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WO1990008134A1 - Derives d'agents chelateurs - Google Patents

Derives d'agents chelateurs Download PDF

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Publication number
WO1990008134A1
WO1990008134A1 PCT/EP1990/000078 EP9000078W WO9008134A1 WO 1990008134 A1 WO1990008134 A1 WO 1990008134A1 EP 9000078 W EP9000078 W EP 9000078W WO 9008134 A1 WO9008134 A1 WO 9008134A1
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WO
WIPO (PCT)
Prior art keywords
group
chr
compound
formula
groups
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.)
Ceased
Application number
PCT/EP1990/000078
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English (en)
Inventor
Torsten Almén
Arne Berg
Jo Klaveness
Pål RONGVED
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GE Healthcare AS
Original Assignee
Nycomed AS
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Nycomed AS filed Critical Nycomed AS
Publication of WO1990008134A1 publication Critical patent/WO1990008134A1/fr
Priority to NO91912755A priority Critical patent/NO912755L/no
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C07C309/14—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl

Definitions

  • the present invention relates to certain
  • chelating agents in particular aminopoly (carboxylic acid or carboxylic acid derivative) compounds,
  • chelating agents for example as stabilizers for pharmaceutical preparations, as antidotes for poisonous heavy metal species and as diagnostic agents for the administration of metal species (e.g. ions
  • diagnostic techniques such as X-ray, magnetic resonance imaging (MRI) or ultrasound
  • Aminopoly (carboxylic acid or carboxylic acid derivative) (hereinafter APCA) chelating agents
  • EP-A-130934 (Schering), EP-A-165728 (Nycomed AS), DE-A-2918842 (Rexolin Chemicals AB), DE-A-3401052
  • Cyclic APCAs are also well known in the art, for example from
  • EP-A-71564 describes paramagnetic metal chelates, for which the chelating agent is nitrilotriacetic acid (NTA), N,N,N',N'-ethylenediaminetetraacetic acid (EDTA), N-hydroxyethyl-N,N',N'-ethylenediamine-triacetic acid (HEDTA) , N,N,N',N",N"-diethylenetriamine-pentaacetic acid (DTPA) and
  • NTA nitrilotriacetic acid
  • EDTA N,N,N',N'-ethylenediaminetetraacetic acid
  • HEDTA N-hydroxyethyl-N,N',N'-ethylenediamine-triacetic acid
  • DTPA N,N,N',N",N"-diethylenetriamine-pentaacetic acid
  • N-hydroxyethylimino-diacetic acid as being suitable as contrast agents for MRI, contrast being achieved by the effect of the magnetic field of the paramagnetic species (e.g. Gd(III)) with the chelating agents serving to reduce the toxicity and to assist administ ration of that paramagnetic species.
  • the paramagnetic species e.g. Gd(III)
  • EP-A-299795 have proposed APCAs which carry hydrophilic groups on the amine nitrogens or on the alkylene chains linking the amine nitrogens.
  • each of the groups Z is a group -CHR 1 X or the groups Z together are a group -(CHR 1 ) q -A'- (CHR 1 ) r - , where A' is an oxygen or sulphur atom or a group N-Y;
  • A is a group N-Y or A- (CHR 1 ) m - represents a carbonnitrogen bond or, when the groups Z together are a group -(CHR 1 ) q -A'-(CHR 1 ) r -, A may also represent an oxygen or sulphur atom;
  • each Y which may be the same or different, is a a group -(CHR 1 ) p N (CHR 1 X) 2 or a group CHR 1 X;
  • each X which may be the same or different, is a
  • each D which may be the same or different is a group of formula OR 2 , NR 2 2 or
  • each R 11 which may be the same or different is a hydrogen atom, a hydroxyl group or an optionally hydroxylated alkyl group,
  • s 0, 1 or 2
  • W is a group CHR 11 , NR 11 or an oxygen atom
  • each R 1 which may be the same or different, is a hydrogen atom, a hydroxyalkyl group or an optionally hydroxylated alkoxy or alkoxyalkyl group;
  • n,m,p,q and r are each 2,3 or 4, preferably 2;
  • each R 2 which may be the same or different is a hydrogen atom, an optionally mono or polyhydroxylated alkyl, alkoxyalkyl or polyalkoxyalkyl group;
  • At least one nitrogen carries a -CHR 1 X moiety
  • X and R 1 are not the same, that at least one group
  • X is other than a group R 1 or COD, and that unless the groups Z together are a -(CHR 1 ) q -A'-(CHR 1 ) r group or A is an N-(CHR 1 ) p - N(CHR 1 X) 2 group at least one R 1 is other than hydrogen) and salts
  • alkyl or alkylene moieties in the R 1 , R 2 and R 11 groups may, unless
  • alkoxy substituents may be carried by alkoxy substituents groups.
  • the invention is a nitrogen-attached heterocyclic
  • ring it particularly preferably is of formula:
  • each group Z is a group -CHR 1 X or the
  • groups Z together are a group -(CHR 1 ) 2 -A'-(CHR 1 ) 2 -;
  • each Y which may be the same or different, is
  • each hydrophilic R 1 group which may be straight-chained or branched, preferably has a carbon atom content of from 1 to 8, especially preferably 1 to 6, carbon atoms.
