IE56857B1 - Physiologically tolerable metal complex salts for use in nmr diagnosis - Google Patents
Physiologically tolerable metal complex salts for use in nmr diagnosisInfo
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- IE56857B1 IE56857B1 IE169/89A IE16989A IE56857B1 IE 56857 B1 IE56857 B1 IE 56857B1 IE 169/89 A IE169/89 A IE 169/89A IE 16989 A IE16989 A IE 16989A IE 56857 B1 IE56857 B1 IE 56857B1
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- 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, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
- C07F9/3817—Acids containing the structure (RX)2P(=X)-alk-N...P (X = O, S, Se)
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
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- 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
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- 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
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
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- A—HUMAN NECESSITIES
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- 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
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
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- 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
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
- A61K49/103—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being acyclic, e.g. DTPA
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- 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
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
- A61K49/103—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being acyclic, e.g. DTPA
- A61K49/105—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being acyclic, e.g. DTPA the metal complex being Gd-DTPA
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- 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
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/14—Peptides, e.g. proteins
- A61K49/143—Peptides, e.g. proteins the protein being an albumin, e.g. HSA, BSA, ovalbumin
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- 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
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/14—Peptides, e.g. proteins
- A61K49/16—Antibodies; Immunoglobulins; Fragments thereof
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- 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
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
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- 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
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1806—Suspensions, emulsions, colloids, dispersions
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- 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
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1806—Suspensions, emulsions, colloids, dispersions
- A61K49/1812—Suspensions, emulsions, colloids, dispersions liposomes, polymersomes, e.g. immunoliposomes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
Abstract
Physiologically tolerable complex salts which contain (a) a central element selected from elements having atomic numbers from 21 to 29, 42, 44 and from 58 to 70, and (b) a radical of a physiologically-tolerable complex-forming acid and, if desired, (c) a radical selected from radicals of inorganic and organic bases and amino acids, and their use in NMR diagnosis.
Description
Pries Wp The invention relates to physiologically tolerable metal complex salts and the use thereof in NMR diagnosis.
Complex compounds and their salts have been used for a long time in medicine, for example, as auxiliaries for the administration of sparingly soluble ions (for example iron) and as antidotes (calcium or zinc complexes being preferred in this case) for detoxication in the case of inadvertent incorporation of heavy metals or their radioactive isotopes.
We have now found that certain physiologically tolerable complex salts containing one or more central elements having the atomic numbers of from 21 to 29, 42, 44 and from 58 to 70 can be used for the manufacture of preparations that are surprisingly outstandingly suitable for use In NMR diagnostics.
The present Invention provides a diagnostic preparation which comprises (1) a physiologically tolerable, non-radioactive complex salt of the general formula I X-CK.
N-A-N CH--X CHR.-V (I) in which X represents the radicals -COOY, -POaHY or -CONHOY wherein each Y represents a hydrogen atom, a metal equivalent, the metal being selected from elements having atomic numbers of from 21 to 29, 42, 44 and from to 70, or a physiologically tolerable cation of an inorganic or organic base or amino acid, Ri represents in each case a hydrogen atom or a methyl group and in which either a) A represents the group -CHRa-CHR3-, -CHa-CHa-(ZCHa-CHa)«-, N(CHaX)a CHa-CH2-N(CHaX)a or -CHa-CH-CHa- -CHaCHa-N-CHa-CHa-, in which X has the meanings given above, Ra and R3 together represent a trimethylene group or a tetramethylene group, or each represent a hydrogen atom, an alkyl radical containing up to 6 carbon atoms, a phenyl radical or a benzyl radical, m represents the integer 1, 2 or 3, and Z represents an oxygen atom or a sulphur atom or the group 4d NCHaX or in which X has the meanings given above and R4 represents an alkyl radical containing up to 6 carbon atoms, and each V has the same meaning as X or represents the group -CHaOH or -COB, in which B represents a protein or lipid radical or an -NH(CHa)„X radical, in which X has the meanings given above and n represents an integer from 1 to 12, with the proviso that at least one of the symbols V represents a -COB group, as defined above, and at least two of the substituents Y are metal equivalents selected from elements having atomic numbers of from 21 to 29, 42, 44 and from 58 to 70, or b) A represents the group -CHRa-CHR3In which R2 represents a hydrogen atom and R3 represents the group -(CH2)v-CeHA-W-protein in which p represents 0 or 1, W represents -W-, -NHCQCH2- or -NHCSand -protein represents a protein radical, and each V has the same meaning as X or represents the group -CHaOH, with the proviso that at least two of the substituents Y are metal equivalents selected from elements having atomic numbers of from 21 to 29, 42, 44 and from 58 to 70, and (il) a physiologically tolerable carrier.
Thus, the physiologically tolerable complex salt of the general formula I may be regarded as containing (a) a central element selected from elements having atomic numbers of from 21 to 29 Inclusive, 42, 44 and from 58 to 70 inclusive, and (b) a radical of a physiologically tolerable complex-forming acid and, if desired, (c) a radical selected from radicals of Inorganic and organic bases and amino acids.
The physiologically tolerable complex salt of the general formula I may contain more than one such central element (a) and more than one such radical (c).
For the intended use of the diagnostic agent according to the invention, the element or elements having an atomic number mentioned above, which forms the central element or elements of the physiologically tolerable complex salt, must not, of course, be radioactive.
Since a preparation of the Invention is to be used in WMR diagnostics (see European Patent Application 71 564), the central element of the complex salt must be paramagnetic.
Such elements are especially the divalent and trivalent elements having an atomic number of from 21 to 29, 42, 44 and from 58 to 70. Suitable elements are, for example, chromium(Hl), manganese(ii), iron(IH), iron(II), cobalt(II), nickel(II), copper(II), praseodymlum(lll), neodymium(III), samarlum(III) and ytterbium(IIl).
Especially preferred, owing to their strong magnetic moment. are gadolinium(III), terbium(III), dysprosium(III), holmium(III) and erbium(lll).
The complex-forming acids from which the physiologically tolerable complex salts of the general formula 1 may be derived are, especially, those containing carboxymethylene groups.
The complex-forming acids from which the physiologically & tolerable complex salts of the general formula I are derived can, as conjugates, be bonded to biomolecules that are known to become especially concentrated in the organ or organ part under examination. Such biomolecules are, for example, proteins or lipids. There come into consideration conjugates with protein hormones, such as insulin, and more especially conjugates with albumens, such as human serum albumen, antibodies, such as, for example, monoclonal antibodies specific to tumour-associated antigens, or antimyosin. The diagnostic preparations formed therefrom are suitable, for example, for use in tumour and infarct diagnosis. For examinations of the liver there are suitable, for example, conjugates or inclusion compounds with liposomes, which are used, for example, as unilamellar or multilamellar phosphatidylcholinecholesterol vesicles.
