the addition of one or more additives usual in galenics, such as, for example, physiologically conpatible buffer solutions (for example sodium dihydrogen phosphate solution), and sterilising the solution. The aqueous solutions can be administered orally, neurally and especially intra-vascularly. if suspensions of the paramagnetic complex salts in water or physiological salt solution are desired, especially for oral administration, the
8
JAN 1986
llECBVED
201372
paramagnetic complex salt is mixed with one or more auxiliaries usual in galenics and/or surfactants and/or aromatic substances for taste correction and suspended in water or physiological salt solution before oral administration. In this case, preferably from 3 to 10 g of paramagnetic complex salt and from 2 to 8 g of one or more auxiliaries, such as, for example, saccharose, highly disperse silica, polyoxyethylenepolyoxypropylene polymers, starch, magnesium stearate, sodium lauryl sulphate, talcum, lactose, sodium carboxyroethylcellulose are used.
of the invention are suitable in the form of aqueous solutions or suspensions which contain from 5 to 250 mmols/litre, preferably 50 to 200 mmols/litre, of the paramagnetic complex salt. The pH of the aqueous solutions may range between 6.5 and 8.0, preferably between 6.5 and 7.5. As a result of the formation of the complex salt according to the present invention the paramagnetic salt is detoxicated, and the effect also achieved is that the salts are stable in water and readily soluble therein in the physiological pH range.
particularly suitable for greater definition or localisation of lesions of the pancreas and liver, and also of tumours and haemorrhages in the cranial area. For diagnosis of the area under examination an aqueous
For NMR-diagnosis in humans, the preparations
Solutions of the complex salts appear to be
201372
solution of the paramagnetic complex salt which is isotonic with blood is, for example, administered intravenously at a dosage of from 1 to 100 pmols/kg.
With a concentration of the complex salt of from 50 5 to 200 mmols/litre, approximately 1 to 50 ml of solution is required for examination of human patients. The exposure of the layer in question is taken approximately 15 to 60 minutes after intravenous administration of the aqueous solution of the paramagnetic complex salt. 10 The physical methods of diagnosis usual in the practice of medicine which can be carried out with little or no operative intervention are, for example, the irradiation of the body with X-rays, scintiscanning and sonography. All these methods either involve risks 15 to health or have a limited range of application. In the case of X-ray procedures and scintiscanning the patient is exposed to the ionising radiation, so that these methods cannot be used as often as might be required or cannot be used at all for groups at risk, 20 for instance for babies or pregnant women.
Sonography does not in fact have these disadvantages , but instead has a very limited range of application, especially in the cranial area.
Since in spite of a great deal of research it 25 has not yet been possible to eliminate completely the above-mentioned disadvantages, attempts have been made to discover image-producing processes which do not have these disadvantages but which provide comparable
o>-
201372
information for diagnostic purposes.
One of these image-producing processes is spin-imaging, which is based on the physical effect of nuclear magnetic resonance (NMR). This method of diagnosis makes it possible to obtain sectional images of the living body and an insight into metabolic processes without the use of ionising rays. The effect of nuclear J resonance is shown by atomic nuclei which, like hydrogen - mainly present in biological tissues as water - have a magnetic moment and therefore align themselves in a strong external magnetic field. By means of a high-frequency impulse (resonant frequency) they are brought out of their position of equilibrium, to which they return at a characteristic speed. The duration of the return to the state of equilibrium, the so-called relaxation time, provides information on the classification of the atoms and on their interaction with their surroundings.
proton density or the relaxation times is of great diagnostic value and provides information concerning the water content and the state of the tissues being examined. For example, tumour tissue displays longer relaxation times than healthy tissue. (A. Ganssen and others, Computertomographie 1, [1981] pp. 2-10: Georg Thieme Verlag, Stuttgart, New York).
It has now been found that paramagnetic ions,
magnetic
The image which is obtained by measuring the
r 15 JAN 1986
- H -
2-Lr"
201372
for example Mn (manganese) or Cu (copper) influence the relaxation times and thus increase the information content.
The solutions of heavy metal salts hitherto used 5 on experimental animals are not, however, suitable for intravenous administration to humans because of their high level of toxicity. Paramagnetic substances which are well tolerated and have a favourable influence on the imaging process are therefore being sought. The 10 latter effect may be produced for example, in that the spin-lattice-relaxation time is greatly reduced in a manner which is as organ-specific as possible, whilst at the same time the spin-spin-relaxation time T2 is kept constant to a great extent. We have now found 15 that the required detoxication of the otherwise toxic metal salts can be effected by complexing, without the . paramagnetic properties being adversely affected. This is surprising, since it is known that the distribution of the d- and f-electrons over the d- and f- orbitals 20 is altered thereby.
Thus in tests on rats in the scanner, with a magnetic field of 0.15 Tesla, an input energy of 300 watt/pulse and a l80°-pulse of 720 |is with exposure times of 2 minutes in each case made 10 minutes after 25 intravenous injection of 20 pmols/kg of manganese edetate as an aqueous methylglucamine salt solution having a concentration of 6 mmols/litre, a noticeably
Hxew&tfomct 201372 i ,15 jan 1986
greater alteration in the signal in the region of the liver parenchyma was observed than for an exposure without the substance, whilst with an aqueous manganese(II) chloride solution of the same molarity under the same test conditions only a comparatively limited contrast was obtained. On the other hand, the desired detoxication of the otherwise toxic paramagnetic salts is achieved by the complex formation. Thus in rats, after intravenous injection of an aqueous solution of the N-methylglucamine salt of manganese edetate an LD^q of 4 mmols/kg was found. In contrast, manganese chloride showed an of only 0.5 mmol/kg when used on rats under identical conditions.
The performance of an NMR-diagnostic investigation using a preparation of the invention is explained in greater detail by means of the following example:
A sterile aqueous solution of the N-methylglucamine salt of the gadolinium-III-complex of diethylene-triamine-penta-acetic acid having a concentration of 0.1 mol/litre was prepared. The pH value of the clear solution is 7.2.
The whole body scanner (Siemens AG/Erlangen)
used for the NMR-tomography operated with a magnetic field of 0.1 T, corresponding to a Larmor proton frequency of 4.99 MHz. The apparatus was equipped with a high frequency transmitting and receiving coil of reduced size in order to allow objects of small size
: 15 JAN 1986 2013*'
to be imaged with sufficient resolution. The investigations were carried out according to a spin-echo method. The time taken for an exposure was between 1 and 3 minutes.
The tests were carried out on male rats of the Wistar-Han-Schering strain (SPF) having a body weight of 250 g. Eight days before the investigation, a Novikoff hepatoma tumour cell suspension is administered to the animals intraperitoneally (0.5 ml with 1 x 10^ cells).
The animals were anaesthetised by means of an intraperitoneal injection of pentobarbital sodium (60 mg/kg of body weight). The animals then have a vaned cannula inserted into one of the tail veins.
The accompanying Figures 1 to 7 show the results of exposures made on the test animals. Figures 1 and 2 show exposures made, before the administration of the contrast agent, in the sagittal and horizontal planes of the body respectively.
The contrast agent is administered intravenously within one minute at a dosage of 1 mmol/kg. In Figures 3 and 4, which were taken between 22 and 25 minutes after administration, a marked increase in brightness in the abdomen was to be observed. After intravenous administration the contrast agent reaches the pathological fluid accumulations and there produced a marked reduction of the spin-lattice-relaxation time (T^), which
:N2.PA>'i^r ■ -
jan 1986 2013^^
led to an increase in the intensity of the signal. Only after administration of the contrast agent was the tumorous fluid accumulation and improved definition of the organs to be observed. Without the administration 5 of a contrast agent, structures in the abdomen could hardly be recognised, since the organs show only small differences in proton density and relaxation times.
The definition of structures was also improved after oral administration of the contrast agent.. For
~ salt
this purpose, 5 ml of the N-methylglucamine I solution of the gadolinium complex of diethylenetriamine-penta-acetic acid having a concentration of 1 mmol/litre was administered by means of a probe to an anaesthetised male rat (body weight: 250 g). Only after administration 15 of the contrast agent (Figures 6 and 7) was clear definition of the stomach or of the intestine in relation to the remaining organs to be seen.
Our own pharmaco-kinetic tests on rats have shown r salt that the N-methylglucamine [of the gadolinium complex 20 of diethylenetriamine-penta-acetic acid after intravenous and subcutaneous administration is completely eliminated, mostly renally, within 24 hours. The gadolinium complex is eliminated from rats by glomerulary filtration with a half life of approximately 20 minutes. The proportion 25 eliminated with the faeces is less than 5 % of the dose administered.
201372
- 15
jan 1986
i^jwobv®
After oral administration no reabsorption of the substance is observed. The pharmaco-kinetic behaviour is similar to that of the classic X-ray contrast agents for uro-angiography.
The paramagnetic complex salts may be prepared according to processes known per se to the man skilled in the art or described in the literature, by dissolving the paramagnetic metal salt of a lanthanide element having an atomic number of from 57 to 70 or of a transition metal having an atomic number of from 21 to 29, or 42 or 44, in water and/or alcohol and adding a solution of the equivalent quantity of the organic component capable of forming a complex in water and/or alcohol and stirring, if necessary while heating at from 50°C to 120°C until the reaction is complete. If alcohol is employed as the solvent,
methanol or ethanol is used. If the complex salt formed is insoluble in the solvent used, it crystallises and can be filtered off. If it is soluble in the solvent used, it can be isolated by evaporating the solution to dryness.