  • R 1 groups may be alkoxy, polyalkoxy, polyhydroxyalkoxy, hydroxlated polyalkoxy, polyhydroxylated
  • polyhydroxylated polyhydroxyalkyl groups but more preferably they will be monohydroxyalkyl or
  • the hydrophilic R 1 groups serve to increase the hydrophilicity and reduce
  • hydrophilic R 1 groups preferably 1 to 4 hydrophilic R 1 groups and that in total the hydrophilic R 1 groups should contain about 6 or more hydroxy or ether oxygen
  • the invention may thus include for example hydroxymethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, 1-(hydroxymethyl)-2-hydroxy-ethyl, methoxymethyl, ethoxymethyl, 2-hydroxyethoxymethyl, methoxyethoxymethyl, (2-hydroxy-ethoxy) ethyl, etc, groups.
  • the carboxyl derivatives which may be represented by the groups X in the compounds of the invention may include, for example, amide groups, ester groups and carboxyl groups, for example groups of formulae
  • R 2 is a hydrogen atom or an optionally hydroxylated alkyl, for example C 1-6 alkyl, group and R 3 is a hydrogen atom, a hydroxyl group or
  • oxygen atom or a group CH 2 or CHOH, s is 0 or 1
  • R 11 is hydrogen or where s is 1 and W is oxygen R 11 may also represent a C 1-4 hydroxy-alkyl group
  • terminal amine nitrogens i.e those carrying two CHR 1 X groups, carry a CHR 1 X group in which
  • formula I wherein one or more X groups are carboxyl groups may form salts or chelate complexes, which are also compounds according to the present invention, in which one or more (but not necessarily all)
  • M + is a monovalent cation or a fraction of a polyvalent cation, for example an ammonium
  • alkali metal or alkaline earth metal examples include alkali metal or alkaline earth metal
  • M + is a cation
  • the chelating agent of formula I is chosen to equal the valency of the metal species to be chelated by the compound formula I.
  • I preferably contains three ion-forming X groups, for example -COOH or -COOM.
  • the metal chelate will be formed as a neutral species, a form preferred since the osmotic pressures in concentrated solutions of such compounds are low and since their toxicities relative to their ionic analogues are significantly reduced.
  • complexing moieties than acetic acid residues may be advantageous.
  • the choice of complexing groups will be dependent upon the metal and complex in accordance to the theory of hard and soft acids and bases (HSAB theory).
  • A' is oxygen or sulphur and at least one
  • the X groups is other than a COD or R 1 group, preferably wherein at least two, more preferably
  • R 1 groups are hydrophilic groups, and particularly preferably wherein at least one R 1 group in each
  • Preferred compounds of formula I include certain compounds of formulae lb to If wherein each moiety
  • -CHR 1 X is of formula -CH 2 X" wherein X" is other
  • Gd 3+ chelates especially Gd 3+ chelates, and salts, e.g. Na + salts, thereof.
  • the invention provides a process for the preparation of the compounds of formula I, said process comprising one or more of the following steps:
  • Lawesson's reagents may also be used in a general
  • Cyano groups may also be converted into thioesters or dithioesters (see Janssen: "The Chemistry of
  • a carboxylic acid, CHR 1 COOH, functional group may be introduced by reaction between an amine
  • L is a leaving group, for example a halogen atom such as chlorine, bromine or iodine
  • R 1' is a group R 1 as described above or a group convertible thereto
  • X' is a COOH moiety or a group convertible thereto.
  • cyclic polyether groups for example as 2,2-dimethyl-1,3-dioxa-cyclopent-4-yl groups,
  • R 3 is a hydrogen atom or a -CHR 1' X 3 group
  • X 3 is as defined for X or is a group convertible
  • the groups Z' are a -(CHR 1' ) q -A"' -(CHR 1' ) r - bridging group where A"' is an oxygen or sulphur atom or
  • A" is a group -N-Y' or -A"-
  • A" may also represent an oxygen or sulphur atom; with the proviso that at least one R 3 moiety is a hydrogen atom.
  • each R 1" is an optionally protected hydroxyalkyl or hydroxyalkoxyalkyl group, for example a -CH 2 -
  • a 2 is a sulphur or oxygen
  • optionally protected hydroxyalkyl groups attached to the alkylene chains between amine nitrogens are preferably benzyl protected groups and the nitrogen-attached protected hydroxyalkyl groups in -CHR 1' X 3 moieties are preferably in the
  • formulae IIa to IIo may for example be by the
  • the starting compound (1) is described by
  • Compounds of formula lib may be prepared from compounds of formula IIa by reductive amination, for example as described by R.F. Borch in J. Org.
  • reaction prepared for example as described by C. Hubhelen in Synthesis (1986) 962.
  • the reaction may for
  • the alpha-formylation described above may be performed using the method described in J. Med. Chem. 8 (1965) 220.