The conjugates are formed either by way of a carboxy group of the complex-forming acid or, in the case of proteins, also by way of a -(CH2)p-C6HA-w- group as defined above under R3. In the conjugate formation of some complexforming acids with proteins or lipids, several acid radicals may be bonded to the macromolecular biomolecule. In that case, each complex-forming acid radical may carry one central element. 4 Suitable complex salts of the general formula I above are, b for example, those of the general formula Ia X-CH V-CHR N"CHR,-CHR3-N (la) CHR^-V in which X, V, Rx, R2 and R3 have the meanings given above.
The following complex forming acids, inter alia, are suitable for the manufacture of the complex salts of the general formula la;ethylenediazninetetraacetic acid, ethylenediaminetetraacetohydroxamic acid, trans-1,2-cyclohexylenediaminetetraacetic acid, DL,-2,3-butylenediaminetetraacetic acid, DL-l,2-butylenediaminetetraacetic acid, DL-1,2propylenediaminetetraacetic acid, 1,2-diphenylethylenediaminetetraacetic acid, ethylenedinitrolotetrakis(methane-phosphonic acid) and M-(2-hydroxyethyl)ethylenediaminetriacetic acid.
Other suitable complex salts of the general formula 1 are, for example, those of the general formula lb X-CH? /CH2~x V-CHR in which X, V, Z, R, and m have the meanings given above. If Z represents an oxygen atom or a sulphur atom, complex salts in which m represents 1 or 2 are preferred.
The following complex-forming acids, inter alia, are suitable for the manufacture of the complex salts of tne general formula lb: diethylenetriaminepentaacetic acid, triethylenetetraminehexaacetic acid, tetraethylenepentamineheptaacetic acid, 13, 23-dioxo-15,18,2l-tris-(carboxymethyl) -12,15,18,21,24-pentaazapentatriacontanoic diacid, 3,9bis-(1-carboxyethyl)-6-carboxymethyl-3,6,9-triazaundecanoic diacid, diethylenetriaminepentakis(methylenephosphonic acid), 1,10-diaza-4,7-dioxadecane1,1,10,10-tetraacetic acid and l,10-diaza-4,7dithiadecane-1,1,10,10-tetraacetic acid.
Other complex-forming acids that are suitable for the manufacture of the complex salts of the general formula I are, for example; . 1,2,3 - tris - [ bis - (carboxymethyl) -amino ] -propane and nitrolotris-(ethylenenitrolo)"hexaacetic acid.
If not all of the acid hydrogen atoms of the complex-forming acid are substituted by the central element or elements, it ls advantageous, for the purpose of increasing the solubility of the complex salt, to substitute the remaining hydrogen atoms by physiologically tolerable cations of inorganic and/or organic bases or amino acids. Suitable inorganic cations are for example, lithium, potassium or, especially, sodium. Suitable cations of organic bases are, inter alia, those of primary, secondary or tertiary amines, such as, for example, ethanolamine, diethanolamine, morpholine, glucamine, Ν,Ν-dimethylglucamine or, especially, W-methylglucamine. Suitable cations of amino acids are, for example, those of lysine, arginine or ornithine.
The complex-forming acids required for the formation of the complex salts of the general formula I are known or can be manufactured in a manner known per se.
For example, 13,23-dioxo-15,18,21-tris-(carboxymethyl)12,15,18,21-24-pentaazapentatriacontanoic diacid is manufactured in the following manner, which is an improvement to the method proposed by R.A.Bulman et al. in Naturwissenschaften 68, (1981) 483: 17.85 g ( = 50 mmol) of l,5-bis-(2,6-dioxomorpholino)-3azapentane-3-acetic acid are suspended in 400 ml of dry dimethylformamide and, after the addition of 20.13 g ( - 100 mmol) of 11-aminoundecanoic acid, the whole is heated at 70°C for 6 hours. The clear solution is concentrated in vacuo. The yellow oily residue is stirred with 500 ml of water at room temperature. in so doing, an almost white, voluminous solid precipitates which is suction-filtered and washed several times with water. For further purification, the resulting product is introduced into 200 ml of acetone and the whole is stirred for 30 minutes at room temperature. After suction-filtering and drying in vacuo at 50°C, 36.9 g ( = 97% of the theoretical yield) of a white powder of melting point 134-138°C are obtained.
Conjugation of the complex-forming acids with biomolecules is likewise effected according to methods known per se, for example by reacting the nucleophilic groups of the biomolecule, such as, for example, amino, hydroxy, thio or imidazole groups, with an activated derivative of the complex-forming acid. il Activated derivatives of the complex-forming acid which come into consideration are, for example, acid chlorides, acid anhydrides, activated esters, nitrenes or isothiocyanates. Conversely, it is also possible to react an activated biomolecule with the complex-forming acid.
For conjugation with proteins, substituents of the structure "CeH4K3 or -CeH4NHCOCH2-halogen may also be considered.
The manufacture of the complex salts of the general formula I can likewise be carried out in a manner known per se by dissolving or suspending the metal oxide or metal salt (for example the nitrate, chloride or sulphate) of the element having an atomic number of from 21 to 29, 42, 44 or from 58 to 70 in water and/or a lower alcohol (such as methanol, ethanol or isopropanol) and adding a solution or suspension of the equivalent amount of the complex-forming acid in water and/or a lower alcohol, and stirring, if necessary while warming or heating to boiling point, until the reaction is complete. If the complex salt formed is insoluble in the solvent used, It is isolated by filtration. If it is soluble, it can be isolated by concentrating the solution to dryness by evaporation, for example by means of spray-drying.
If acid groups are still present in the resulting complex salt, lt is often advantageous to convert the acid complex salt into a neutral complex salt or salts by means of inorganic and/or organic bases or amino acids that form physiologically tolerable cations and to isolate the neutral salt. In many cases, this is indeed unavoidable since the dissociation of the complex salt is so suppressed by the shift in the pH value to neutral that only in that manner can uniform products be at all Isolated or at least purified.
The manufacture Is advantageously carried out with the aid of organic bases or basic amino acids. It can, however, also be advantageous if the neutralisation is carried out by means of inorganic bases (hydroxides, carbonates or bicarbonates) of sodium, potassium or lithium.
* For the manufacture of the neutral salts there may, for example, be added to the acid complex salts in aqueous ** solution or suspension as much of the desired base as is necessary to obtain the neutral point. The resulting solution can subsequently be concentrated to dryness in vacuo. It is frequently of advantage to precipitate the resulting neutral salts by adding water-miscible solvents, such as, for example, lower alcohols (methanol, ethanol, isopropanol, etc.), lower ketones (acetone, etc.), and polar ethers (tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.), and thus obtain crystallisates that are easily isolated and readily purified. It has been found especially advantageous to add the desired base to the reaction mixture during the complex formation and thereby dispense with one process step.
