CA1218597A - Paramagnetic complex salts, their preparation, and their use in nmr-diagnostics - Google Patents
Paramagnetic complex salts, their preparation, and their use in nmr-diagnosticsInfo
- Publication number
- CA1218597A CA1218597A CA000407923A CA407923A CA1218597A CA 1218597 A CA1218597 A CA 1218597A CA 000407923 A CA000407923 A CA 000407923A CA 407923 A CA407923 A CA 407923A CA 1218597 A CA1218597 A CA 1218597A
- Authority
- CA
- Canada
- Prior art keywords
- acid
- hydroxy
- preparation according
- halogen
- numbers
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 28
- 230000005298 paramagnetic effect Effects 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000002253 acid Substances 0.000 claims abstract description 12
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 9
- 150000002367 halogens Chemical class 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 9
- 229960003330 pentetic acid Drugs 0.000 claims abstract description 9
- 150000007513 acids Chemical class 0.000 claims abstract description 8
- 150000002500 ions Chemical class 0.000 claims abstract description 8
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims abstract description 6
- 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
- -1 hydroxy, amino Chemical group 0.000 claims abstract description 5
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 5
- 229910052747 lanthanoid Inorganic materials 0.000 claims abstract description 4
- 150000002602 lanthanoids Chemical class 0.000 claims abstract description 4
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 4
- 229930195734 saturated hydrocarbon Natural products 0.000 claims abstract description 4
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 4
- 150000003624 transition metals Chemical class 0.000 claims abstract description 4
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims abstract description 4
- 125000005843 halogen group Chemical group 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 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 description 6
- 229960001484 edetic acid Drugs 0.000 claims description 6
- RJOJUSXNYCILHH-UHFFFAOYSA-N gadolinium(3+) Chemical compound [Gd+3] RJOJUSXNYCILHH-UHFFFAOYSA-N 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims 1
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 claims 1
- 229910052688 Gadolinium Inorganic materials 0.000 claims 1
- XQRLCLUYWUNEEH-UHFFFAOYSA-N diphosphonic acid Chemical compound OP(=O)OP(O)=O XQRLCLUYWUNEEH-UHFFFAOYSA-N 0.000 claims 1
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 claims 1
- 150000002430 hydrocarbons Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 13
- 238000003745 diagnosis Methods 0.000 abstract description 5
- 125000001183 hydrocarbyl group Chemical group 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 6
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012620 biological material Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- CMIHHWBVHJVIGI-UHFFFAOYSA-N gadolinium(iii) oxide Chemical compound [O-2].[O-2].[O-2].[Gd+3].[Gd+3] CMIHHWBVHJVIGI-UHFFFAOYSA-N 0.000 description 3
- 229910052748 manganese Inorganic materials 0.000 description 3
- 239000011572 manganese Substances 0.000 description 3
- 239000012266 salt solution Substances 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
- WAEMQWOKJMHJLA-UHFFFAOYSA-N Manganese(2+) Chemical compound [Mn+2] WAEMQWOKJMHJLA-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 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
- 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
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 235000013681 dietary sucrose Nutrition 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000000706 filtrate Substances 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
- 238000001990 intravenous administration Methods 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
- 230000005291 magnetic effect Effects 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
- 229920000642 polymer Polymers 0.000 description 2
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-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
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 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
- 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
- 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
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 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
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910001938 gadolinium oxide Inorganic materials 0.000 description 1
- 229940075613 gadolinium oxide Drugs 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