The process is to be explained in detail, by way of example, with the aid of the following instructions for procedure:
' v ■
JAN 1986
- 16 - is received m iriTn ■ • II I-Tiiri Preparation of the manganese(II) complex of ethylene-diaminetetraacetic acid:
14.6 g of ethylenediaminetetraacetic acid are added to a suspension of 6.17 g of manganese(II) carbonate in 500 ml of water and the whole is heated on a vapour bath while stirring, gas being evolved. The initially pink colour disappears after approximately 20 minutes and the whole mixture goes into solution except for a small residue. After stirring for one hour at 110°C the undissolved portion is filtered off and the filtrate is cooled. After standing for 15 hours the crystallisate is filtered off with suction and dried:
Yield = 14.1 g (molecular weight 345.17) M.p. : 256°/258-259°C
Preparation of the gadolinium(III) complex of diethylene-triaminepentaacetic acid:
A suspension of 435 g of gadolinium oxide (GdjO^) and 944 g of diethylenetriaminepentaacetic acid in 12 litres of water is heated while stirring to from 90°C to 100°C and stirred at this temperature for 48 hours. The undissolved portion is filtered off and the filtrate is evaporated to dryness. The amorphous residue is pulverised.
Yield 144 gr (molecular weight 547.58)
M.p.: melts from 235° and remains undecomposed up to 320°C.
20137*
/
201372
If there is/are still one or more acidic group(s) in the resulting paragmagnetic complex compound, the resulting complex compound can then, if desired, be dissolved or suspended in water and the desired inorganic or organic base can be added thereto until the neutral point is reached. After filtering off the undissolved constituents, the solution is concentrated by evaporating and the desired complex salt is obtained as the residue. Those compounds comprising an organic base component are new.
The following complex salts may be mentioned more especially.
The di-N-methylglucamine salt of the manganese (II)-complex of ethylenediamine-tetra-acetic acid.
The di-N-methylglucamine salt of the nickel (II)-complex
The di-ethanolamine salt of the c<
18
115 JAN 1986 201372 Kece
I)-complex of ethylenediamine-tetra-acetic acid.
The di-morpholine salt of the manganese (II)-complex of ethylenediamine-tetra-acetic acid.
The di-diethanolamine salt of the copper(II)-complex of ethylenediamine-tetra-acetic acid.
The tri-diethanolamine salt of*the manganese(II)-complex of diethylenetriamine-penta-acetic acid.
The tri-N-methylglucamine salt of the manganese (II)-complex of diethylenetriamine-penta-acetic acid.
The N-methylglucamine salt of the gadolinium(III)-complex of ethylenediamine-tetra-acetic acid.
The N-methylglucamine salt of the dysprosium(III)-complex of ethylenediamine-tetra-acetic acid.
The di-N-methylglucamine salt of the holmium(III)-complex of diethylenetriamine-penta-acetic acid.
The N-methylglucamine salt of the iron (II)-complex of ethane-1-hydroxy-1,1,-diphosphonic acid.
The N-methylglucamine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid.
The di-lysine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid.
201372
15JANI986
- 19 - _
IKBVEC
The following Examples illustrate the invention:-
Example 1
Preparation of the di-N-methylglucamine salt of the manganese(II)-complex of ethylenediamine-tetra-acetic 5 acid, C24H48N4Ol8Mn
7.4 g (= 20 mmols) of the manganese(II)-complex of ethylenediamine-tetra-acetic acid (water content : 6.9%) are suspended in 30 ml of water and by the addition of approximately 7.8 g ( = approx. 40 mmols) of N-methyl-10 glucamine are dissolved at a pH of 7.5. After filtering off a little undissolved material the solution is evaporated to dryness under vacuum. A solid foam is produced in a quantitative yield, starting to melt at 95°C and becoming viscous at 170°C.
. Analysis: calculated C 39.19% H 6.58% N 7.61% Mn 7.47% Found in the dry substance C 39.23% H 7.10% N 7.26% Mn 7.53%
H20 3.26%
Equivalent weight: calculated 367.8, found 369 (titra-20 tion with tetramethylammonium hydroxide in aqueous acetone).
By dissolving in hot ethanol and evaporating to dryness under vacuum the substance is obtained as a white, hydroscopic powder.
The following compounds are obtained in an analogous manner:
201372
The di-N-methylglucamine salt of the nickel(II)-complex of ethylenediamine-tetra-acetic acid, C^H^l^O^gNi, as a blue powder.
The di-ethanolamine salt of the cobalt(II)-complex of ethylenediamine-tetra-acetic acid, 4H28N4°1qCo, as a pink-coloured powder.
The di-morpholine salt of the manganese(II)-complex of ethylenediamine-tetra-acetic acid, C^gH^l^O^QMn, as a white powder.
The di-diethanolamine salt of the copper(II)-complex of ethylenediamine-tetra-acetic acid, Cj gH^N^^ 2Cu, as a blue powder.
The tri-diethanolamine salt of the manganese(II)-complex of diethylenetriamine-penta-acetic acid,
C26H54N6°16*^' as a ye3-*ow powder.
The tri-N-methylglucamine salt of the manganese(II)-complex of diethylenetriamine-penta-acetic acid, C^H^NgO^Mn, as a white powder.
Example 2
Preparation of the N-methylglucamine salt of the gadolin-ium(III)-complex of ethylenediamine-tetra-acetic acid
(a.,HonN„O^Gd)
17 30 3 13
4.58 g (= 10 mmols) of the geee*8rnnam\ x 11) -
201372
complex of ethylenediamine-tetra-acetic acid (water content: 2.7%) are suspended in 15 ml of water and by the addition of 1.95 g (= 10 mmols) of N-methylglucamine 5 are dissolved in a pH of 7.4. The solution is filtered and then evaporated to dryness under vacuum, whereupon a solid foam is produced. The yield, taking into account the water content of 8.5%, is practically quantitative. The substance starts to sinter at 90°C, and foam begins 10 to develop at 140°C.
Analysis: Calculated C 26.90% H 2.44% N 6.27% Gd 35.22% Found in the dry substance C 26.78% H 2.96% N 5.77% Gd 34.99%
Equivalent weight: calculated 641.7, found 634 (titration 15 with tetramethylammoniuro hydroxide in aqueous acetone).
By dissolving in hot ethanol and evaporating to dryness under vacuum the substance is obtained as a white powder.
The following are obtained in an analogous manner:
The N-methylglucamine salt of the dysprosium(III)-complex of ethylenediamine-tetra-acetic acid, C^H^QN^O^Dy-
The di-N-methylglucamine salt of the holmium(III)-complex of diethylenetriamine-penta-acetic acid, ^28H54^5°20Ho"
The di-lysine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid, C26B48N7°14Gd-
The N-methylglucamine salt of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid, C28H54N5°20Gd'
/
Example 3
SS, 201372
L4 5 JAN 1986
Preparation of a solution of the di-N-methylglucamine salt of the manganese(II)-complex of ethylenediamine-tetra-acetic acid
3.68 g (= 5 mmols) of the substance described in
Example 1 are dissolved in 70 ml of water pro iniectione (p.i.) and 0.4 g of sodium chloride are added to the solution. The solution is then made up to 100 ml with water p.i. and the solution is introduced into ampoules 10 through a sterile filter. The solution is isotonic with blood at 280 mOsm.
Example 4
Preparation of a solution of the N-methylglucamine salt of the gadolinium(III)-complex of ethylenediamine-15 tetra-acetic acid
9.63 g ( = 15 mmols) of the substance described in Example 2 are dissolved in 100 ml of water p.i.. The solution, which is approximately isotonic with blood, is introduced into ampoules through a sterile filter.
2q Example 5
Preparation of a solution of the di-N-methylglucamine salt of the gadolinium(III)-complex of diethylene-triamine-penta-acetic acid
201372
.35 g (= 9 mmols) of the gadolinium(III)-complex of diethylenetriamine-penta-acetic acid (water content 8%) are dissolved in 50 ml of water p.i. and neutralised to pH 7.5 by the addition of approximately 3.2 g 5 (corresponding to approximately 18 mmols) of N-methylglucamine. The solution is then made up to 100 ml with water p.i., introduced into ampoules and heat-sterilised. The concentration of the solution is made isotonic with blood (approximately 280 mOsm.).
^ o Example 6
Preparation of a solution of the di-N-methylglucamine salt of the dysprosium(III)-complex of diethylenetriamine-penta-acetic acid
8.00 g (= 15 mmols) of the dysprosium(III)-
complex of diethylenetriamine-penta-acetic acid are dissolved in 80 ml of water p.i. at a pH of 7.5 with the addition of approximately 5.3 g (corresponding to approximately 30 mmols) of N-methylglucamine. The solution is then made up to 170 ml with water p.i..
The solution, which is approximately isotonic with blood, is introduced into ampoules and heat-sterilised.
PAcmx
jan1986
201372
Example 7
Preparation of a solution of the di-N-methylglucamine salt of the holmium(III)-complex of diethylenetriamine-penta-acetic acid
8.02 g (= 15 mmols) of the holmium(III)-complex of diethylenetriamine-penta-acetic acid are dissolved in 80 ml of water p.i. at a pH of 7.2 with the addition of approximately 5.3 g (corresponding to approximately 30 mmols) of N-methylglucamine. The solution is then
made up to 170 ml with water p.i. The solution, which is approximately isotonic with blood, is introduced into ampoules and heat-sterilised.
The solution may 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 di-sodium salt manganese(II)-complex of ethylenediamine-tetra-acetic acid
5.55 g (15 mmols) of the manganese(II)-complex of ethylenediamine-tetra-acetic acid (water content: 6.9%) are dissolved in 80 ml of water p.i. at a pH of 7.5 with the addition of dilute sodium hydroxide solution. The solution is then made up to 170 ml with
water p.i.. filtered into ampoules and heat-sterilised.