If the acid complex salts contain several free acid groups, it is often advantageous to produce neutral mixed salts that contain both inorganic and organic physiologically tolerable cations as ions of opposite charge. This can be effected, for example, by reacting the complex-forming acid in aqueous suspension or solution with the oxide or salt of the element supplying the central element and with half the amount of organic base required for neutralisation, isolating the complex salt formed, if desired purifying it, and then v 30 adding to it the amount of inorganic base required for complete neutralisation. The order in which the bases are added can also be reversed.
The manufacture of the diagnostic preparations according to the invention is likewise effected in a manner known per se by suspending or dissolving the complex salts in an aqueous medium, for example water or physiological salt solution, optionally with the addition of the additives customary in galenical pharmacy, and subsequently sterilising the v solution or suspension. Suitable additives are, for example, physiologically tolerable buffers (such as, for example, tromethamine hydrochloride), small additions of » complex formers (such as, for example, diethylenetriaminepentaacetic acid), or, if necessary, electrolytes (such as, for example, sodium chloride).
In principle, it is also possible to manufacture the diagnostic preparations of the invention even without isolating the complex salts. In each case, particular care must be taken to effect the chelate formation in such a manner that the salts and salt solutions according to the invention are virtually free of non-complexed toxically acting metal ions. This can be ensured, for example, with the aid of colour indicators, such as xylenol orange, by test titrations during the manufacturing process. The invention also therefore provides processes for the manufacture of the complex salts and of the aforesaid preparations containing them. As a final safeguard, there is always purification of the isolated complex salt.
If suspensions of the complex salts in water or physiological salt solution are desired for oral administration or other purposes, a sparingly soluble complex salt is mixed with one or more auxiliaries customary in galenical pharmacy and/or surfactants and/or aromatic substances for taste correction.
The diagnostic preparations of the invention contain * preferably from 1 pmol to 1 mol per litre of the complex salt and are, as a rule, administered in doses of from 0.001 to 5 mmol/kg. They are intended for oral, and especially parenteral, administration. If desired, they may be in a dosage form suitable for administration orally, neurally or intravasally. When the preparations are in a form suitable for injections, they may be contained in ampoules.
The diagnostic preparations of the invention meet the many requirements for suitability as contrast agents for nuclear spin tomography. For example, after oral or parenteral administration, they are outstandingly suitable for improving the information that can be provided by the image obtained with the aid of nuclear spin tomography, as a result of increasing the signal intensity. They also exhibit the high activity necessary to keep to a minimum the amount of foreign substances introduced into the body and the good tolerability necessary to maintain the non-invasive character of the examination (the compounds mentioned in J.Comput. Tomography 5,6: 543-46 (1981), in Radiology 144,343 (1982) and in Brevet Special de Medicament Mo. 484 M (1960) are, for example, too toxic. The ready watersolubility of the complex salts used in the preparations of the invention enables the preparation of highly concentrated solutions, so that the volume introduced into the circulation can be kept within reasonable limits and the dilution by body fluid can be compensated, that is to say the NMR diagnostic preparations must be 100 to 1000 times more water-soluble than is necessary for NMR spectroscopy. Furthermore, the diagnostic preparations of the invention are not only highly stable in vitro but also exhibit a surprisingly high stability in vivo, so that the per se toxic ions that are not covalently bonded in the complexes are released or exchanged only extremely slowly. The conjugates with proteins and antibodies which are used, for example, for the diagnosis of tumours bring about a surprisingly high intensification of the signal at such a low dosage that It Is possible to use In this case solutions of correspondingly low concentration.
Especially low doses (under 1 mg/kg) and therewith solutions of lower concentrations (1 pmol/1 to 5 mmol/l) than are specified in EP 71 564 are required for organ-specific NMR diagnostics, for example for detecting tumours and coronary infarcts.
The invention also provides physiologically tolerable, nonradioactive complex salts of the general formula I, as defined above. In those complex salts of the general formula X containing more than two of the radicals represented by X, it may be advantageous for at least one of the substituents Y to be a physiologically tolerable cation of an organic base or amino acid.
The present invention further provides the use of a physiologically tolerable, non-radioactive complex salt of the general formula I, as defined above, for the manufacture of a preparation for a method of NMR diagnosis of the human or animal body.
The following Examples illustrate the invention Example 1 Preparation of the disodium salt of the gadolinium(III) complex of 13,23-dioxo-15,18,2l-tris-(carboxymethyl) 12,15,18,21,24-pentaazapentatriacontanoic diacid, C3eHeoG3Oia . 2 Na .2 g ( = 20 mmol) of 13,23-dioxo-15,18,21-tris(carboxymethyl) -12,15,18,21,24-pentaazapentatriacontanoic diacid are suspended in 400 ml of water and the suspension Is heated to 95°C. 7.43 g ( = 20 mmol) of gadolinium(III) chloride hexahydrate, dissolved in 60 ml of water, are slowly added dropwise. The whole is maintained at this temperature for 2 hours and then, in order to neutralise the hydrochloric acid formed, 60 ml in IN sodium hydroxide solution are added.
When the reaction is complete (testing with xylenol orange) 'a the precipitate obtained is filtered and washed free of sodium chloride with water. 17.60 g (96¾ of the theoretical yield) of a water-insoluble, white powder of melting point 290-292°C are obtained. GadoliniumfIII) complex of 13,23dioxo-15,18,21-tris-(carboxymethyl)-12,15,18,21,24pentaazapentatriacontanoic diacid.
Analysis: (calculated) (found) C 47.30 H 6.84 H 6.83 N 7.66 Gd 17.20 N 7.60 Gd 17.06 C 47.13 14.6 g ( - 16 mmol) of the gadolinlum(III) complex so obtained are suspensed in 200 ml of water, and 31.4 1 of IN sodium hydroxide solution are added dropwise thereto. After 20 1 hour a clear solution is obtained which is filtered and then concentrated in vacuo. After drying in vacuo at 80°C 13.2 g (87 % of the theoretical yield) of a readily water- soluble, white powder obtained. of melting point 279-285°C are * 25 Analysis: (calculated) c 45.13 H 6.31 N 7.31 Gd 16.41 Na 4.80 (found) C 45.20 H 6.12 N 7.28 Gd 16.26 Na 4.75 ti In analogous manner there 1$ obtained, using N- methylglucamine in place of sodium hydroxide solution, the di-N-methylglucamine salt of the gadollnium(III) complex of 13,23-dioxo-15,18-21-tris-(carboxymethyl)-12,15,18,21,24pentaazapentatriacontanoic diacid, CsoHseGd^vOaa* Example 2 s Preparation of a solution of the disodium salt of the gadolinium(III) complex of 13,23-dioxo-15,18,21-tris(carboxymethyl )-12,15,18,21,24-pentaazapentatriacantanoic p diacid 392.0 g ( = 400 mmol) of the salt described in Example 1 are made into a paste in 500 ml of water p.l. (pro injectione) and dissolved by making up the volume to 1000 ml with water p. i. while heating slightly. The solution is placed In bottles and heat-sterilised.