- 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
- 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
- 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
- 210000004185 liver Anatomy 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
- 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
- MBKDYNNUVRNNRF-UHFFFAOYSA-N medronic acid Chemical compound OP(O)(=O)CP(O)(O)=O MBKDYNNUVRNNRF-UHFFFAOYSA-N 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
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 239000000843 powder Substances 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
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 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
- 230000001954 sterilising effect Effects 0.000 description 1
- 230000003637 steroidlike Effects 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
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 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)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Radiology & Medical Imaging (AREA)
- Organic Chemistry (AREA)
- Condensed Matter Physics & Semiconductors (AREA)
- General Physics & Mathematics (AREA)
- Signal Processing (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- High Energy & Nuclear Physics (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Optics & Photonics (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Preparations for influencing the relaxation times in NMR-diagnostics, comprising at least one physiologically compatible paramagnetic complex salt from aminopolycarboxy-lic acids having the formulae I to IV
(I) N-hydroxy-ethyl-N,N',N'-ethylene-diamine triacetic acid, (II) N,N,N',N",N"-diethylene-triamine pentaacetic acid, HOH2C-CH2N(CH2COOH)2 (III) N-hydroxy-ethyl-imino diacetic acid, (IV), wherein m represents the numbers 1 to 4, n represents the numbers 0 to 2, R1 represents a saturated or unsaturated hydrocarbon radical containing 1 to 4 hydrocarbon atoms or the group -CH2-COOH, or disphosphonic acids having the general formula V
Preparations for influencing the relaxation times in NMR-diagnostics, comprising at least one physiologically compatible paramagnetic complex salt from aminopolycarboxy-lic acids having the formulae I to IV
(I) N-hydroxy-ethyl-N,N',N'-ethylene-diamine triacetic acid, (II) N,N,N',N",N"-diethylene-triamine pentaacetic acid, HOH2C-CH2N(CH2COOH)2 (III) N-hydroxy-ethyl-imino diacetic acid, (IV), wherein m represents the numbers 1 to 4, n represents the numbers 0 to 2, R1 represents a saturated or unsaturated hydrocarbon radical containing 1 to 4 hydrocarbon atoms or the group -CH2-COOH, or disphosphonic acids having the general formula V
Description
The present invention provides a preparation for influencing the relaxation times in NMR-diagnostics.
According to the present invention there is pro-vided a pharmaceutical preparation for use in influencing the relation ti.mes in NMR diagnostics which comprises a physiologically acceptable carrier and at least one phy-siologically compatible paramagnetic complex salt from ani.mopolycarboxyl.ic acids having the formulae I to IV
],0 ooCC~i z Cii C~Or.
N- ( C ~ ~ Z
~ 0~ CCil/ CH2COO~ (I) N-hydroxy-ethyl-N,N',N'-ethylene-diamine -tri.acetic acid, ~50~:. C C~2C0~-; /c~ZC^
According to the present invention there is pro-vided a pharmaceutical preparation for use in influencing the relation ti.mes in NMR diagnostics which comprises a physiologically acceptable carrier and at least one phy-siologically compatible paramagnetic complex salt from ani.mopolycarboxyl.ic acids having the formulae I to IV
],0 ooCC~i z Cii C~Or.
N- ( C ~ ~ Z
~ 0~ CCil/ CH2COO~ (I) N-hydroxy-ethyl-N,N',N'-ethylene-diamine -tri.acetic acid, ~50~:. C C~2C0~-; /c~ZC^
2 ~_(rH~ -(C~
u_r'~zC~ ~ 2 2 2 ~ C~i2c~c~(1~) N,N,N',N",N"-diethylene-triamine pentaacetic acid, HOH2C-CH2N(cH2cOoH)2 (III) N-hydroxy-ethyl-imino diacetic acid, nl C~
0 ~ N-(C'~ ) -(C~ ) -(CH ) -~\ l H3GrCH2/ ~ 2 2 n .z m 2 H(IV), wherein m represents the numbers 1 to 4, n represents tlle numbers 0 to 2, Rl represents a saturated or unsaturated hydrocarbon radical containing 1 to 4 hydrocarbon atoms or the group -CH2-COOH, or disphosphonic acids having the general .~ 2 formula V
. ' '.
R - C R
~ 1 3 (V), where.i.n R2 represents hydrogen, alkyl containing 1 to 4 carbon atoms, halogen, the hydroxy, amino or-CH2-COOH group and R3 represents hydrogen, alkyl containing 1 to 4 carbon atoms, the -Cl-12-COOH group or also halogen when R2 represents halogen, and from the ions of the lanthanide elements having the atomic numbers 57 to 7 or from the ions of the transi-tion metals having the atomic numbers 21 to 29, 42 and 44, and, if desired, an inorganic base.