"A solution of the di-sodium salt of the gadolinium (III)complex of N,N,N',N",N"-diethylene-triamine pentaacetic acid can be t-* v Arv ^ z-\ t f i m n 1 2 V fa cV\ T
201372
Example 9
Preparation of a solution of the N-methylglucamine salt of the iron(II)-complex of ethane-1-hydroxy-1,1-diphosphonic acid
1.27 g (= 10 mmols) of iron(II) chloride are dissolved in 8.8 ml of methanol and there are added to the solution 3.2 ml of a 60% by weight solution of ethane-1-hydroxy-1,1-diphosphonic acid in water. The solution is evaporated to dryness under vacuum and 10 the residue is washed three times with anhydrous methanol. After drying, the residue is taken up in 50 ml of water p.i. and dissolved at a pH of 7.5 by the addition of approximately 1.8 g (corresponding to approximately 10 mmols) of N-methylglucamine. The solution is then 15 made up to 100 ml with water p.i. and introduced into ampoules after sterile filtration.
- 26 - 201372
Example 10
Preparation of a solution of the di-N-methylglucamine salt of the manganese(II)-complex of hexy.lenediainine-tetra-acetic acid
In analogy with the method described in Example 6f a solution which is ready for use is prepared from 6.02 g (-^15 mmols) of the manganese(II)-complex of hexylene -diamine-tetra-acetic acid and 5.86 g (^30 mmols) of N-methylglucamine
Example 11
(Composition of a powder for the preparation of a suspension)
4.000 g gadolinium(III) complex of diethylenetriamine-pentaacetic acid (water content 8%)
\
3.895 g saccharose
0.100 g polyoxyethylenepolyoxypropylene polymer 0.005 g aromatic substances
8.000 g
Claims (2)
- -27 - 201372 What we claim is: l.A physiologically compatible paramagnetic complex salt of (a) an aminopolycarboxylic acid of any one of the formulae 1 to IV HOOCCH_ CH_COOH \ / 2 N-(CH_)_-N (I) / \ HOH2CCH2 CH2COOH N-hydroxyethyl-N.N*,N'-ethylenediaminetriacetic acid (HEDTA)^ HOOCH C CH2COOH CH-COOH 2 \ ' / 2 N-(CH2)2-N-(CH2)2-N (II) HOOCH2C ^ CH2COOH N.N,N'.N".N"-diethylenetriaminepentaacetic acid (DTPA) hoh2c-ch2n(ch2cooh)2 (iii) N-hydroxyethyl iminodiacetic acid/ ri ch3 ch2cooh \ N-(CH2'ir,-(CH2-N-CH2)n-<CH2)n, "N x (IV> hoocch2 ch2cooh wherein m represents an integer from 1 to 4, n represents an integer from 0 to 2, and '4L 1 R represents a saturated or unsaturated hydrocarbon group with 4 to 12 _28 201372 carbon atoms" or the group -ch2-cooh, or a diphosphonic acid of the general formula V» P03H2 r2-c-r3 (v) P03H2 wherein R represents hydrogen, alkyl of 1 to 4 carbon atoms, halogen, or a hydroxy . amino or -ch-cooh group , and F? represents hydrogen, alkyl of 1 to 4 carbon atoms, or the -ch2~cooh group, an ion of any one of the lanthanide elements of numbers 57 to 70 or an ion of any one of the transition metals of numbers 21 to 29, 42 and 44 and an organic base.
- 2. A physiologically compatible paramagnetic complex salt according to claim 1 wherein the organic base is N-methylglucamine, N,N-dimethylglucamine, ethanolamine, diethanolamine, morpholine, lysine, glucamine, ornithine or arginine. S ' . 3. a nhysiologically compatible paramagnetic complex salte> 1 or 2, p ^ j{J according to claim\> wherein as|aminopolycarboxylie \ 2 6 may 1986. 201372 -29 - acid N, N, N', N'-ethy1ened iaminetetraacetic acid (EDTA) is used. A physiologically compatible paramagnetic complex salt 1 or 2, .according to claim wherein as the aminopolycarboxylic acid N,N,N',N",N"-diethylenetriaminepentaacetic acid (DTPA) is used. A physiologically compatible paramagnetic complex salt 1 or 2. according to claimNy wherein as the diphosphonic acid ethane-l-hydroxy-1,1-diphosphonic acid, methane-diphosphonic acid or ethane-l-amino-1,1-diphosphonic acid is used. The di-N-methylglucamine salt of the manganese(II)-complex of ethylenediaminetetraacetic acid. the di-N-methylglucamine salt of the nickel(II)-complex of ethylenediaminetetraacetic acid, the tri-N-methylglucamine salt of the manganese(II)-complex of diethylenetriaminepentaacetic acid, the N-methylglucamine salt of the gadoliniumCIII)-complex of ethylenediaminetetraacetic acid, the N-methylglucaraine salt of the dysprosiumC111)-complex of ethylenediaminetetraacetic acid, the di-N-methylglucamine salt of the holmi.um(III)-complex of diethylenetriaminepentaacetic acid and the N-methylglucamine salt of the iron(II)-complex of ethane-l-hydroxy-1,1-diphosphonic acid. The di-N-methylglucamine salt of the gadolinium(III)-complex of diethylenetriaminepentaacetic acid. ) -30 - 201375 8. The c|i-ethanolamine salt of the cobalt (II)-complex of the dy ethylenediaminetetraacetic acid .J di-^ethanolamine salt of the copper(II)-complex of ethylenediamine- the tetraacetic acid and^tri-diethanolamine salt of the manganese(II)-complex of diethylenetriaminepentaacetic acid. 9. The di-morpholine salt of the manganese(II)-complex of ethylenediaminetetraacetic acid. 10.- The di-lysine salt of the gadolinium(III)-complex of diethylenetriaminepentaacetic acid. .11. A physiologically compatible paramagnetic complex salt of (a) an aminopolycarboxylic acid of any one of the formulae 1 to IV hoocch- ch-cooh 2\ X 2 n-(ch_k-n (i) / \ hoh2cch2 ch2cooh N-kydroxyethyl-N.N',N'-ethylenediaminetriacetic acid (HEDTA) hooch2c ch2cooh ch2cooh n-(ch2)2-n-(ch2)2-nn^ (ii) hooch2c ch2cooh n.n.n' ,n" ,n"- cjlethylenetriaminepentaacetic acid (dtpa) hoh2c-ch2n(ch2cooh)2 (iii) N-hydroxy ethyl iminodiacetic acid^, •jv^ 201372 - 31 - R1 CH3 CH2COOH \ i / n-(ch2)m-(ch2-n-ch2)n-(ch2)in (iv) HOOCCH2 CH2COOH wherein m represents an integer from 1 to \ n represents integer from 0 tQ 2* and R1 represents a saturated or unsaturated hydrocarbon group with 4 to 12 carbon atoms or the group -CHj-COOH, or 21 diphosphonic acid of the general formula V: *°3H2 Ra-C-R3 (V) P03H2 wherein fft®* represents hydrogen, alkyl of 1 to 4 carbon atoms, halogen,or a hydroxy , amino or -CH-COOH group # and z \ IR7 represents hydrogen, alkyl of 1 to 4 carbon atoms, or the -CH2-COOH group. v an ion of any one of the lanthanide elements of numbers 57 to 70 or an ion of any one of the transition metals of numbers 21 - 32 - 201372 to 29. 42 and 44 and an organic base, in a form suitable for use in NMR diagnosis. 12. A physiologically compatible paramagnetic complex salt according to claim 11 wherein the organic base is N-methylglucamine, N,N-dimethylglucamine, ethanolamine, diethanolamine, morpholine, lysine, glucamine, ornithine or arginine, in a form suitable for use in NMR diagnosis. 13 . A physiologically compatible paramagnetic complex salt 11 or 12, the according to claim wherein as^jaminopolycarboxylic acid N.N.N',N'-ethylenediaminetetraacetic acid (EDTA) is used, in a form suitable for use in NMR diagnosis. -14. A physiologically compatible paramagnetic complex salt 11 or 12/ the according to claim>^> wherein as^J aminopolycarboxylic acid N.N.N'.N",N"-diethylenetriaminepentaacetic acid (DT'PA) is used, in a form suitable for use in NMR diagnosis. 15. A physiologically compatible paramagnetic complex salt or 12, the according to claim > wherein as^diphosphonic acid ethane-l-hydroxy-1.1-diphosphonic acid. methane-diphosphonic acid or ethane-1- amino-1.1-diphosphonic acid is used, in a form suitable for use in NMR diagnosis. .16. The di-N-methylglucamine salt of the manganese(II)-complex of ethylenediaminetetraacetic acid,~tta_ di-N-methylglucamine salt of the nickel(II)-complex ot9- O the -vw ethylenediaminetetraacetic acidj tri-N- iz ""V H 26may 1986"! methylglucamine salt of the manganese(11)-complex of \ NX I _33 _ 201372 diethylenetriaminepentaacetic acid, the N-methylglucamine salt of the gadolinium(111)-complex of ethylenediaminetetraacetic acid, the N-methylglucamine salt of the .dysprosium(III)-complex of ethylenediaminetetraacetic acid, the di-N-methylglucamine salt of the holmium(III)-complex of diethylenetriaminepentaacetic acid or the N-methylglucamine salt of the iron(II)-complex of ethane-l-hydroxy-1.1-diphosphonic acid, in a form suitable for use in NMR diagnosis. 17. The di-N-methylglucamine salt of the gadolinium(III)- complex of diethylenetriaminepentaacetic acid?in a form suitable for Use in NMR diagnosis. 