  • Ilf may be prepared by replacing the formylation step (e) by reaction with chloromethylbenzylalcohol (available from Fluka) to yield the starting compounds (15) and (16) for the reduction step (f):
  • Compounds of formula (17) may be produced by mono-protection of aminopropandiol at the primary hydroxyl group and may be mono or di-alkylated
  • the mono and di-alkylation products may be separated by distillation.
  • the mono-alkylation product, compound (18), is used in the preparation of compounds of formula Ilg
  • Compounds of formula IIo can be prepared analogously to compounds of formula Ilg by omitting the initial mono-/di-alkylation step (h).
  • the cyclic compounds of formula IIi may be prepared by peptide condensation followed by reduction of the amide carbonyl groups, substantially as
  • an amine group may be prepared by alkylation of an iminodiacetic acid derivative and the ether
  • starting compounds may be prepared analogously by formylation of the corresponding
  • Compounds of formula IIi are particularly preferred starting materials as they may be used to form non-ionic or mono-ionic chelates with trivalent metal ions according to the selection of A 2 .
  • the cyclic compounds of formula IIj may be prepared by the well known routes for the preparation of cyclic polyamines. Thus, in a method analogous to that described by J.E. Richmann et al. in J.
  • step (p) are known, as described for example by W. Rasshofer et al. in Liebigs Ann Chem. (1977) 1344.
  • the group R 6 may be a protecting group resistant to the detosylation conditions allowing the possibility of substituting the nitrogen to which it is attached with a carboxymethyl derivative, etc.
  • a tetrapeptide or a protected tetrapeptide may be reduced, and the corresponding tetraamine may be cyclized in a way similar to that described by M.K.Moi et al. in J.Am.Chem. Soc. 110 (1988) 6266.
  • the asymmetric compounds of formula III may be prepared by peptide condensation of protected amino acids followed reduction of the amide carbonyl groups, for example using the following scheme:
  • cyclic compounds of formula I may also be prepraed by methods analogous to those described by Guerbet in EP-A-287465.
  • a compound of formula I may also be prepraed by methods analogous to those described by Guerbet in EP-A-287465.
  • formula IIi may be formed by reacting a polyamine of formula (43)
  • T represents a displaceable group such as a tosyl, mesyl or benzenesulphonyl group
  • L represent a leaving group such as a halogen atom, e.g. chlorine, bromine or iodine
  • Y 3 represents a group T
  • Chelants of formula I may be used as the
  • one X or R 1 group a bond or linkage to a macromolecule or polymer, e.g. a tissue specific biomolecule or a backbone polymer such as polylysine or polyethyleneimine which may carry several chelant groups and may
  • a macromolecule or polymer e.g. a tissue specific biomolecule or a backbone polymer such as polylysine or polyethyleneimine which may carry several chelant groups and may
  • MR magnetic resonance
  • X-ray or ultrasound diagnostics e.g. MR
  • the chelated metal species is particularly suitably a paramagnetic species, the metal conveniently
  • Radioactivity is a characteristic which is neither required nor desirable for MR-diagnostics contrast agents.
  • the chelated metal species is preferably a heavy
  • metal species for example a non-radioactive metal with an atomic number greater than 37, preferably greater than 50, e.g. Dy 3+
  • the chelated metal species must of course be radioactive and any conventional complexable radioactive metal isotope, such as 99m Tc or 111 In for example, may
  • the chelating agent for radiography, the chelating agent
  • the chelating agent must be in salt form with a
  • physiologically acceptable counterion e.g. sodium, calcium, ammonium, zinc or meglumine, e.g. as the sodium salt of the chelate of the compound of formula I with zinc or calcium.
  • Gd DTPA it will conveniently be used in the form of a salt with a physiologically acceptable counterion, for example an ammonium, substituted ammonium,
  • invention provides a diagnostic or therapeutic
  • agent comprising a metal chelate, whereof the chelating entity is the residue of a compound according to
  • the present invention together with at least one pharmaceutical or veterinary carrier or excipient, or adapted for formulation therewith or for inclusion in a pharmaceutical formulation for human or veterinary use.
  • the present invention provides a detoxification agent comprising a chelating agent according to the invention in the form of
  • the present invention may be formulated with conventional pharmaceutical or veterinary formulation