Suitable aminopolycarboxylic acids are those com-pounds of this class of substances which can form chelate complexes, for example:
1~185~7 formula N-hydroxyethyl-N,N',N'-ethylenediamine-triacetic acid (HEDTA) s N~N~Nl~Nll~N~-diethylenetriamine-penta-acetic acid (DTPA), and II
N-hydroxyethylimino-diacetic acid III
DTPA is preferred.
Also suitable are the aminopolycarboxylic acids of the ~eneral formula CH3 / CHzCOOH
N-(CH2)m~(CH2_N_CH2)n (CH2)m (IV) HOOCCH
., ~
~21~5~
wherein m represents the integers 1 to 4, n represents the integers 0 to 2, and R5 represents a saturated or unsatura-ted hydrocarbon radical having from 4 to 12 carbon atoms or the group -CH2-COOH. Preferred is N,N,N',N'-ethylenediamine-tetra acetic acid (EDTA) ~ ;
~21~9'~
There are also suitable phosphoric acids of the general f ormula 1, R2~ R3 (V) wherein R2 represents hydrogen, alkyl containing 1 to 4 carbon atoms, halogen, the hydroxy, amino or-cH2-cooH group and R3 represents hydrogen, alkyl containing 1 to 4 carbon atoms, the -CH2-COOH group or also halogen when R2 represents lS halogen. There may be mentioned, more especially, ethane-l-hydroxy-l,l-diphosphonic acid, methane-diphosphonic acid and ethane-l-amino-l,l-diphosphonic acid.
If desired, it is also possible to bind the phy-siologically tolerable complex salts of the invention tobio-molecules in order in this way to enable the 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, peptides, amino-sugars and lipids.
The coupling of the paramagentic 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 amino, phenol, mercapto or imidazole group with an activated deri-vative of the complex compound.
The activated derivatives which may be considered ~, "; l;~l~S~
are for example, acid chlorides, mixed anhydrides (whieh ean be prepared from the carboxyl derivative of the eomplex compound with chlorocarbonic acid ester), activated esters, nitrenes or isothiocyanates.
It is also possible to reaet an aetivated deriva-tive of the biomolecule with a nucleophilie derivative of the eomplex compound. As organic bases for salt formation there may be used, for example, sodium hydroxide.
~ - 7 -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 compa-tible buffer solutions (for example sodium dihydrogen phos-phate solution), and sterilising the solution. The aqueous solutions can be administered orally, neurally and especially intervascularly. If suspensions of the paramagnetic complex salts in water or physiological salt solution are desired, especi.ally for oral administration, the 5~
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 carboxymethylcellulose are used.
For ~MR-diagnosis in humans, the preparations of the invention are suitable in the form of aqueous solutions os suspensions which contain from 5 to 250 mmols/litre, preferably 50 to 200 mmols/litre, of the paramagnetic complex salt. The p~ 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.
Solutions of the complex salts appear to be particularly suitable for greater definition or local-isation of lesions of the pancreas and liver, and alsoof tumours and haemorrhages in the cranial area. For diagnosis of the area under examination an aqueous ' ;
lZ1~35~7 solution of the paramagnetic complex salt which is isotonic with blood is, for example, administered intravenously at a dosage of from 1 to ~00 ~mols/kg.
With a concentration of the complex salt of from 50 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 approxi-mately 15 to 60 minutes after intravenous administration of the aqueous solution of the paramagnetic complex salt.
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 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, for instance for babies or pregnant women.
Sonography does not in fact have these dis-advantages, but instead has a very limited range of ap~lication, especially in the cranial area.
Since in spite of a great deal of research it 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 S~
- 11 _ information for diagnostic purposes.
One of these image-producing processes is spin-imaging, which is based on the physical effect of nuclear magnetic resonance tNMR). 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 resonance is shown by atomic nuclei which, like hydrogen - mainly present in ~iological tissues as water - have a magnetic moment and therefrom 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.