Example 3 Preparation of a solution of the di-N-methylglucamine salt of the gadolinium(III) complex of l3,23-dloxo-15,18,21-tris(carboxymethyl )-12,15,18,21,24-pentaazapentatriacontanoic diacid _ 130.4 g ( = 100 mmol) of the di-N-methylglucamine complex salt listed in Example 1 are made into a paste in 250 ml of water p.i and dissolved while heating. The solution is made up to 500 ml with water P 1 , introduced into ampoules and heat-sterilised.
Example 4 Preparation of a solution of the gadolinium(lll) complex of the conjugate of diethylenetriaminepentaacetic acid with human serum albumen _ mg of l,5-bis-(2,6-dioxomorpholino)"3-azapentane-3-acetic acid (that is the anhydride of diethylenetriaminepentaacetic acid) are added to 20 ml of a solution of 3 mg of the protein in a 0.05 molar sodium bicarbonate buffer (pH 7-8).
The whole is stirred for 30 minutes at room temperature and is then dialysed against a 0.3 molar sodium phosphate buffer. 50 mg of gadolinium(III) acetate are then added and purification is effected by gel chromatography over a Sephadex G25 column; Sephadex is a Registered Trade Mark.
The fraction obtained is sterile-filtered and placed in multi-dose phials. Freeze-drying produces a dry preparation that can be stored.
In an analogous manner, there is obtained with immunoglobulin a solution of the corresponding complex conjugate.
Example 5 Preparation of a solution of the gadolinium(III) complex of the conjugate of a diethylenetriaminepentaacetic acid (DTPA) with a monoclonal antibody _ mg of a mixed DTPA anhydride (obtained, for example, from DTPA and isobutyl chloroformate) is added to 20 pi of a solution of 0.3 mg of a monoclonal antibody in a 0.05 molar sodium bicarbonate buffer (pH 7-8) and the whole is stirred for 30 minutes at room temperature. Dialysis is carried out against a 0.3 molar sodium phosphate buffer, and 2 mg of the gadolinium(IU) complex of ethylenediaminetetraacetic acid (EDTA) are added to the antibody fraction obtained. After purification by gel chromatography over Sephadex G25, the sterile-filtered solution is placed in multi-dose phials and freeze-dried.
Using the mixed anhydride of trans-1,2-diaminocyclohexanetetraacetlc acid (CDTA) there is obtained, in analogous manner, a solution of the corresponding gadolinium(III) complex of the CDTA antibody.
Using the manganese(II) complex of ethylenediaminetetraacetic acid there is obtained in an analogous manner the manganese(II) complexes of the antibodies coupled with DTP A or CDTA.
Example 6 Preparation of a solution of the gadolinium(III) complex of the conjugate of 1-phenyl-ethylenediaminetetraacetic acid with immunoglobulin According to the procedure described in J.Med. Chem. 1974, vol. 17, p. 1307, a 2% solution of the protein in a 0.12 molar sodium bicarbonate solution containing 0.01 mol of ethylenediaminetetraacetic acid is cooled to +4‘*C and there is added dropwise the proportion, equivalent to the protein, of a freshly prepared ice-cold diazonium salt solution of 1(£-aminophenyl)-ethylenediaminetetraacetic acid. The whole is stirred overnight (pH 8.1) at +4°C and is then dialysed against a 0.1 molar sodium citrate solution. When dialysis is complete, an excess of gadolinium(III) chloride is added to the solution of the conjugate and ultra-filtration is carried out to remove ions* Finally, the sterile-filtered solution is placed in multi-dose phials and freeze-dried.
Example 7 Preparation of a colloidal dispersion of a Mn( II)-CDTA-lipid 5 conjugate 0.1 mmol of distearoylphosphatidylethanolamine and 0.1 mmol of the bisanhydride of trans-I,2-dlamlnocyclohexanetetraacetic acid in 50 ml of water are stirred at room temperature for 24 hours. 0.1 mmol of manganese(H) carbonate is added and stirring Is again carried out at room temperature for 6 hours. After purification over a sephadex G50 column, the sterile-filtered solution is placed In multi-dose phials and freeze-dried.
A colloidal dispersion of the gadolinium-DTPA-lipid conjugate can be obtained analogously with gadoliniura(III) oxide.
Example 8 Preparation of liposomes charged with gadolinium(Ill)-OTPA _ According to the procedure described in Proc. ftatl. Acad. Sci. U.S.A. 75, 4194, a lipid mixture comprising 75 mol % of egg phosphatidylcholine and 25 mol % of cholesterol is prepared as a dry substance. 500 mg thereof are dissolved r 25 in 30 ml of diethyl ether and, in an ultrasonic bath, 3 ml of a 0.1 molar solution of the di-W-methylglucamine salt of the gadolinium(III) complex of dlethylenetriaminepentaacetic acid in water p.i. are added dropwise thereto. When the addition of the solution is complete, the exposure to •i ultrasonic waves is continued for 10 minutes and then concentration is carried out in a rotary evaporator. The gel-like residue is suspended in a 0.125 molar sodium chloride solution and, at 0C, repeatedly freed of non5 encapsulated contrast agent portions by centrifugation (20000 g/29 minutes). Finally, the liposomes so obtained are freeze-dried in multi-dose phials. The preparation is administered as a colloidal dispersion in a 0.9 % by weight sodium chloride solution. *
Claims (42)
1.CLAIMS 1. A diagnostic preparation which comprises (i) a physiologically tolerable, non-radioactive complex salt of the general formula I in which X represents the radicals -COOY, -PO 3 HY or -CONHOY wherein each Y represents a hydrogen atom, a metal equivalent, the metal being selected from elements having atomic numbers of from 21 to 29, 42, 44 and from 58 to 70, or a physiologically tolerable cation of an inorganic or organic base or amino acid, R t represents in each case a hydrogen atom or a methyl group and in which either a) A represents the group -CHR a -CHR 3 -, -CH a -CH a -(ZCH a -CH a , N(CH a X) 2 CH a -CH a -N(CH a X) a or -CH a -CH-CH a “ -CH a CH a -N-CH a -CH a -, in which X has the meanings given above, R a and R n together represent a trimethylene group or a tetramethylene group, or each represent a hydrogen atom, an alkyl radical containing up to 6 carbon atoms, a phenyl radical or a benzyl radical, m represents the integer 1, 2 or 3, k and Z represents an oxygen atom or a sulphur atom or the group 1 2. ^LNCH a X or ^2^-NCH a CH 2 0R 4 , in which X has the meanings given above and R« represents an alkyl radical containing up to 6 carbon atoms, and each V has the same meaning as X or represents the group -CH = OH or -COB, in which B represents a protein or lipid radical or an -NH(CH a )„X radical, in which X has the meanings given above and n represents an integer from 1 to 12, with the proviso that at least one of the symbols V represents a -COB group, as defined above, and at least * two of the substituents Y are metal equivalents selected from elements having atomic numbers of from 21 to 29, 42, 44 and from 58 to 70, * or b) A represents the group -CHR a -CHR 3 in which R 3 represents a hydrogen atom and R a represents the group -(CH 2 ) n -C 6 H 4 -W-protein in which p represents 0 or 1, W represents -NN-, -NHCOCH a - or -NHCSand -protein represents a protein radical, and each V has the same meaning as X or represents the group -CH a OH, with the proviso that at least two of the substituents Y are metai equivalents selected from elements having atomic numbers of from 21 to 29, 42, 44 and from 58 to 70, and (ii) a physiologically tolerable carrier.