  • etc. may be in a form suitable for parenteral or enteral administration, for example injection or infusion or administration directly into a body cavity having an external escape duct, for example the gastrointestinal tract, the bladder or the
  • agent of the present invention may be in a conventional pharmaceutical administration form such as a tablet, capsule, powder, solution, suspension, dispersion, syrup, suppository, etc;
  • physiologically acceptable carrier media for example water for injections
  • the carrier medium incorporating the chelate or the chelating agent salt is preferably isotonic or somewhat hypertonic.
  • a chelate or salt of a toxic metal species for example a heavy metal ion, or atom, it may
  • the diagnostic agent of the present invention if in solution, if in solution,
  • suspension or dispersion form will generally contain the metal chelate at concentration in the range
  • the diagnostic agent may however be supplied in a more concentrated form for dilution prior
  • the diagnostic agent of the invention is to administration.
  • the diagnostic agent of the invention is to administration.
  • inventions may conveniently be administered in amounts of from 10 -4 to 3 mmol of the metal species per
  • the dose of the contrast agent should generally be higher and for scintigraphic examination the dose should generally be lower
  • invention provides a method of generating enhanced images of the human or non-human animal body, which method comprises administering to said body a diagnostic agent according to the present invention and generating an X-ray, MR-diagnostics, ultrasound or scintigraphic image of at least a part thereof.
  • invention provides a method of radiotherapy practised on the human or non-human animal body, which method comprises administering to said body a chelate
  • the present invention provides a method of heavy metal detoxification practised on the human or non-human animal body, which method comprises administering to said body a chelating agent according to the invention in the form of a weak complex or salt with a
  • the present invention also provides the use of the compounds, especially the metal chelates, according to the invention for the manufacture of diagnostic or therapeutic agents for use in methods of image generation, detoxification or radiotherapy practised on the human or non-human animal body.
  • the present invention provides a process for the preparation of the metal chelates of the invention which process comprises admixing in a solvent a compound of formula I or a salt (e.g. the sodium salt) or chelate thereof together with an at least sparingly soluble compound of said metal, for example a chloride, oxide or carbonate.
  • a solvent e.g. the sodium salt
  • an at least sparingly soluble compound of said metal for example a chloride, oxide or carbonate.
  • the present invention provides a process for the preparation of the diagnostic or therapeutic agent of the present invention, which comprises admixing a metal chelate according to the invention, or a physiologically acceptable salt thereof, together with at least one pharmaceutical or veterinary carrier or excipient.
  • the present invention provides a process for the preparation of the detoxification agent of the invention, which comprises admixing a chelating agent according to the invention in the form of a salt with a physiologically acceptable counterion together with at least one pharmaceutical or veterinary carrier or excipient.
  • the title compound was isolated as a white powder.
  • Example 5 (Example 5) was dissolved in 20 ml of distilled water. The solution was filtered, placed in a
  • the solution contained 0.5 mmol gadolinium per ml.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Toxicology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biochemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Hydrogenated Pyridines (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Sont décrits des agents chélateurs particulièrement utiles pour al préparation d'agents diagnostiques et thérapeutiques destinés à l'imagerie par résonance magnétique, la scintigraphie, l'imagerie ultrasonore, la radiothérapie et la détoxication des métaux lourds, lesdits agents étant des composés de formule (I): X-CHR1-NZ-(CHR1)n-A-(CHR1)m-NZ-CHR1-X (dans laquelle chacun des groupes Z est un groupe -CHR1X ou bien les groupes Z ensemble sont un groupe -(CHR1)q-A'-(CHR1)r-, où A' est un atome d'oxygène ou de soufre ou un groupe N-Y; m, n, q et r valent chacun 2, 3 ou 4, de préférence 2; et les groupes A, X, Y et R1 ont la notation ci-définie.
PCT/EP1990/000078 1989-01-13 1990-01-15 Derives d'agents chelateurs Ceased WO1990008134A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
NO91912755A NO912755L (no) 1989-01-13 1991-07-12 Chelateringsmiddel-derivater.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB898900732A GB8900732D0 (en) 1989-01-13 1989-01-13 Agents
GB8900732.2 1989-01-13