The image which is obtained by measuring the 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, 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 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 latter effect may be produced for example, in that the spin-lattice-relaxation time Tl is greatly reduced in a man-ner 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 that the required detoxication of the otherwlse toxic metal salts can be effected by complexing, with-out the paramagnetic properties being adversely affected. Thisis surprising, since it is known that the distribution of the d-and f-electrons over the d- and f- orbitals is altered thereby.
~.
The paramagnetic complex salts may be prepared accord-ing 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 elemen~ 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 neces-sary while heating at from 50C to 120C 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:
. ~.
121~5~
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 110C
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 (Gd203) and 944 g of diethylenetriaminepentaacetic acid in 12 litres of water is heated while stirring to from 90C to 100C 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 g, (molecular weight 547.58) ~p.: melts from 235 and remains undecomposed up to 320C.
35~
If there is/are still one or more acidic group(s) in the resulting paramagnetic complex compound, the result-ing complex compound can then, if desired, be dissolved or suspended in water and the desired inorganic base can be added thereto until the neutral point is reached. After filtering off the undissolved constituents, the solution is concentrated by evaporation and the desired complex salt is obtained as the residue.
The following Example illustrates the invention:-Example 1 Preparation of a solution of the di-sodium sal-t of the manganese(II)-complex of ethylenediamine-tetra-acetic acid 5.55 g (15 mmoles) 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 wi-th the addition of dilute sodium hydroxide solution. The solu-tion is then made up to 170 ml with water p , filtered into ampoules and heat-sterilised.
1~
-- ~} --1~8597 1~ .
.~`.,.
Example ~
(Composition of a powder for the preparation of a suspension) 4.000 g gadolinium(III) complex of diethylenetriamine-pentaacetic acid (water content 8%)
u_r'~zC~ ~ 2 2 2 ~ C~i2c~c~(1~) N,N,N',N",N"-diethylene-triamine pentaacetic acid, HOH2C-CH2N(cH2cOoH)2 (III) N-hydroxy-ethyl-imino diacetic acid, nl C~
0 ~ N-(C'~ ) -(C~ ) -(CH ) -~\ l H3GrCH2/ ~ 2 2 n .z m 2 H(IV), wherein m represents the numbers 1 to 4, n represents tlle numbers 0 to 2, Rl represents a saturated or unsaturated hydrocarbon radical containing 1 to 4 hydrocarbon atoms or the group -CH2-COOH, or disphosphonic acids having the general .~ 2 formula V
. ' '.
R - C R
~ 1 3 (V), where.i.n R2 represents hydrogen, alkyl containing 1 to 4 carbon atoms, halogen, the hydroxy, amino or-CH2-COOH group and R3 represents hydrogen, alkyl containing 1 to 4 carbon atoms, the -Cl-12-COOH group or also halogen when R2 represents halogen, and from the ions of the lanthanide elements having the atomic numbers 57 to 7 or from the ions of the transi-tion metals having the atomic numbers 21 to 29, 42 and 44, and, if desired, an inorganic base.
Suitable aminopolycarboxylic acids are those com-pounds of this class of substances which can form chelate complexes, for example:
1~185~7 formula N-hydroxyethyl-N,N',N'-ethylenediamine-triacetic acid (HEDTA) s N~N~Nl~Nll~N~-diethylenetriamine-penta-acetic acid (DTPA), and II
N-hydroxyethylimino-diacetic acid III
DTPA is preferred.