18. The di-ethanolamine salt of the cobalt(II)-complex of ethylenediaminetetraacetic acid, the di-diethanolamine salt of the copper(II)-complex of ethylenediaminetetraacetic acid or the tri-diethanolamine salt of the manganese(II)-complex of diethylenetriaminepentaacetic acid, in a form suitable for use in NMR diagnosis. 19. The di-morpholine salt of the manganese(II)-complex of ethylenediaminetetraacetic acid, in a form suitable for use in NMR d iagnosis. 20. The di-lysine salt of the gadolinium(III)-complex of diethylenetriaminepentaacetic acid, in a form suitable for use in NMR diagnosis. 21. A material for NMR diagnosis containing at least one % * physiologically compatible paramagnetic complex sal^^f fV ^ 26WI986" 201.372 -34 - an aminopolycarboxylic acid of any one of the formulae 1 to IV HOOCCH, CH-COOH \ / N-(CH-)--N (I) 2 2 \ HOH2CCH2 CH2COOH N-Hydroxyethyl-N.N',N'-ethylenediaminetriacetic acid (HEDTA^ HOOCH C CH2COOH CHoC00H \ 1 / 2 N-(CH2)2-N-(CH2)2-N ^ (II) HOOCH2C ^ CH2COOH N.N.N',N",N"-diethylenetriaminepentaacetic acid (DTPA)^ HOH2C-CH2N(CH2COOH)2 (III) N-Wydroxyethyliminodiacetic acid^ D1 CH, CH-COOH \ i / x N-(CH2),,-(cH2-M-CH2)n-(CH2)» -H. (IV) \ HOOCCH2 CH2COOH wherein m represents an integer from 1 to ^ n represents an integer from 0 to 2, and R1 represents a saturated or unsaturated hydrocarbon group with 4 to 12 carbon atoms or the group -CH--COOH. \c -„g f/& <£ v> -35 - 201372 or a diphosphonic acid of the general formula V \ ?°3H2 R^-C-R3 (V) P°3H2 wherein o R represents hydrogen, alkyl of 1 to 4 carbon atoms, halogen, or a hydroxy . amino or v -CHjCOOH group , and R represents hydrogen, alkyl of 1 to 4 carbon atoms, or the -CH2~COOH group ^ an ion of any one of the lanthanide elements of numbers 57 to 70 or an ion of any one of the transition metals of numbers 21 to 29. 42 and 44 and an organic base, optionally with the usual additives in the art,dissolved or suspended in water or physiological salt solution. A material according to claim 21 wherein the organic base is N-methylglucamine. N.N-dimethylglucamine. ethanolamine. diethanolamine. morpholine. lysine, glucamine, ornithine Of arginine. ~ E * A material for NMR diagnosis according to claim 21 or #4 the !r^ ^' wherein as^jaminopolycarboxylic acid C 20(372- r ~ 36 " N.N.N*,N'-ethylenediaminetetraacetic acid (EDTA) is used. 24. A material for NMR diagnosis according to claim 21 or 22, wherein as the aminopolycarboxylie acid N.N.N',N",N"-diethylenetriaminepentaacetic acid (DTPA) is used. / 25. A material for NMR diagnosis according to claim 21 or 22, containing at least one paramagnetic, physiologically compatible complex salt of an aminopolycarboxylic acid of any one of formulae I to IV, an ion of any one of the lanthanide elements of numbers 57 to 70 and an organic base. 26. A material for.NMR diagnosis according to claim 21 or 22, containing at least one paramagnetic, physiologically r complex compatible]salt of an aminopolycarboxylic acid of any one of formulae I to IV, an ion of any one of the transition metals of mumbeis 21 to 29, 42 and 44 and an organic base. 27. A material for NMR diagnosis according to claim 21 or 22, containing at least one paramagnetic, physiologically (compatible complex salt of a diphosphonic acid of the general formula V, an ion of any one of the lanthanide elements of numbers 57 to 70 and an organic base. 28. A imaterial for NMR diagnosis according to claim 21 or 22, (containing at least one paramagnetic, physiologically ccompatible complex salt of a diphosphonic acid of the •general formula V, an ion of any one of the transition metals of mumbers 21 to 29. 42 and 44 and an organic base. '•7 * 13JUNW86, -37 - 201372 29. A material for NMR diagnosis according to claim 21 or 22, containing at least one paramagnetic, physiologically compatible complex salt, wherein as the diphosphonic acid .ethane-l-hydroxy-1.1-diphosphonic acid, methane diphosphonic acid or ethane-l-amino-1.1-diphosphonic acid is used. 30A material for NMR diagnosis according to claim 21 or 22, containing the di-N-methylglucamine salt of the manganese(II)-complex of ethylenediaminetetraacetic acid, the di-methylglucamine salt of the nickel(II)-complex of ethylenediaminetetraacetic acid, the tri-N-methylglucamine salt of the manganese(II)- complex of diethylenetriaminepentaacetic acid, the N-methylglucamine salt of the gadolinium(III)-complex of ethylenediaminetetraacetic acid, the N-methylglucamine salt of the dysprosium(III)-complex of ethylenediaminetetraacetic acid, the di-N-methylglucamine salt of the holmium(III)-complex of diethylenetriaminepentaacetic acid or the N-methylglucamine salt of the iron(II)-complex of ethane-l-hydroxy-1.1-diphosphonic acid. 31. A material for NMR diagnosis according to claim 21 or 22, containing the di-N-methylglucamine salt of the gadolinium(III)-complex of diethylenetriaminepentaacetic acid. - 38 _ 201372 32. A material for NMR diagnosis according to claim 21 or 22, containing the di-ethanolamine salt of the cobalt(II)-complex of ethylenediaminetetraacetic acid. 4-y . thediVfethanolamine salt of the copper(11)-complex of ethylenediaminetetraacetic acid or the tri-diethanolamine salt of the manganese(II)-complex of diethylene— triaminepentaacetic acid. 33. a material for NMR diagnosis according to claim 21 or 22, containing the di-morpholine salt of the manganese(II)-complex of ethylenediaminetetraacetic acid. 34. A material for NMR diagnosis according to claim 21 or 22, containing the di-lysine salt of the gadolinium(III)-complex of diethylenetriaminepentaacetic acid. 35 . a process for the preparation of the material according to any one of claims 21 to 34, characterised in that the paramagnetic complex saltCs)^ dissolved or suspended in water or a is/are, physiological salt solution, brought into a form suitable for oral or intravascular application, optionally with the usual additives in the art. 36. The use of at least one physiologically compatible paranja) magnetic complex salt of an aminopolycarboxylic - ,39 - 201372 acid of any one of the formulae I to IV: hoocch- ch-cooh 2\ / 2 n-(CH2)2-n (i) N-hydroxyethyl-n.n',n'-ethylenediaminetriacetic acid (HEDTA); hoh2cch2 ch2cooh hooch c ch2cooh ch-cooh 2 \ I X n-(ch2)2-n-(ch2)2-n ^ (ii) hooch2c ^ ch2cooh N.N.N'.N".N"-diethylenetriaminepentaacetic acid (DTPA), hoh2c-ch2n(ch2cooh)2 (iii) N-hydroxyethyliminodiacetic acid, _1 ch, ch cooh \ l / /N-<CH2)m-<CH2-N-CH2)n-(CH2'm 'N hoocch2 ch2cooh - 40 - 201372 wherein m represents an integer from 1 to 4, n represents an integer from 0 to 2, and R1 represents a saturated or unsaturated hydrocarbon group with 4 to 12 carbon atoms or the group -ch2-cooh, or diphosphoni^cid of the general formula V: f°3H2 R2-C-R3 (V) I P°3H2 wherein 2 R represents hydrogen, alkyl of 1 to 4 carbon atoms, halogen, or a hydroxy, amino or -CH2COOH group, and O R represents hydrogen, alkyl of 1 to 4 carbon atoms, or the -CH2-COOH group, an ion of any one of the lanthanide elements of numbers 57 to 70 or an ion of any one of the transition metals of to 29. 42 and 44 il*i and 126mm ) an organic base,in the preparation of a material for NMR diagnosis. The use according to claim 36 wherein the organic base i N-methylglucamine, N,N-dimethylglucamine, glucamine, - 41 - 201372 ethanolamine, diethanolamine, morpholine, lysine, ornithine or arginine 38. The use of at least one physiologically compatible para- or 37 K magnetic complex salt according to claim 36 ^wherein as the aminopolycarboxylic acid N,N,N',N'-ethylenediaminetetraacetic ris used, acidjin the preparation of a material for NMR diagnosis. 39. The use of at least one physiologically compatible para- or 37,, magnetic complex salt according to claim 36 \>wherein as the aminopolycarboxylic acid N,N ,N1,N",N"- diethylenetriaminepent- ris usedf aacetic acid (DTPA) Jin the preparation of a material for NMR diagnosis. 40. The use of at least one physiologically compatible paramagnetic or 37,, complex salt according to claim 36 ^wherein as the diphosphonic acid ethane-l-hydroxy-1,1-di phosphonic acid, methane-di - .is used, phosphonic acid or ethane-l-amino-1,1-diphosphonic acidj in the preparation of a material for NMR diagnosis. 