2. A diagnostic preparation as claimed in claim 1, wherein the carrier (11) is an aqueous carrier.
3. A diagnostic preparation as claimed in claim 2, wherein the carrier (11) is water or physiological salt solution, and the complex salt (1) is dissolved or suspended in it.
4. A diagnostic preparation as claimed in claim 2 or claim 3, wherein the complex salt (i) is present in a concentration of from 1 pmoi to 1 mol per litre.
5. A diagnostic preparation as claimed in any one of claims 1 to 4, wherein the complex salt (1) is derived from diethylenetriaminepentaacetic acid.
6. A diagnostic preparation as claimed in any one of claims 1 to 4, wherein the complex salt (1) is derived from ethylenediaminetetraacetic acid.
7. A diagnostic preparation as claimed in any one of claims 1 to 4, wherein the complex salt (i) is derived from trans-l,2-cyclohexylenediaminetetraacetic acid or 13,23-dioxo-15, 18,21-tris-(carboxymethyl) 12,15,18,21,24-pentaazapentatriacontanoic diacid.
8. A diagnostic preparation as claimed in any one of claims 1 to 7, wherein the„complex salt (1) is derived from a complex-forming acid linked as a conjugate with a biomolecule.
9. A diagnostic preparation as claimed in claim 8, wherein the biomolecule is a lipid.
10. A diagnostic preparation as claimed in claim 8, wherein the biomoiecule is a protein.
11. A diagnostic preparation as claimed wherein the protein is insulin. in claim t 10,
12. A diagnostic preparation as claimed wherein the protein is an albumen. in claim 10,
13. A diagnostic preparation as claimed in claim 10, wherein the protein is a monoclonal antibody. 11.
14. A diagnostic preparation as claimed in claim 13, wherein the monoclonal antibody is specific to tumourassociated antigens. 12.
15. A diagnostic preparation as claimed in any one of j 5 claims 1 to 7, wherein the complex salt (i) is derived from a complex-forming acid forming a conjugate or inclusion compound with a liposome. t 13.
16. A diagnostic preparation as claimed in any one of claims 1 to 4, wherein the complex salt (i) is the di10 H-methylglucamine salt of the gadolinlum(IIl) complex of 13,23-dioxo-15,18,21-tris-(carboxymethyl) 12,15,18,21,24-pentaazapentatriacontanoic diacid. 14.
17. A diagnostic preparation as claimed in any one of claims 1 to 4, wherein the complex salt (i) is the 15 gadolinium(III) complex of the conjugate of diethylenetriaminepentaacetic acid with immunoglobulin. 15.
18. A diagnostic preparation as claimed in any one of claims 1 to 4, wherein the complex salt (i) is the gadolinium(III) complex of the conjugate of diethylene20 triaminepentaacetic acid with human serum albumen. 16.
19. A diagnostic preparation as claimed in any one of claims 1 to 4, wherein the complex salt (i) Is the gadolinium(III) complex of the conjugate of diethylenetriaminepentaacetic acid with a monoclonal antibody. 25
20. A diagnostic preparation as claimed in any one of claims 1 to 4, wherein the complex salt (i) is the manganese(11) complex of the conjugate of trans-1,2cyclohexyienediaminetetraacetic acid with a monoclonal antibody.
21. A diagnostic preparation as claimed in any one of claims 1 to 4, wherein the complex salt (1) Is the manganese(II) complex of a lipid conjugate of trans1r 2-cyclohexylenediaminetetraacetic acid.
22. A diagnostic preparation as claimed in any one of claims 1 to 4, wherein the complex salt (i) is the gadolinium(III) complex of an inclusion compound of diethylenetriaminepentaacetlc acid with a liposome. i
23. A diagnostic preparation as claimed in any one of claims 1 to 4, wherein the complex salt (i) is the disodium salt of the gadolinium(III) complex of 13,23dioxo-15,18,21-tris- (carboxymethyl)-12,15,18,21,24pentaazapentatriacofttanoic diacid. >
24. A diagnostic preparation as claimed in claim 1, substantially as described in any one of Examples 2 to 8 herein.
25. A diagnostic preparation as claimed in any one of claims 1 to 23, which is in a dosage form suitable for administration orally, neurally or intravasally.
26. An ampoule containing a diagnostic preparation as claimed in any one of claims 1 to 23, in a form suitable for injection.
27. A process for the manufacture of a diagnostic preparation as claimed in any one of claims 1 to 23, wherein the complex salt (i) is dissolved or suspended in water or physiological salt solution, and is made 2 up, if desired with the incorporation of one or more physiologically tolerable adjuncts, in a form that is suitable for intravasal or oral administration. 4
28. A process for the manufacture of a diagnostic preparation as claimed in claim 1, conducted substantially as described in any one of Examples 2 to 8 herein. 5
29. A physiologically tolerable, non-radioactive complex salt of the general formula 1 in which X represents the radicals -COOY, -PO 3 HY or -COE3HOY 10 wherein each Y represents a hydrogen atom, a metal equivalent, the metal being selected from elements having atomic numbers of from 21 to 29, 42, 44 and from 58 to 70, or a physiologically tolerable cation of an inorganic or organic base or amino 15 acid, Rx represents in each case a hydrogen atom or a methyl group and in which either a) A represents the group -CHR a -CHR 3 -, -CH 2 -CH 2 -(ZCH 3 -CH 2 )„-, K(CH a X) a CH a -CH a -M(CH a X) 3 or -CH a -CH-CH a - -CH a CH a -K-CH a -CH a -, in which - 28 X has the meanings given above, R 3 and R n together represent a trimethylene group or a tetramethylene group, or each represent a hydrogen atom, an alkyl radical containing up to 6 carbon atoms, a phenyl radical or a benzyl radical, m represents the integer 1, 2 or 3, and Z represents an oxygen atom or a sulphur atom or the group or ^^NCH a CH a OR 4 , in which X has the meanings given above and R 4 represents an alkyl radical containing up to 6 carbon atoms, and each V has the same meaning as X or represents the group -CH a OH or -COB, in which B represents a protein or lipid radical or an -NH(CH a )„X radical, in which X has the meanings given above and n represents an integer from 1 to 12, with the proviso that at least one o£ the symbols V represents a -COB group, as defined above, and at least two of the substituents Y are metal equivalents selected from elements having atomic numbers of from 21 to 29, 42, 44 and from 58 to 70, or b) A represents the group -CHR a ~CHR a - in which Ra represents a hydrogen atom and Ra represents the group -(CHaJ^-CeH^-W-protein τ in which p represents 0 or 1, W represents -MN-, -WHCOCH a - or -B3HCS10 and -protein represents a protein radical, and each V has the same meaning as K or represents the group -CH a OH, 15 with the proviso that at least two of the substituents Y are metal equivalents selected from elements having atomic numbers of from 21 to 29, 42, 44 and from 58 to 70.