Also suitable are the aminopolycarboxylic acids of the ~eneral formula CH3 / CHzCOOH
N-(CH2)m~(CH2_N_CH2)n (CH2)m (IV) HOOCCH
., ~
~21~5~
wherein m represents the integers 1 to 4, n represents the integers 0 to 2, and R5 represents a saturated or unsatura-ted hydrocarbon radical having from 4 to 12 carbon atoms or the group -CH2-COOH. Preferred is N,N,N',N'-ethylenediamine-tetra acetic acid (EDTA) ~ ;
~21~9'~
There are also suitable phosphoric acids of the general f ormula 1, R2~ R3 (V) wherein R2 represents hydrogen, alkyl containing 1 to 4 carbon atoms, halogen, the hydroxy, amino or-cH2-cooH group and R3 represents hydrogen, alkyl containing 1 to 4 carbon atoms, the -CH2-COOH group or also halogen when R2 represents lS halogen. There may be mentioned, more especially, ethane-l-hydroxy-l,l-diphosphonic acid, methane-diphosphonic acid and ethane-l-amino-l,l-diphosphonic acid.
If desired, it is also possible to bind the phy-siologically tolerable complex salts of the invention tobio-molecules in order in this way to enable the 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, peptides, amino-sugars and lipids.
The coupling of the paramagentic 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 amino, phenol, mercapto or imidazole group with an activated deri-vative of the complex compound.
The activated derivatives which may be considered ~, "; l;~l~S~
are for example, acid chlorides, mixed anhydrides (whieh ean be prepared from the carboxyl derivative of the eomplex compound with chlorocarbonic acid ester), activated esters, nitrenes or isothiocyanates.
It is also possible to reaet an aetivated deriva-tive of the biomolecule with a nucleophilie derivative of the eomplex compound. As organic bases for salt formation there may be used, for example, sodium hydroxide.
~ - 7 -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 compa-tible buffer solutions (for example sodium dihydrogen phos-phate solution), and sterilising the solution. The aqueous solutions can be administered orally, neurally and especially intervascularly. If suspensions of the paramagnetic complex salts in water or physiological salt solution are desired, especi.ally for oral administration, the 5~
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 carboxymethylcellulose are used.
For ~MR-diagnosis in humans, the preparations of the invention are suitable in the form of aqueous solutions os suspensions which contain from 5 to 250 mmols/litre, preferably 50 to 200 mmols/litre, of the paramagnetic complex salt. The p~ 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.
Solutions of the complex salts appear to be particularly suitable for greater definition or local-isation of lesions of the pancreas and liver, and alsoof tumours and haemorrhages in the cranial area. For diagnosis of the area under examination an aqueous ' ;
lZ1~35~7 solution of the paramagnetic complex salt which is isotonic with blood is, for example, administered intravenously at a dosage of from 1 to ~00 ~mols/kg.
With a concentration of the complex salt of from 50 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 approxi-mately 15 to 60 minutes after intravenous administration of the aqueous solution of the paramagnetic complex salt.
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 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, for instance for babies or pregnant women.
Sonography does not in fact have these dis-advantages, but instead has a very limited range of ap~lication, especially in the cranial area.
Since in spite of a great deal of research it 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 S~
- 11 _ information for diagnostic purposes.
One of these image-producing processes is spin-imaging, which is based on the physical effect of nuclear magnetic resonance tNMR). 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 resonance is shown by atomic nuclei which, like hydrogen - mainly present in ~iological tissues as water - have a magnetic moment and therefrom 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.
The image which is obtained by measuring the 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, 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 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 latter effect may be produced for example, in that the spin-lattice-relaxation time Tl is greatly reduced in a man-ner 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 that the required detoxication of the otherwlse toxic metal salts can be effected by complexing, with-out the paramagnetic properties being adversely affected. Thisis surprising, since it is known that the distribution of the d-and f-electrons over the d- and f- orbitals is altered thereby.
~.
The paramagnetic complex salts may be prepared accord-ing 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 elemen~ 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 neces-sary while heating at from 50C to 120C 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:
. ~.
121~5~
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 110C
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 (Gd203) and 944 g of diethylenetriaminepentaacetic acid in 12 litres of water is heated while stirring to from 90C to 100C 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 g, (molecular weight 547.58) ~p.: melts from 235 and remains undecomposed up to 320C.