41. The use of the di-N-methylglucamine salt of the manganese(II) -complex of ethylenediaminetetraacetic acid, the di-N-methyl-glucamine salt of the nickel(II)-complex of ethylenediaminetetra acetic acid, the tri-N-methylglucamine salt of the manganese (II) (M 2 6 MAY 1985 -■\ nil *>)} // JlV - 42 - 201372 complex of diethylenetriaminepentaacetic acid, the N-methylglucamine salt of the gadolinium (III)-complex of ethylene-diaminetetraacetic acid, the N-methylglucamine salt of the dysprosium(III)-complex of ethylenediaminetetraacetic acid, the di-N-methylglucamine salt of the holmium(III)-complex of diethylenetriaminepentaacetic acid or the N-methylglucamine salt of the iron(II)-complex of ethane-l-hydroxy-1,1-diphosphonic acid in the preparation of a material for NMR diagnosis. 42. The use of the di-N-methylglucamine salt of the gadolinium(III)-complex of diethylenetriaminepentaacetic acid in the preparation of a material for NMR diagnosis. 43. The use of the di-ethanolamine salt of the cobalt(II)-complex of ethylenediaminetetraacetic acid, the di-diethanolamine salt of the copper(II)-complex of ethylenediaminetetraacetic acid or the tri-diethanolamine salt of the manganese(II)-complex of diethylenetriaminepentaacetic acid in the preparation of a material for NMR diagnosis. 44. The use of the di-morpholine salt of the manganese(II)-complex of ethylenediaminetetraacetic acid in the preparation of a material for NMF diagnosis. 45. The use of the di-lysine salt of the gadolinium(III)-complex of diethylenetriaminepentaacetic acid in the preparation of a material for NMR diagnosis. c 201372 46;. A pharmaceutical preparation in a form suitable for use in NMR diagnosidwhich comprises a physiologically acceptable carrier and at least one physiologically compatible paramagnetic complex salt of (a) an aminopolycarboxylic acid of any one of the formulae 1 to IV HOOCCH- CH-COOH \ / N-CCH ) -N (I) / \ H0H2CCH2 CH2COOH N-bydroxyethyl-N.N',N'-ethylenediaminetriacetic acid (HEDTA) HOOCH C CH2COOH CH COOH \ i / N-(CH2)2-N-(CH2)2-N ^ (II) HOOCH2C ^ CH2COOH N.N.N',N",N"-diethylenetriaminepentaacetic acid (DTPA) HOH2C-CH2N(CH2COOH)2 (III) N-hydroxyethyliminodiacetic aci< D1 CH_ CH-COOH \ i / HOOCCH2 ' CH2COOH wherein m represents an integer from 1 to ^ n represents an integer from 0 to 2, and R1 represents a saturated or unsaturated hydrocarbon group with 4 to 12 carbon atoms or the group -ch2-coo*u " "o §* ^ 1 >- % £ \\ _ 44 _ / 201372 or a diphosphonic acid of the general formula V; *°3H2 Ra-C-Rs (V) P°3H2 vherein R2 represents hydrogen, alkyl of 1 to 4 carbon atoms,-halogen, or a hydroxy , amino or -CI^COOH group . and I? represents hydrogen, alkyl of 1 to 4 carbon atoms, or the -CH2-COOH group, an ion of any one of the lanthanide elements of numbers 57 to 70 or an ion of any one of the transition metals of numbers 21 to 29. 42 and 44 and optionally an organic or inorganic base. 47 . A preparation according to claim 46 in which the complex salt includes an inorganic base. 48. A preparation according to claim 47 in which the inorganic base is sodium hydroxide. 49 . A preparation according to claim -46or 47 in which the aminopolycarboxylic acid is N,N,NN1-ethylene-diamine tetraacetic acid iZDrA). "4 ). ' 50 . A preparation according to claim 46 or 47 in which the aminopolycarboxylic acid is N,N,N',N",N"-diethylene-C^triamine pentaacetic ac id CDTPA) • _ 45 - 201372 51 A preparation according to claim 4 6 or 4 7 in which the diphosphonic acid is ethane-1-hydroxy-1,1-diphosphonic acid, methane diphosphonic acid or ethane-1 - ami no-1,1-diphosphonic acid. 52. A preparation according to claim 47 in which the complex salt is the disodium salt of the gadolinium (il^-complex of N,N,N',N",N"-diethyl-ene-triamine pen tabetic acid. A SCHERING AKTIENGESELLSCHAFT By their attorneys HENRY HUGHES LIMITED By:
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE3129906A DE3129906C3 (en) | 1981-07-24 | 1981-07-24 | Paramagnetic complex salts, their preparation and agents for use in NMR diagnostics |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ201372A true NZ201372A (en) | 1986-08-08 |
Family
ID=6137999
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ201372A NZ201372A (en) | 1981-07-24 | 1982-07-23 | Paramagnetic complex salts,and use in nmr-diagnostics |
Country Status (12)
Country | Link |
---|---|
EP (2) | EP0169299B1 (en) |
JP (3) | JPS5829718A (en) |
AT (2) | ATE52247T1 (en) |
AU (2) | AU566007B2 (en) |
CA (2) | CA1218597A (en) |
DE (3) | DE3129906C3 (en) |
IE (1) | IE53639B1 (en) |
LU (1) | LU88291I2 (en) |
NL (1) | NL930072I2 (en) |
NO (2) | NO164458C (en) |
NZ (1) | NZ201372A (en) |
ZA (1) | ZA825313B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112525943A (en) * | 2020-11-19 | 2021-03-19 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | By using q1Method for quantitatively analyzing ethanol and acetic acid in fermented fruit and vegetable juice by H-NMR technology |
Families Citing this family (135)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4957939A (en) * | 1981-07-24 | 1990-09-18 | Schering Aktiengesellschaft | Sterile pharmaceutical compositions of gadolinium chelates useful enhancing NMR imaging |
DE3129906C3 (en) * | 1981-07-24 | 1996-12-19 | Schering Ag | Paramagnetic complex salts, their preparation and agents for use in NMR diagnostics |
DE3448606C2 (en) * | 1983-01-21 | 2001-12-13 | Schering Ag | Diagnostic agents, processes for their production and their use |
NL194579C (en) * | 1983-01-21 | 2002-08-05 | Schering Ag | Diagnostic. |
US4735796A (en) * | 1983-12-08 | 1988-04-05 | Gordon Robert T | Ferromagnetic, diamagnetic or paramagnetic particles useful in the diagnosis and treatment of disease |
EP0330801A1 (en) * | 1983-02-08 | 1989-09-06 | Schering Aktiengesellschaft | Ferromagnetic, diamagnetic or paramagnetic particles useful in the diagnosis and treatment of disease |
SE8301395L (en) * | 1983-03-15 | 1984-09-16 | Wallac Oy | KELATIZING COMPOUNDS WITH FUNCTIONAL GROUPS WHICH ALLOW COVALENT COUPLING TO BIO-ORGANIC MOLECULES |
US4972837A (en) * | 1983-04-26 | 1990-11-27 | Regents Of The University Of California | Contrast agents for nuclear magnetic resonance imaging |
DE3316703A1 (en) * | 1983-05-04 | 1984-11-08 | Schering AG, 1000 Berlin und 4709 Bergkamen | ORAL CONTRAST AGENT FOR MRI MRI AND THE PRODUCTION THEREOF |
DE3324235A1 (en) * | 1983-07-01 | 1985-01-10 | Schering AG, 1000 Berlin und 4709 Bergkamen | NEW COMPLEX ILLUMINATORS, COMPLEX AND COMPLEX SALTS |
DE3328365A1 (en) * | 1983-08-03 | 1985-02-21 | Schering AG, 1000 Berlin und 4709 Bergkamen | NEW DIAGNOSTIC AGENTS |
CA1242643A (en) * | 1983-08-12 | 1988-10-04 | Eric T. Fossel | Nmr imaging utilizing chemical shift reagents |
FR2550449B1 (en) * | 1983-08-12 | 1986-01-31 | Commissariat Energie Atomique | SPECIFIC ORGAN OR PATHOLOGY RELAXATION AGENTS FOR USE IN MODIFYING CONTRASTS IN MEDICAL IMAGING BY NUCLEAR MAGNETIC RESONANCE |
CA1243602A (en) * | 1983-08-25 | 1988-10-25 | Hong-Ning Yeung | Methods for enhancing the contrast in nmr imaging |
US4615879A (en) * | 1983-11-14 | 1986-10-07 | Vanderbilt University | Particulate NMR contrast agents for gastrointestinal application |
US5720939A (en) * | 1985-08-15 | 1998-02-24 | Nycomed Imaging As | Method of contrast enhanced magnetic resonance imaging using magnetically responsive-particles |
US5618514A (en) * | 1983-12-21 | 1997-04-08 | Nycomed Imaging As | Diagnostic and contrast agent |
GB8408127D0 (en) * | 1984-03-29 | 1984-05-10 | Nyegaard & Co As | Contrast agents |
US4728575A (en) * | 1984-04-27 | 1988-03-01 | Vestar, Inc. | Contrast agents for NMR imaging |
GB8413772D0 (en) * | 1984-05-30 | 1984-07-04 | Nyegaard & Co As | Chemical compounds |
GB8413849D0 (en) * | 1984-05-31 | 1984-07-04 | Amersham Int Plc | Nmr contrast agents |
CA1268208A (en) * | 1984-08-10 | 1990-04-24 | Truman Brown | Magnetic micro-particles as contrast agents in nuclear magnetic resonance imaging |
US4749560A (en) * | 1984-08-13 | 1988-06-07 | Research Corporation | Metal organo phosphorous compounds for NMR analysis |