30. A physiologically tolerable complex salt as claimed in 17. 20 claim 29, which contains more than two of the radicals represented by X and In which at least one of the substituents Y is a physiologically tolerable cation of an organic base or amino acid.
31. Any one of the physiologically tolerable complex salts 18. 25 as claimed In claim 29, specified in any one of the Examples herein. x
32. A process for the manufacture of a physiologically tolerable complex salt as claimed in any one of claims * 29 to 31, substantially as described herein.
33. A physiologically tolerable complex salt as claimed in claim 29, for use in a method of NMR diagnosis of the human or animal body.
34. A physiologically tolerable complex salt as claimed in claim 30, for use in a method of NMR diagnosis of the human or animal body. 1
35. A physiologically tolerable complex salt as claimed in ,, claim 31, for use in a method of NMR diagnosis of the human or animal body.
36. The use of a physiologically tolerable complex salt as claimed in claim 29, for the manufacture of a preparation for a method of NMR diagnosis of the human or animal body.
37. The use of a physiologically tolerable complex salt as claimed in claim 30, for the manufacture of a preparation for a method of NMR diagnosis of the human or animal body.
38. The use of a physiologically tolerable complex salt as claimed in claim 31, for the manufacture of a preparation for a method of NMR diagnosis of the human or animal body.
39. A diagnostic preparation as claimed in claim 1 substantially as hereinbefore described with reference to the examples.
40. An ampoule as claimed in claim 26 substantially as . hereinbefore described with reference to the examples.
41. A process as claimed in claim 27 substantially as hereinbefore described with reference to the examples.
42. A complex salt as claimed in claim 29 substantially as hereinbefore described with reference to the examples.
Priority Applications (1)
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Families Citing this family (117)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3324235A1 (en) * | 1983-07-01 | 1985-01-10 | Schering AG, 1000 Berlin und 4709 Bergkamen | NEW COMPLEX ILLUMINATORS, COMPLEX AND COMPLEX SALTS |
US5618514A (en) * | 1983-12-21 | 1997-04-08 | Nycomed Imaging As | Diagnostic and contrast agent |
US5720939A (en) * | 1985-08-15 | 1998-02-24 | Nycomed Imaging As | Method of contrast enhanced magnetic resonance imaging using magnetically responsive-particles |
GB8408127D0 (en) * | 1984-03-29 | 1984-05-10 | Nyegaard & Co As | Contrast agents |
ZA852979B (en) * | 1984-04-27 | 1985-11-27 | Vestar Research Inc | Contrast agents for nmr imaging |
US4728575A (en) * | 1984-04-27 | 1988-03-01 | Vestar, Inc. | Contrast agents for NMR imaging |
DE3577550D1 (en) * | 1984-09-21 | 1990-06-13 | Dow Chemical Co | AMINOCARBONIC ACID COMPLEXES FOR TREATING BONE TUMORS. |
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 |
US5362476A (en) * | 1984-10-18 | 1994-11-08 | Board Of Regents, The University Of Texas System | Alkyl phosphonate polyazamacrocyclic cheates for MRI |
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 |
US5188816A (en) * | 1984-10-18 | 1993-02-23 | Board Of Regents, The University Of Texas System | Using polyazamacrocyclic compounds for intracellular measurement of metal ions using MRS |
US4639365A (en) * | 1984-10-18 | 1987-01-27 | The Board Of Regents, The University Of Texas System | Gadolinium chelates as NMR contrast agents |
CA1317937C (en) * | 1984-10-18 | 1993-05-18 | A. Dean Sherry | Gadolinium chelates with carboxymethyl derivatives of polyazamacrocycles as nmr contrast agents |
EP0184899B1 (en) * | 1984-11-01 | 1990-04-18 | Nycomed As | Paramagnetic contrast agents for use in "in vivo" diagnostic methods using nmr, and their preparation |
SE465907B (en) * | 1984-11-01 | 1991-11-18 | Nyegaard & Co As | DIAGNOSTIC AGENT CONTENT AND PARAMAGNETIC METAL |
DE3508000A1 (en) * | 1985-03-04 | 1986-09-04 | Schering AG, Berlin und Bergkamen, 1000 Berlin | Ferromagnetic particles for NMR diagnosis |
DE3443252A1 (en) * | 1984-11-23 | 1986-05-28 | Schering AG, 1000 Berlin und 4709 Bergkamen | Dextran-magnetite complexes 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 |
US4758422A (en) * | 1985-01-04 | 1988-07-19 | Salutar Inc. | Ferrioxamine paramagnetic contrast agents for MR imaging |
US4980148A (en) * | 1985-02-06 | 1990-12-25 | Mallinckrodt, Inc. | Methods for enhancing magnetic resonance imaging |
US4675173A (en) * | 1985-05-08 | 1987-06-23 | Molecular Biosystems, Inc. | Method of magnetic resonance imaging of the liver and spleen |
GB8518300D0 (en) * | 1985-07-19 | 1985-08-29 | 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) |
AU6621586A (en) * | 1985-11-18 | 1987-06-02 | University Of Texas System, The | Polychelating agents for image and spectral enhancement (and spectral shift) |
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 |
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 |
HU200104B (en) * | 1986-04-07 | 1990-04-28 | Francois Dietlin | New contrast composition for tomodensitometry |
FR2596992B1 (en) * | 1986-04-11 | 1988-12-16 | Guerbet Sa | GYSOLINIUM-DOTA COMPLEX LYSINE SALT AND ITS APPLICATIONS TO DIAGNOSIS |
EP0250358A3 (en) * | 1986-06-20 | 1988-10-05 | Schering Aktiengesellschaft | Novel complex compounds |
US4951675A (en) * | 1986-07-03 | 1990-08-28 | Advanced Magnetics, Incorporated | Biodegradable superparamagnetic metal oxides as contrast agents for MR imaging |
DE3625417C2 (en) * | 1986-07-28 | 1998-10-08 | Schering Ag | Tetraazacyclododecane derivatives |