35~
If there is/are still one or more acidic group(s) in the resulting paramagnetic complex compound, the result-ing complex compound can then, if desired, be dissolved or suspended in water and the desired inorganic base can be added thereto until the neutral point is reached. After filtering off the undissolved constituents, the solution is concentrated by evaporation and the desired complex salt is obtained as the residue.
The following Example illustrates the invention:-Example 1 Preparation of a solution of the di-sodium sal-t of the manganese(II)-complex of ethylenediamine-tetra-acetic acid 5.55 g (15 mmoles) 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 wi-th the addition of dilute sodium hydroxide solution. The solu-tion is then made up to 170 ml with water p , filtered into ampoules and heat-sterilised.
1~
-- ~} --1~8597 1~ .
.~`.,.
Example ~
(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 (8)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A pharmaceutical preparation for use in influen-cing the relation times in NMR diagnostics which comprises a physiologically acceptable carrier and at least one phy-siologically compatible paramagnetic complex salt from animopolycarboxylic acids having the formulae I to IV
(I) n-hydroxy-ethyl-N,N',N'-ethylene-diamine triacetic acid, (II) N,N,N',N",N"-diethylene-triamine pentaacetic acid, HOH2C-CH2N(CH2COOH)2 (III) N-hydroxy-ethyl-imino diacetic acid, (IV) wherein m represents the numbers 1 to 4, n represents the numbers 0 to 2, R1 represents a saturated or unsaturated hydrocarbon radical containing 1 to 4 hydrocarbon atoms or the group -CH2-COOH, or disphosphonic acids having the general formula V
(V) wherein R2 represents hydrogen, alkyl containing 1 to 4 carbon atoms, halogen, the hydroxy, amino or -CH2-COOH group and R3 represents hydrogen, alkyl containing 1 to 4 carbon atoms, the -CH2-COOH group or also halogen when R2 represents halogen, and from the ions of the lanthanide elements having the atomic numbers 57 to 70 or from the ions of the transi-tion metals having the atomic numbers 21 to 29, 42 and 44.
(I) n-hydroxy-ethyl-N,N',N'-ethylene-diamine triacetic acid, (II) N,N,N',N",N"-diethylene-triamine pentaacetic acid, HOH2C-CH2N(CH2COOH)2 (III) N-hydroxy-ethyl-imino diacetic acid, (IV) wherein m represents the numbers 1 to 4, n represents the numbers 0 to 2, R1 represents a saturated or unsaturated hydrocarbon radical containing 1 to 4 hydrocarbon atoms or the group -CH2-COOH, or disphosphonic acids having the general formula V
(V) wherein R2 represents hydrogen, alkyl containing 1 to 4 carbon atoms, halogen, the hydroxy, amino or -CH2-COOH group and R3 represents hydrogen, alkyl containing 1 to 4 carbon atoms, the -CH2-COOH group or also halogen when R2 represents halogen, and from the ions of the lanthanide elements having the atomic numbers 57 to 70 or from the ions of the transi-tion metals having the atomic numbers 21 to 29, 42 and 44.
2. A preparation according to claim 1, in which the complex salt includes an inorganic base.
3. A preparation according to claim 2, in which the inorganic base is sodium hydroxide.
4. A preparation according to claim 1 or 2, in which the aminopolycarboxylic acid is N,N,N',N'-ethylene-diamine tetraacetic acid.
5. A preparation according to claim 1 or 2, in which the aminopolycarboxylic acid is N,N,N',N",N"-diethylene-triamine pentaacetic acid.
6. A preparation according to claim 1 or 2 in which the diphosphonic acid is ethane-1-hydroxy-1,1-diphos-phonic acid, methane diphosponic acid or ethane-1-amino-1,1-diphosphonic acid.
7. A preparation according to claim 2, in which the complex salt is the disodium salt of the gadolinium(III) complex of diethylene-triamine pentaacetic acid.