US4859450A (en) * | 1984-08-13 | 1989-08-22 | The General Hospital Corporation | Method of NMR imaging using antibody to cardiac myosin |
US4687659A (en) | 1984-11-13 | 1987-08-18 | Salutar, Inc. | Diamide-DTPA-paramagnetic contrast agents for MR imaging |
US4859451A (en) * | 1984-10-04 | 1989-08-22 | Salutar, Inc. | Paramagnetic contrast agents for MR imaging |
US4687658A (en) * | 1984-10-04 | 1987-08-18 | Salutar, Inc. | Metal chelates of diethylenetriaminepentaacetic acid partial esters for NMR imaging |
US5342606A (en) * | 1984-10-18 | 1994-08-30 | Board Of Regents, The University Of Texas System | Polyazamacrocyclic compounds for complexation of metal ions |
US5316757A (en) * | 1984-10-18 | 1994-05-31 | Board Of Regents, The University Of Texas System | Synthesis of polyazamacrocycles with more than one type of side-chain chelating groups |
US4639365A (en) * | 1984-10-18 | 1987-01-27 | The Board Of Regents, The University Of Texas System | Gadolinium chelates as NMR contrast agents |
US5362476A (en) * | 1984-10-18 | 1994-11-08 | Board Of Regents, The University Of Texas System | Alkyl phosphonate polyazamacrocyclic cheates for MRI |
DE3577185D1 (en) * | 1984-11-01 | 1990-05-23 | Nycomed As | PARAMAGNETIC CONTRAST AGENTS FOR USE IN "IN VIVO" NMR DIAGNOSTIC METHODS AND THE PRODUCTION THEREOF. |
SE465907B (en) * | 1984-11-01 | 1991-11-18 | Nyegaard & Co As | DIAGNOSTIC AGENT CONTENT AND PARAMAGNETIC METAL |
DE3443252A1 (en) * | 1984-11-23 | 1986-05-28 | Schering AG, 1000 Berlin und 4709 Bergkamen | Dextran-magnetite complexes for NMR diagnosis |
PT81498B (en) * | 1984-11-23 | 1987-12-30 | Schering Ag | METHOD FOR PREPARING COMPOSITIONS FOR DIAGNOSTICS CONTAINING MAGNETIC PARTICLES |
DE3508000A1 (en) * | 1985-03-04 | 1986-09-04 | Schering AG, Berlin und Bergkamen, 1000 Berlin | Ferromagnetic particles for NMR diagnosis |
DE3443251C2 (en) * | 1984-11-23 | 1998-03-12 | Schering Ag | Iron oxide complexes for NMR diagnosis, diagnostic compounds containing these compounds, their use and process for their preparation |
US5089644A (en) * | 1985-01-04 | 1992-02-18 | Salutar Inc. | Preparation of oxamine complexes |
US4637929A (en) * | 1985-01-04 | 1987-01-20 | Salutar, Inc. | Ferrioxamine-paramagnetic contrast agents for MR imaging, composition, apparatus and use |
US4758422A (en) * | 1985-01-04 | 1988-07-19 | Salutar Inc. | Ferrioxamine paramagnetic contrast agents for MR imaging |
US4986256A (en) * | 1985-02-28 | 1991-01-22 | The United States Of America As Represented By The Department Of Health And Human Services | Use of paramagnetic metalloporphyrins as contrast agents for tumors in MRI imaging |
US4746507A (en) * | 1985-04-02 | 1988-05-24 | Salutar, Inc. | EDHPA based contrast agents for MR imaging, apparatus and methods |
US4899755A (en) * | 1985-05-08 | 1990-02-13 | The General Hospital Corporation | Hepatobiliary NMR contrast agents |
US5422096A (en) * | 1985-05-08 | 1995-06-06 | The General Hospital Corporation | Hydroxy-aryl metal chelates for diagnostic NMR imaging |
US4880008A (en) * | 1985-05-08 | 1989-11-14 | The General Hospital Corporation | Vivo enhancement of NMR relaxivity |
US4830847A (en) * | 1985-06-28 | 1989-05-16 | The Procter & Gamble Company | Diphosphonate-derivatized macromolecules |
US4735210A (en) * | 1985-07-05 | 1988-04-05 | Immunomedics, Inc. | Lymphographic and organ imaging method and kit |
US5776093A (en) | 1985-07-05 | 1998-07-07 | Immunomedics, Inc. | Method for imaging and treating organs and tissues |
GB8518300D0 (en) * | 1985-07-19 | 1985-08-29 | Amersham Int Plc | Contrast agent |
US5010191A (en) * | 1985-08-19 | 1991-04-23 | The Regents Of The University Of California | Imaging agents for in vivo magnetic resonance and scintigraphic imaging |
GB8522535D0 (en) * | 1985-09-11 | 1985-10-16 | Amersham Int Plc | Contrast agent |
US5336762A (en) * | 1985-11-18 | 1994-08-09 | Access Pharmaceuticals, Inc. | Polychelating agents for image and spectral enhancement (and spectral shift) |
ATE90879T1 (en) * | 1985-11-18 | 1993-07-15 | Access Pharma Inc | POLYCHELATING MATERIALS FOR IMAGE AND SPECTRAL ENHANCEMENT (AND SPECTRAL SHIFTING). |
US4885363A (en) * | 1987-04-24 | 1989-12-05 | E. R. Squibb & Sons, Inc. | 1-substituted-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane and analogs |
DE3772785D1 (en) * | 1986-01-23 | 1991-10-17 | Squibb & Sons Inc | 1-SUBSTITUTED-4,7,10-TRISCARBOXYMETHYL-1,4,7,10-TETRAAZACYCLODODECAN AND ANALOG. |
MX174467B (en) * | 1986-01-23 | 1994-05-17 | Squibb & Sons Inc | 1,4,7-TRISCARBOXIMETHYL-1,4,7,10-TETRAAZACICLODO DECAN SUBSTITUTE IN 1 AND ANALOG COMPOUNDS |
IT1213029B (en) * | 1986-01-30 | 1989-12-07 | Bracco Ind Chimica Spa | PARAMAGNETIC METAL ION CHELATES. |
JPS62231168A (en) * | 1986-03-21 | 1987-10-09 | ハイブリテツク・インコ−ポレイテツド | Improvement method for forming internal standard for analyzing analite-receptor |
KR880701111A (en) * | 1986-04-07 | 1988-07-25 | 제뜨랭 프랑쎄 | Composition for use in tomometry |
US5342607A (en) * | 1986-07-03 | 1994-08-30 | Advanced Magnetics, Inc. | Receptor mediated endocytosis type magnetic resonance imaging contrast agents |
US5352432A (en) * | 1986-07-03 | 1994-10-04 | Advanced Magnetics, Inc. | Hepatocyte specific composition and their use as diagnostic imaging agents |
US5679323A (en) * | 1986-07-03 | 1997-10-21 | Advanced Magnetics, Inc. | Hepatocyte-specific receptor-mediated endocytosis-type compositions |
AU608759B2 (en) * | 1986-08-04 | 1991-04-18 | Amersham Health Salutar Inc | NMR imaging with paramagnetic polyvalents metal salts of poly-(acid-alkylene-amido)-alkanes |
IL83966A (en) * | 1986-09-26 | 1992-03-29 | Schering Ag | Amides of aminopolycarboxylic acids and pharmaceutical compositions containing them |
US5707604A (en) * | 1986-11-18 | 1998-01-13 | Access Pharmaceuticals, Inc. | Vivo agents comprising metal-ion chelates with acidic saccharides and glycosaminoglycans, giving improved site-selective localization, uptake mechanism, sensitivity and kinetic-spatial profiles |
US5672334A (en) * | 1991-01-16 | 1997-09-30 | Access Pharmaceuticals, Inc. | Invivo agents comprising cationic metal chelators with acidic saccharides and glycosaminoglycans |
DE3640708C2 (en) * | 1986-11-28 | 1995-05-18 | Schering Ag | Improved pharmaceuticals containing metals |
GB8700431D0 (en) * | 1987-01-09 | 1987-02-11 | Amersham Int Plc | Contrast agents |
DE3709851A1 (en) * | 1987-03-24 | 1988-10-06 | Silica Gel Gmbh Adsorptions Te | NMR DIAGNOSTIC LIQUID COMPOSITIONS |
DE3710730A1 (en) * | 1987-03-31 | 1988-10-20 | Schering Ag | SUBSTITUTED COMPLEX ILLUMINATORS, COMPLEX AND COMPLEX SALTS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THEM |
ES2026257T3 (en) * | 1987-06-23 | 1992-04-16 | Hafslund Nycomed Innovation Ab | IMPROVEMENTS INTRODUCED IN THE PRESENTATION OF IMAGES BY NUCLEAR MAGNETIC RESONANCE. |
US5531978A (en) * | 1987-07-16 | 1996-07-02 | Nycomed Imaging As | Aminopolycarboxylic acids and derivatives thereof |
US5198208A (en) * | 1987-07-16 | 1993-03-30 | Nycomed Imaging As | Aminopolycarboxylic acids and derivatives thereof |
DE3724188C2 (en) * | 1987-07-17 | 1995-05-18 | Heinz Dr Gries | Metal-containing oligosaccharide polysulfates, process for their preparation and pharmaceutical compositions containing them |
DE3927444A1 (en) * | 1989-08-16 | 1991-02-28 | Schering Ag | USE OF AMID COMPLEX COMPOUNDS |
GB8801646D0 (en) * | 1988-01-26 | 1988-02-24 | Nycomed As | Chemical compounds |
DE3806795A1 (en) * | 1988-02-29 | 1989-09-07 | Schering Ag | POLYMER-TIED COMPLEX IMAGERS, THEIR COMPLEXES AND CONJUGATES, METHOD FOR THEIR PRODUCTION AND PHARMACEUTICAL AGENTS CONTAINING THEM |
DE3809671A1 (en) * | 1988-03-18 | 1989-09-28 | Schering Ag | PORPHYRINE COMPLEX COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THEM |
JP3038339B2 (en) * | 1988-05-02 | 2000-05-08 | ザイナクシス・テクノロジーズ・インコーポレーテッド | Compounds that bind bioaffecting substances to the surface membrane of bioparticles |
GB8813144D0 (en) * | 1988-06-03 | 1988-07-06 | Nycomed As | Compositions |
GB8817137D0 (en) * | 1988-07-19 | 1988-08-24 | Nycomed As | Compositions |
US5137711A (en) † | 1988-07-19 | 1992-08-11 | Mallickrodt Medical, Inc. | Paramagnetic dtpa and edta alkoxyalkylamide complexes as mri agents |