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 |
US5567411A (en) * | 1986-11-10 | 1996-10-22 | State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of The University Of Oregon | Dendritic amplifier molecules having multiple terminal active groups stemming from a benzyl core group |
US4863717A (en) * | 1986-11-10 | 1989-09-05 | The State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of The University Of Oregon | Methods for circumventing the problem of free radial reduction associated with the use of stable nitroxide free radicals as contrast agents for magnetic reasonance imaging |
US5252317A (en) * | 1986-11-10 | 1993-10-12 | The State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of The University Of Oregon | Amplifier molecules for diagnosis and therapy derived from 3,5-bis[1-(3-amino-2,2-bis (aminomethyl)-propyl) oxymethyl] benzoic acid |
US5135737A (en) * | 1986-11-10 | 1992-08-04 | The State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of The University Of Oregon | Amplifier molecules for enhancement of diagnosis and therapy |
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 |
DE3640708C2 (en) * | 1986-11-28 | 1995-05-18 | Schering Ag | Improved pharmaceuticals containing metals |
IT1224416B (en) * | 1987-12-24 | 1990-10-04 | Bracco Ind Chimica Spa | MACROCYCLIC CHELANTS AND THEIR CHELATES |
FI80801C (en) * | 1987-01-14 | 1990-07-10 | Innofarm Oy | KJJUGAT AV EN MONOCLONAL ANTIKROPP OCH ANVAENDNING. ELLER ETT FRAGMENT DAERAV OCH ETT KELATERANDE AEMNE, DESS FRAMSTAELLNING |
GB8701054D0 (en) * | 1987-01-16 | 1987-02-18 | Amersham Int Plc | Contrast agent for nmr scanning |
FR2612400A1 (en) * | 1987-03-16 | 1988-09-23 | Centre Nat Rech Scient | Microcapsules containing a radioactive and/or paramagnetic label in chelate form, and their use in the field of medical imaging |
DE3709851A1 (en) * | 1987-03-24 | 1988-10-06 | Silica Gel Gmbh Adsorptions Te | NMR DIAGNOSTIC LIQUID COMPOSITIONS |
US5482700A (en) * | 1987-03-31 | 1996-01-09 | Schering Aktiengesellschaft | Substituted polyamino, polycarboxy complexing agent dimers for MRI and X-ray contrast |
US5693309A (en) * | 1987-03-31 | 1997-12-02 | Schering Aktiengesellschaft | Substituted complexing agents, complexes, and complex salts, processes for their production, and pharmaceuticals containing same |
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 |
US5223538A (en) * | 1987-03-31 | 1993-06-29 | Duke University | Superoxide dismutase mimic |
FR2614020B1 (en) * | 1987-04-14 | 1989-07-28 | Guerbet Sa | NOVEL NITROGEN CYCLIC LIGANDS, METAL COMPLEXES FORMED BY SUCH LIGANDS, DIAGNOSTIC COMPOSITIONS CONTAINING THESE COMPLEXES AND PROCESS FOR PREPARING LIGANDS. |
DE3713842A1 (en) * | 1987-04-22 | 1988-11-17 | Schering Ag | SUBSTITUTED CYCLIC COMPLEX MAKERS, COMPLEX AND COMPLEX SALTS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THEM |
ATE111231T1 (en) * | 1987-06-23 | 1994-09-15 | Nycomed Innovation Ab | IMPROVEMENTS IN MAGNETIC RESONANCE IMAGING. |
AU617338B2 (en) * | 1987-07-16 | 1991-11-28 | Nycomed As | Aminopolycarboxylic acids and derivatives thereof |
RU2073005C1 (en) * | 1987-07-16 | 1997-02-10 | Нюкомед АС | Metal chelate compound |
US5531978A (en) * | 1987-07-16 | 1996-07-02 | Nycomed Imaging As | Aminopolycarboxylic acids and derivatives thereof |
JP2520262B2 (en) * | 1987-08-21 | 1996-07-31 | 春幸 川原 | Patch test material |
DE3728525A1 (en) * | 1987-08-24 | 1989-03-16 | Schering Ag | MULTI-CORE SUBSTITUTED COMPLEX ILLUMINATORS, COMPLEX AND COMPLEX SALTS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS 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 |
DE3825040A1 (en) | 1988-07-20 | 1990-01-25 | Schering Ag | 5- OR 6-RING MACROCYCLIC POLYAZA COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THEM |
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 |
ATE82140T1 (en) * | 1988-08-08 | 1992-11-15 | Biomira Inc | PHOTOCHEMICAL LINKING OF CHELATING GROUPS TO BIOMOLECULES. |
NZ230778A (en) * | 1988-09-27 | 1993-01-27 | Salutar Inc | Diagnostic imaging contrast medium comprising biscarbamoyl derivatives |
US4889931A (en) * | 1988-09-27 | 1989-12-26 | Salutar, Inc. | Manganese (II) chelate manufacture |
US5260050A (en) * | 1988-09-29 | 1993-11-09 | Ranney David F | Methods and compositions for magnetic resonance imaging comprising superparamagnetic ferromagnetically coupled chromium complexes |
US5213788A (en) * | 1988-09-29 | 1993-05-25 | Ranney David F | Physically and chemically stabilized polyatomic clusters for magnetic resonance image and spectral enhancement |
GB8900719D0 (en) * | 1989-01-13 | 1989-03-08 | Nycomed As | Compounds |
US6139603A (en) * | 1989-02-22 | 2000-10-31 | L'air Liquide, Societe Anonyme Pour L'etude Et L'exploitation Des Procedes Georges Claude | Process for recovering oxygen |
US5011925A (en) * | 1989-03-09 | 1991-04-30 | Mallinckrodt, Inc. | Morpholinoamido EDTA derivatives |
US5364613A (en) * | 1989-04-07 | 1994-11-15 | Sieving Paul F | Polychelants containing macrocyclic chelant moieties |
US5384108A (en) * | 1989-04-24 | 1995-01-24 | Mallinckrodt Medical, Inc. | Magnetic resonance imaging agents |
DE3922005A1 (en) * | 1989-06-30 | 1991-01-10 | Schering Ag | DERIVATIVED DTPA COMPLEXES, PHARMACEUTICAL AGENTS CONTAINING THESE COMPOUNDS, THEIR USE AND METHOD FOR THE PRODUCTION THEREOF |
US5087440A (en) * | 1989-07-31 | 1992-02-11 | Salutar, Inc. | Heterocyclic derivatives of DTPA used for magnetic resonance imaging |
EP0490897A1 (en) * | 1989-09-05 | 1992-06-24 | Mallinckrodt, Inc. | Novel magnetic resonance imaging agents |
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 |