8. A preparation according to claim 1 or 2, in which the ion is gadolinium.
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CA000487858A CA1240679A (en) | 1981-07-24 | 1985-07-31 | Paramagnetic complex salts, their preparation, and their use in nmr-diagnostics |
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DE3129906A DE3129906C3 (en) | 1981-07-24 | 1981-07-24 | Paramagnetic complex salts, their preparation and agents for use in NMR diagnostics |
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JP (3) | JPS5829718A (en) |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US5250672A (en) * | 1985-09-11 | 1993-10-05 | Guerbet S.A. | Contrast agent for NMR imaging |
US8669236B2 (en) | 2005-05-12 | 2014-03-11 | The General Hospital Corporation | Biotinylated compositions |
US10532104B2 (en) | 2012-08-31 | 2020-01-14 | The General Hospital Corporation | Biotin complexes for treatment and diagnosis of Alzheimer'S disease |
Families Citing this family (133)
Publication number | Priority date | Publication date | Assignee | Title |
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DE3129906C3 (en) * | 1981-07-24 | 1996-12-19 | Schering Ag | Paramagnetic complex salts, their preparation and agents for use in NMR diagnostics |
US4957939A (en) * | 1981-07-24 | 1990-09-18 | Schering Aktiengesellschaft | Sterile pharmaceutical compositions of gadolinium chelates useful enhancing NMR imaging |
NL194579C (en) * | 1983-01-21 | 2002-08-05 | Schering Ag | Diagnostic. |
DE3448606C2 (en) * | 1983-01-21 | 2001-12-13 | Schering Ag | Diagnostic agents, processes for their production and their use |
EP0330801A1 (en) * | 1983-02-08 | 1989-09-06 | Schering Aktiengesellschaft | Ferromagnetic, diamagnetic or paramagnetic particles useful in the diagnosis and treatment of disease |
US4735796A (en) * | 1983-12-08 | 1988-04-05 | Gordon Robert T | 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 |
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- 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 (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5250672A (en) * | 1985-09-11 | 1993-10-05 | Guerbet S.A. | Contrast agent for NMR imaging |
US8669236B2 (en) | 2005-05-12 | 2014-03-11 | The General Hospital Corporation | Biotinylated compositions |
US10532104B2 (en) | 2012-08-31 | 2020-01-14 | The General Hospital Corporation | Biotin complexes for treatment and diagnosis of Alzheimer'S disease |
Also Published As
Publication number | Publication date |
---|---|
EP0071564B1 (en) | 1986-03-26 |
JPH0339045B2 (en) | 1991-06-12 |
DE3129906C3 (en) | 1996-12-19 |
DE3280157D1 (en) | 1990-05-31 |
ZA825313B (en) | 1983-05-25 |
NO1994031I1 (en) | 1994-12-30 |
NO822546L (en) | 1983-01-25 |
LU88291I2 (en) | 1994-05-04 |
CA1240679A (en) | 1988-08-16 |
DE3129906C2 (en) | 1990-05-17 |
AU566007B2 (en) | 1987-10-08 |
AU601916B2 (en) | 1990-09-20 |
AU1018688A (en) | 1988-04-28 |
JPS62123159A (en) | 1987-06-04 |
JPH03209389A (en) | 1991-09-12 |
EP0169299A2 (en) | 1986-01-29 |
DE3270097D1 (en) | 1986-04-30 |
EP0169299A3 (en) | 1986-12-03 |
NO164458B (en) | 1990-07-02 |
NL930072I2 (en) | 1994-01-17 |
IE821766L (en) | 1983-01-24 |
EP0071564A1 (en) | 1983-02-09 |
DE3129906A1 (en) | 1983-02-10 |
NO164458C (en) | 1992-11-23 |
ATE52247T1 (en) | 1990-05-15 |
EP0169299B1 (en) | 1990-04-25 |
JPS5829718A (en) | 1983-02-22 |
NL930072I1 (en) | 1993-09-01 |
JP2548436B2 (en) | 1996-10-30 |
IE53639B1 (en) | 1989-01-04 |
AU8633082A (en) | 1983-01-27 |
ATE18719T1 (en) | 1986-04-15 |
NZ201372A (en) | 1986-08-08 |
JPH0768193B2 (en) | 1995-07-26 |
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