DE4001655A1 (en) * | 1990-01-18 | 1991-07-25 | Schering Ag | 6-RING MACROCYCLIC TETRAAZA COMPOUNDS, METHOD FOR PRODUCING THE SAME AND PHARMACEUTICAL PRODUCTS CONTAINING THEM |
DE3825040A1 (en) * | 1988-07-20 | 1990-01-25 | Schering Ag, 13353 Berlin | 5- OR 6-RING MACROCYCLIC POLYAZA COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THEM |
WO1990001295A1 (en) * | 1988-08-04 | 1990-02-22 | Advanced Magnetics, Incorporated | Receptor mediated endocytosis type mri contrast agents |
GB8819753D0 (en) * | 1988-08-19 | 1988-09-21 | Nycomed As | Apparatus |
US5314681A (en) * | 1988-12-23 | 1994-05-24 | Nycomed Innovation Ab | Composition of positive and negative contrast agents for electron spin resonance enhanced magnetic resonance imaging |
GB8900719D0 (en) * | 1989-01-13 | 1989-03-08 | Nycomed As | Compounds |
US5516503A (en) * | 1989-11-16 | 1996-05-14 | Guerbet S.A. | Diagnostic composition comprising a binuclear complex, its method of preparation and its use in magnetic resonance imaging |
FR2654344B1 (en) * | 1989-11-16 | 1994-09-23 | Cis Bio Int | GADOLINIUM PARAMAGNETIC COMPLEX, ITS PREPARATION METHOD AND ITS USE FOR MRI DIAGNOSIS. |
DE3938992A1 (en) * | 1989-11-21 | 1991-05-23 | Schering Ag | Cascade polymer-bound complex formers, their complexes and conjugates, process for their preparation and pharmaceutical compositions containing them |
WO1991007911A1 (en) * | 1989-11-27 | 1991-06-13 | Concat Ltd. | Mri image enhancement of bone and related tissue using complexes of paramagnetic cations and polyphosphonate ligands |
CH679742A5 (en) * | 1990-01-09 | 1992-04-15 | Byk Gulden Lomberg Chem Fab | |
CA2072080A1 (en) * | 1990-01-19 | 1991-07-20 | Jo Klaveness | Chelating compounds |
FR2667506B1 (en) * | 1990-10-05 | 1993-08-20 | Medgenix Group Sa | CONTRAST AGENT COMPRISING A PARAMAGNETIC CATION ASSOCIATED WITH A SCHIFF BASE. |
FR2670113A1 (en) * | 1990-12-06 | 1992-06-12 | Medgenix Group Sa | CONTRAST AGENT CONSTITUTED BY A NEUTRAL COMPLEX OF A PARAMAGNETIC CATION AND LIGAND TO FORM A COMPLEX. |
US5885549A (en) * | 1991-02-01 | 1999-03-23 | Imarx Pharmaceutical Corp. | Phosphorylated materials as contrast agents for use in magnetic resonance imaging of the gastrointestinal region |
US5143716A (en) * | 1991-02-01 | 1992-09-01 | Unger Evan C | Phosphorylated sugar alcohols, Mono- and Di-Saccharides as contrast agents for use in magnetic resonance imaging of the gastrointestinal region |
US5360459A (en) | 1991-05-13 | 1994-11-01 | The Lubrizol Corporation | Copper-containing organometallic complexes and concentrates and diesel fuels containing same |
GB9208908D0 (en) * | 1992-04-24 | 1992-06-10 | Nycomed As | Contrast agents |
DE4302287A1 (en) * | 1993-01-25 | 1994-07-28 | Schering Ag | Derivatized DTPA complexes, pharmaceutical compositions containing these compounds, their use and processes for their preparation |
DE4340809C2 (en) * | 1993-11-24 | 2000-08-03 | Schering Ag | 1.4,7,10-tetraazacyclododecane derivatives, pharmaceutical compositions containing them and process for their preparation |
US5582814A (en) * | 1994-04-15 | 1996-12-10 | Metasyn, Inc. | 1-(p-n-butylbenzyl) DTPA for magnetic resonance imaging |
US6693190B1 (en) | 1994-05-11 | 2004-02-17 | Bracco International B.V. | Enhanced relaxivity monomeric and multimeric compounds |
US5672335A (en) * | 1994-11-30 | 1997-09-30 | Schering Aktiengesellschaft | Use of metal complexes as liver and gallbladder X-ray diagnostic agents |
TW319763B (en) | 1995-02-01 | 1997-11-11 | Epix Medical Inc | |
DE19508058A1 (en) * | 1995-02-21 | 1996-08-22 | Schering Ag | Process for the preparation of DTPA tetraesters of the terminal carboxylic acids and their use for the production of pharmaceutical agents |
DE19507820A1 (en) * | 1995-02-21 | 1996-08-22 | Schering Ag | Novel substituted DTPA derivatives, their metal complexes, pharmaceutical compositions containing these complexes, their use in diagnostics, and methods for producing the complexes and compositions |
DE19507819A1 (en) * | 1995-02-21 | 1996-08-22 | Schering Ag | New di:ethylene-tri:amine penta:acetic acid amide complexes |
DE19507822B4 (en) * | 1995-02-21 | 2006-07-20 | Schering Ag | Substituted DTPA monoamides of the central carboxylic acid and its metal complexes, pharmaceutical compositions containing these complexes, their use in diagnostics and therapy, and methods for the preparation of the complexes and agents |
US6106866A (en) * | 1995-07-31 | 2000-08-22 | Access Pharmaceuticals, Inc. | In vivo agents comprising cationic drugs, peptides and metal chelators with acidic saccharides and glycosaminoglycans, giving improved site-selective localization, uptake mechanism, sensitivity and kinetic-spatial profiles, including tumor sites |
US5804164A (en) * | 1996-03-13 | 1998-09-08 | Research Corporation Technologies, Inc. | Water-soluble lipophilic contrast agents |
DE19646762B4 (en) * | 1996-11-04 | 2004-05-13 | Schering Ag | Use of metal compounds for the production of agents for radiotherapy of tumors |
DE19719033C1 (en) * | 1997-04-29 | 1999-01-28 | Schering Ag | Ion pairs, processes for their preparation and their use as contrast agents |
EP1060174B1 (en) * | 1997-12-23 | 2004-09-22 | Amersham Health AS | Nitric oxide releasing chelating agents and their therapeutic use |
IT1297035B1 (en) | 1997-12-30 | 1999-08-03 | Bracco Spa | 1,4,7,10-TETRAAZACICLODODECAN-1,4-DIACETIC ACID DERIVATIVES |
US7169410B1 (en) | 1998-05-19 | 2007-01-30 | Sdg, Inc. | Targeted liposomal drug delivery system |
DE59900055D1 (en) * | 1999-09-09 | 2001-04-12 | Schering Ag | Calcium complex of (4R) -4-bis (carboxy-kappa.O) methyl amino-.kappa.N-6,9-bis (carboxy-.kappa.O) methyl-1- (4,4-diphenylcyclohexyl) oxy-1-hydroxy-2-oxa-6,9-diaza-1-phosphaundecan-11-yl-acid-.kappa.N6, .kappa.N9, .kappa.O11 1-oxidato (6 -) -, hexahydrogen , its salts, pharmaceutical compositions containing these complexes, their use in therapy and as an additive in diagnostics, and methods for producing the complexes and compositions |
DE19964224B4 (en) * | 1999-09-09 | 2005-09-01 | Schering Ag | Pharmaceutical compositions containing calcium complex of [[(4R) -4- [bis [(carboxy-.kappa.O) methyl] amino-.kappa.N] -6,9-bis [(carboxy-.kappa.O) methyl] -1 - [(4,4-diphenylcyclohexyl) oxy] -1-hydroxy-2-oxa-6,9-diaza-1-phosphaundecan-11-yl-acid-.kappa.N6, .kappa.N9, .kappa.011] 1-oxidato (6 -)], tetrahydrogen (MS-325) and its salts, and process for their preparation |
DE19944893C2 (en) * | 1999-09-09 | 2001-09-20 | Schering Ag | Calcium complex of [[(4R) -4- [bis [(carboxy-.kappa.O) methyl] amino-. kappa.N] -6,9-bis [(carboxy-.kappa.O) methyl] -1 - [(4,4-diphenylcyclohexyl) oxy] -1-hydroxy-2-oxa-6,9-diaza-1 -phosphaundecan-11-yl-acid-.kappa.N6, .kappa.N9, .kappa.O11] 1-oxidato (6 -)] -, hexahydrogen, its salts and pharmaceutical compositions containing these complexes |
US6559330B1 (en) | 1999-09-09 | 2003-05-06 | Schering Aktiengesellschaft | Calcium complex of [[(4r)-4-[bis{carboxy-.kappa.o)methyl]amino-.kappa.n]-6,9-bis[(carboxy.kappa.o)methyl]-1-[(4,4-diphenylcyclohexyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-phosphaundecan-11-ylic-acid-.kappa.n6,.kappa.n9,.kappa.011]1-oxidato(6-)]-, hexahydrogen, its salts, pharmaceutical agents that contain these complexes, their use in treatment and as additives in diagnosis, as well as processes for the production of the complexes and agents |
EP2990417A1 (en) | 2001-12-21 | 2016-03-02 | Human Genome Sciences, Inc. | Albumin insulin fusion protein |
DE10305462A1 (en) * | 2003-02-04 | 2004-08-12 | Schering Ag | Conjugates of enantiomerically pure (4S, 8S) - and (4R, 8R) -4-p-benzyl-8-methyl-3,6,9-triaza-3N, 6N, 9N-tricarboxymethyl-1,11-undecanedioic acid with biomolecules, method for their manufacture and use for manufacture |
FR2867473B1 (en) | 2004-03-12 | 2006-06-23 | Guerbet Sa | PORPHYRINE COMPOUND AND HIGH FIELD USE IN MRI |
US8540966B2 (en) | 2004-07-02 | 2013-09-24 | Bracco Imaging S.P.A. | Contrast agents endowed with high relaxivity |
WO2006124726A2 (en) | 2005-05-12 | 2006-11-23 | The General Hospital Corporation | Novel biotinylated compositions |