CA2072080A1 (en) * | 1990-01-19 | 1991-07-20 | Jo Klaveness | Chelating compounds |
PT98000B (en) * | 1990-06-18 | 1998-11-30 | Dow Chemical Co | METHOD OF USING AMINOFOSPHONIC ACID COMPLEXES AS IMAGE PRODUCING AGENTS |
US5310539A (en) * | 1991-04-15 | 1994-05-10 | Board Of Regents, The University Of Texas System | Melanin-based agents for image enhancement |
CA2115275A1 (en) * | 1991-08-09 | 1993-02-18 | David L. White | Amino acid, ester and/or catechol contrast agents for mri |
US5464696A (en) * | 1992-08-13 | 1995-11-07 | Bracco International B.V. | Particles for NMR imaging |
DE4317588C2 (en) * | 1993-05-24 | 1998-04-16 | Schering Ag | Macrocyclic metal complexes containing fluorine, process for their preparation and their use |
DE4318369C1 (en) * | 1993-05-28 | 1995-02-09 | Schering Ag | Use of macrocyclic metal complexes as temperature probes |
US5405601A (en) * | 1993-07-02 | 1995-04-11 | Mallinckrodt Medical Inc. | Functionalized tripodal ligands for imaging applications |
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 |
DE19500665A1 (en) * | 1995-01-12 | 1996-07-18 | Axel Prof Dr Haase | Process for the spatially resolving imaging of an area of a biological object with the help of electromagnetic rays using contrast media |
TW319763B (en) | 1995-02-01 | 1997-11-11 | Epix Medical Inc | |
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 |
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 |
DE19507819A1 (en) * | 1995-02-21 | 1996-08-22 | Schering Ag | New di:ethylene-tri:amine penta:acetic acid amide complexes |
DE19505960A1 (en) * | 1995-02-21 | 1996-08-22 | Deutsches Krebsforsch | Conjugate for the individual dosage of drugs |
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 |
US6777217B1 (en) | 1996-03-26 | 2004-08-17 | President And Fellows Of Harvard College | Histone deacetylases, and uses related thereto |
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 |
IT1315263B1 (en) * | 1999-12-21 | 2003-02-03 | Bracco Spa | CHELATING COMPOUNDS, THEIR CHELATES WITH PARAMAGNETIC METAL IONS, THEIR PREPARATION AND USE |
US20030129724A1 (en) | 2000-03-03 | 2003-07-10 | Grozinger Christina M. | Class II human histone deacetylases, and uses related thereto |
US7244853B2 (en) | 2001-05-09 | 2007-07-17 | President And Fellows Of Harvard College | Dioxanes and uses thereof |
AU2006226861B2 (en) | 2005-03-22 | 2012-08-16 | Dana-Farber Cancer Institute, Inc. | Treatment of protein degradation disorders |
US8669236B2 (en) | 2005-05-12 | 2014-03-11 | The General Hospital Corporation | Biotinylated compositions |
WO2008091349A1 (en) * | 2006-02-14 | 2008-07-31 | The President And Fellows Of Harvard College | Bifunctional histone deacetylase inhibitors |
US8304451B2 (en) | 2006-05-03 | 2012-11-06 | President And Fellows Of Harvard College | Histone deacetylase and tubulin deacetylase inhibitors |
DE102007002726A1 (en) | 2007-01-18 | 2008-07-31 | Bayer Schering Pharma Aktiengesellschaft | New cascade polymer complexes, processes for their preparation and pharmaceutical compositions containing them |
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 |
US20090208421A1 (en) | 2008-02-19 | 2009-08-20 | Dominique Meyer | Process for preparing a pharmaceutical formulation of contrast agents |
JP5397976B2 (en) * | 2008-05-07 | 2014-01-22 | 公立大学法人大阪府立大学 | Paramagnetic metal-containing polyamidoamine dendron lipids |
KR101708946B1 (en) | 2008-07-23 | 2017-02-21 | 다나-파버 캔서 인스티튜트 인크. | Deacetylase inhibitors and uses thereof |
FR2945448B1 (en) | 2009-05-13 | 2012-08-31 | Guerbet Sa | PROCESS FOR THE PREPARATION OF A PHARMACEUTICAL FORMULATION OF LANTHANIDE CHELATE AS A POWDER |
WO2011019393A2 (en) | 2009-08-11 | 2011-02-17 | President And Fellows Of Harvard College | Class- and isoform-specific hdac inhibitors and uses thereof |
EP2338874A1 (en) * | 2009-12-16 | 2011-06-29 | Bracco Imaging S.p.A | Process for the preparation of chelated compounds |
KR20190079682A (en) | 2011-04-21 | 2019-07-05 | 바이엘 인텔렉쳐 프로퍼티 게엠베하 | Preparation of high-purity gadobutrol |
JP6431480B2 (en) | 2012-08-31 | 2018-11-28 | ザ ジェネラル ホスピタル コーポレイション | Biotin conjugates for the treatment and diagnosis of Alzheimer's disease |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1070695A (en) * | 1975-09-02 | 1980-01-29 | Michael D. Loberg | Iminodiacetic acid pharmaceutical |
US4176173A (en) * | 1977-07-18 | 1979-11-27 | Medi-Physics, Inc. | Radiographic compositions |
US4352751A (en) * | 1979-09-10 | 1982-10-05 | Analytical Radiation Corporation | Species-linked diamine triacetic acids and their chelates |
DE3033651A1 (en) * | 1980-09-06 | 1982-03-25 | Wilhelm Bögle KG, 7410 Reutlingen | HOLDING DEVICE FOR FABRIC-COVERED PANELED WALLS |
DE3038853A1 (en) * | 1980-10-10 | 1982-05-27 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | NEW N-HYDROXY-ALKYLATED DICARBONIC ACID-BIS- (3,5-DICARBAMOYL-2,4,6-TRIJODANILIDES), THEIR PRODUCTION AND THEIR CONTAINING X-RAY CONTRAST AGENTS (II) |
US4385046A (en) * | 1980-12-15 | 1983-05-24 | Minnesota Mining And Manufacturing Company | Diagnostic radio-labeled polysaccharide derivatives |
DE3129906C3 (en) * | 1981-07-24 | 1996-12-19 | Schering Ag | Paramagnetic complex salts, their preparation and agents for use in NMR diagnostics |
CA1242643A (en) * | 1983-08-12 | 1988-10-04 | Eric T. Fossel | Nmr imaging utilizing chemical shift reagents |
US4687658A (en) * | 1984-10-04 | 1987-08-18 | Salutar, Inc. | Metal chelates of diethylenetriaminepentaacetic acid partial esters for NMR imaging |
-
1984
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1985
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1986
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