EP1991577A2 (en) | 2006-01-31 | 2008-11-19 | Parkinson, John F. | Modulation of mdl-1 activity for treatment of inflammatory disease |
DE102007058220A1 (en) | 2007-12-03 | 2009-06-04 | Bayer Schering Pharma Aktiengesellschaft | New metal complexes useful e.g. for manufacturing agent for X-ray diagnostics and magnetic resonance tomography-diagnostics of brain infarcts and liver tumor, and/or space-process in liver and abdomen tumors and musculoskeletal tumors |
US8637026B2 (en) | 2007-12-26 | 2014-01-28 | Vaccinex, Inc. | Anti-C35 antibody combination therapies and methods |
US8722020B2 (en) * | 2010-03-31 | 2014-05-13 | General Electric Company | Hydroxylated contrast enhancement agents |
EP2890788A1 (en) | 2012-08-31 | 2015-07-08 | The General Hospital Corporation | Biotin complexes for treatment and diagnosis of alzheimer's disease |
CN103664672B (en) * | 2013-10-21 | 2016-01-13 | 河北一品制药有限公司 | A kind of preparation method of suitability for industrialized production Gadopentetate Meglumine |
EP3562517A1 (en) | 2016-12-29 | 2019-11-06 | Inventure, LLC | Solvent-free gadolinium contrast agents |
CN106928078A (en) * | 2017-02-27 | 2017-07-07 | 南昌大学 | A kind of threonine chelated iron and its application |
CN107632037A (en) * | 2017-08-24 | 2018-01-26 | 北京中科乾和环保科技服务有限公司 | Based on liquid phase31The analysis method of organophosphor in the deposit of P NMR technologies |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US401594A (en) * | 1889-04-16 | Combined punch | ||
FR1111504A (en) * | 1950-03-06 | 1956-03-01 | Cassella Farbwerke Mainkur Ag | Process for the preparation of cobalt compounds |
FR484M (en) * | 1960-05-02 | 1961-05-08 | ||
FR988M (en) * | 1960-12-01 | 1961-12-11 | ||
US3252082A (en) * | 1964-01-02 | 1966-05-17 | Chevron Res | Method and composition for aiding nuclear magnetic well logging |
US3818061A (en) * | 1971-11-09 | 1974-06-18 | Merck Sharp & Dohme | Transparent nmr shift reagents |
JPS5441575B2 (en) * | 1972-07-28 | 1979-12-08 | ||
JPS49103693A (en) * | 1973-02-02 | 1974-10-01 | ||
US4167564A (en) * | 1974-09-23 | 1979-09-11 | Albion Laboratories, Inc. | Biological assimilation of metals |
DE2527158A1 (en) * | 1975-06-18 | 1976-12-23 | Herz Eberhard | MEDICINAL PRODUCTS FOR THE TREATMENT OF INFECTIOUS DISEASES AND INFLAMMATION IN HUMAN AND VETERINAL MEDICINE THAT CANNOT BE DETECTED BY MICROORGANISMS |
US4066743A (en) * | 1976-06-21 | 1978-01-03 | Mallinckrodt, Inc. | X-ray contrast agents |
US4125599A (en) * | 1976-08-19 | 1978-11-14 | Mallinckrodt, Inc. | X-ray contrast agents |
US4176173A (en) * | 1977-07-18 | 1979-11-27 | Medi-Physics, Inc. | Radiographic compositions |
ZA786403B (en) * | 1977-12-01 | 1979-10-31 | Ici Australia Ltd | Process |
GB1598610A (en) * | 1978-05-31 | 1981-09-23 | Rexolin Chem Ab | Aliphatic polyamino polycarboxylic acid and its salts and their use as chelating agents |
JPS5759841A (en) * | 1980-09-30 | 1982-04-10 | Showa Denko Kk | Treating method of waste liquor from preparation of metallic chelate of ethylenediaminetraacetic acid |
US4647447A (en) * | 1981-07-24 | 1987-03-03 | Schering Aktiengesellschaft | Diagnostic media |
DE3129906C3 (en) * | 1981-07-24 | 1996-12-19 | Schering Ag | Paramagnetic complex salts, their preparation and agents for use in NMR diagnostics |
DE3518267A1 (en) * | 1985-05-17 | 1986-11-20 | Martin Prof. Dr. 1000 Berlin Wenzel | Compositions for increasing contrast in magnetic resonance imaging |
GB8518300D0 (en) * | 1985-07-19 | 1985-08-29 | Amersham Int Plc | Contrast agent |
IT1213029B (en) * | 1986-01-30 | 1989-12-07 | Bracco Ind Chimica Spa | PARAMAGNETIC METAL ION CHELATES. |
-
1981
- 1981-07-24 DE DE3129906A patent/DE3129906C3/en not_active Expired - Lifetime
-
1982
- 1982-07-19 DE DE8282730097T patent/DE3270097D1/en not_active Expired
- 1982-07-19 AT AT85102713T patent/ATE52247T1/en not_active IP Right Cessation
- 1982-07-19 AT AT82730097T patent/ATE18719T1/en active
- 1982-07-19 EP EP85102713A patent/EP0169299B1/en not_active Expired - Lifetime
- 1982-07-19 EP EP82730097A patent/EP0071564B1/en not_active Expired
- 1982-07-19 DE DE8585102713T patent/DE3280157D1/en not_active Expired - Lifetime
- 1982-07-22 AU AU86330/82A patent/AU566007B2/en not_active Expired
- 1982-07-23 IE IE1766/82A patent/IE53639B1/en not_active IP Right Cessation
- 1982-07-23 JP JP57127810A patent/JPS5829718A/en active Granted
- 1982-07-23 NZ NZ201372A patent/NZ201372A/en unknown
- 1982-07-23 ZA ZA825313A patent/ZA825313B/en unknown
- 1982-07-23 CA CA000407923A patent/CA1218597A/en not_active Expired
- 1982-07-23 NO NO822546A patent/NO164458C/en not_active IP Right Cessation
-
1985
- 1985-07-31 CA CA000487858A patent/CA1240679A/en not_active Expired
-
1986
- 1986-01-24 JP JP61012237A patent/JPH0768193B2/en not_active Expired - Lifetime
-
1988
- 1988-01-08 AU AU10186/88A patent/AU601916B2/en not_active Expired
-
1990
- 1990-08-15 JP JP2214464A patent/JP2548436B2/en not_active Expired - Lifetime
-
1993
- 1993-06-09 LU LU88291C patent/LU88291I2/en unknown
- 1993-06-14 NL NL930072C patent/NL930072I2/en unknown
-
1994
- 1994-12-30 NO NO1994031C patent/NO1994031I1/en unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112525943A (en) * | 2020-11-19 | 2021-03-19 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | By using q1Method for quantitatively analyzing ethanol and acetic acid in fermented fruit and vegetable juice by H-NMR technology |
CN112525943B (en) * | 2020-11-19 | 2024-04-19 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | Q is adopted1Method for quantitatively analyzing ethanol and acetic acid in fermented fruit and vegetable juice by H-NMR technology |
Also Published As
Publication number | Publication date |
---|---|
CA1240679A (en) | 1988-08-16 |
NO1994031I1 (en) | 1994-12-30 |
EP0169299B1 (en) | 1990-04-25 |
NL930072I1 (en) | 1993-09-01 |
AU1018688A (en) | 1988-04-28 |
AU8633082A (en) | 1983-01-27 |
JPH03209389A (en) | 1991-09-12 |
EP0169299A2 (en) | 1986-01-29 |
NO164458C (en) | 1992-11-23 |
NO164458B (en) | 1990-07-02 |
DE3280157D1 (en) | 1990-05-31 |
EP0169299A3 (en) | 1986-12-03 |
EP0071564B1 (en) | 1986-03-26 |
IE821766L (en) | 1983-01-24 |
JPH0339045B2 (en) | 1991-06-12 |
AU601916B2 (en) | 1990-09-20 |
EP0071564A1 (en) | 1983-02-09 |
CA1218597A (en) | 1987-03-03 |
JP2548436B2 (en) | 1996-10-30 |
ZA825313B (en) | 1983-05-25 |
LU88291I2 (en) | 1994-05-04 |
NL930072I2 (en) | 1994-01-17 |
NO822546L (en) | 1983-01-25 |
DE3270097D1 (en) | 1986-04-30 |
JPS5829718A (en) | 1983-02-22 |
DE3129906C2 (en) | 1990-05-17 |
JPS62123159A (en) | 1987-06-04 |
ATE18719T1 (en) | 1986-04-15 |
IE53639B1 (en) | 1989-01-04 |
JPH0768193B2 (en) | 1995-07-26 |
DE3129906A1 (en) | 1983-02-10 |
DE3129906C3 (en) | 1996-12-19 |
AU566007B2 (en) | 1987-10-08 |
ATE52247T1 (en) | 1990-05-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
NZ201372A (en) | Paramagnetic complex salts,and use in nmr-diagnostics | |
AT397465B (en) | DIAGNOSTIC MEANS | |
TW319763B (en) | ||
US4647447A (en) | Diagnostic media | |
JP2894879B2 (en) | Diagnostic contrast agent | |
KR100189388B1 (en) | Chelating compounds and their use | |
EP0436579B1 (en) | Chelate compositions | |
JPS60100526A (en) | Specific alliviating agent for organ or pathology | |
DE69314613T3 (en) | NEW CHELATION AGENT, COMPLEX COMPOUNDS CONSTRUCTED FROM THIS AGENT AND METAL ATOMS, AND DIAGNOSTIC AGENTS CONTAINING THESE COMPOUNDS | |
JPH09500115A (en) | Functionalized tripodal ligands for imaging | |
CA2077556A1 (en) | Lipophilic contrast agents for diagnostic image analysis | |
EP0948361B1 (en) | Magnetic resonance blood pool agents | |
US5858329A (en) | MRI diagnostic procedures using tripodal pyridinyl metal complexes | |
US5824288A (en) | Thio-substituted pyridines as MRI ligand precursors | |
US5820851A (en) | Tripodal pyridine ligands as MRI contrast agents | |
RU2059642C1 (en) | Gadolinium chelates and a method of their synthesis | |
WO1995009564A1 (en) | Compositions and methods for magnetic resonance imaging, x-ray imaging and radiopharmaceuticals | |
WO1995032004A1 (en) | Functionalized bicyclo[2.2.1] heptane and [2.2.2] octane system as preorganized ligands for imaging applications |