Publications (1)

Publication Number Publication Date
WO1990008134A1 true WO1990008134A1 (fr) 1990-07-26

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ID=10649976

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1990/000078 Ceased WO1990008134A1 (fr) 1989-01-13 1990-01-15 Derives d'agents chelateurs

Country Status (5)

Country Link
EP (1) EP0453507A1 (fr)
JP (1) JPH04502919A (fr)
AU (1) AU5044690A (fr)
GB (1) GB8900732D0 (fr)
WO (1) WO1990008134A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993002045A1 (fr) * 1991-07-17 1993-02-04 Nycomed Salutar, Inc. Derives hydroxamate et hydrazide de polyamines et leur utilisation medicale comme chelateurs
DE19507820A1 (de) * 1995-02-21 1996-08-22 Schering Ag Neuartig substituierte DTPA-Derivate, deren Metallkomplexe, diese Komplexe enthaltende pharmazeutische Mittel, deren Verwendung in der Diagnostik, sowie Verfahren zur Herstellung der Komplexe und Mittel
US5562894A (en) * 1991-08-09 1996-10-08 Regents Of The University Of California Amino-acyl-type and catecholamine-type contrast agents for MRI
US5684149A (en) * 1993-01-22 1997-11-04 Research Foundation Of State University Of New York Metal complexes for promoting catalytic cleavage of RNA by transesterification

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB744926A (en) * 1952-06-11 1956-02-15 Dow Chemical Co Polyhydroxyamino acid compounds
US3726912A (en) * 1970-07-02 1973-04-10 Dow Chemical Co Substituted alkanolamine chelating agents
US4187245A (en) * 1975-06-02 1980-02-05 Petrolite Corporation Hydroxypropylene-amino-phosphonic-sulfonic acids
EP0210043A2 (fr) * 1985-07-19 1987-01-28 Guerbet S.A. Agent de contraste pour diagnostic par RMN
EP0130934B1 (fr) * 1983-07-01 1987-08-05 Schering Aktiengesellschaft Agents complexants, complexes et sels complexes
EP0258616A1 (fr) * 1986-08-04 1988-03-09 Salutar, Inc. Imagerie RMN avec des sels de métaux polyvalents paramagnétiques de poly-(acide-alkylène-amino)-alcanes
EP0299795A2 (fr) * 1987-07-16 1989-01-18 Nycomed As Acides aminopolycarboxyliques et leurs dérivés

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB744926A (en) * 1952-06-11 1956-02-15 Dow Chemical Co Polyhydroxyamino acid compounds
US3726912A (en) * 1970-07-02 1973-04-10 Dow Chemical Co Substituted alkanolamine chelating agents
US4187245A (en) * 1975-06-02 1980-02-05 Petrolite Corporation Hydroxypropylene-amino-phosphonic-sulfonic acids
EP0130934B1 (fr) * 1983-07-01 1987-08-05 Schering Aktiengesellschaft Agents complexants, complexes et sels complexes
EP0210043A2 (fr) * 1985-07-19 1987-01-28 Guerbet S.A. Agent de contraste pour diagnostic par RMN
EP0258616A1 (fr) * 1986-08-04 1988-03-09 Salutar, Inc. Imagerie RMN avec des sels de métaux polyvalents paramagnétiques de poly-(acide-alkylène-amino)-alcanes
EP0299795A2 (fr) * 1987-07-16 1989-01-18 Nycomed As Acides aminopolycarboxyliques et leurs dérivés

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993002045A1 (fr) * 1991-07-17 1993-02-04 Nycomed Salutar, Inc. Derives hydroxamate et hydrazide de polyamines et leur utilisation medicale comme chelateurs
US5869651A (en) * 1991-07-17 1999-02-09 Nycomed Salutar Hydrazide derivatives of polyamides and their medical use as chelating agents
US5562894A (en) * 1991-08-09 1996-10-08 Regents Of The University Of California Amino-acyl-type and catecholamine-type contrast agents for MRI
US5684149A (en) * 1993-01-22 1997-11-04 Research Foundation Of State University Of New York Metal complexes for promoting catalytic cleavage of RNA by transesterification
DE19507820A1 (de) * 1995-02-21 1996-08-22 Schering Ag Neuartig substituierte DTPA-Derivate, deren Metallkomplexe, diese Komplexe enthaltende pharmazeutische Mittel, deren Verwendung in der Diagnostik, sowie Verfahren zur Herstellung der Komplexe und Mittel

Also Published As

Publication number Publication date
GB8900732D0 (en) 1989-03-08
EP0453507A1 (fr) 1991-10-30
AU5044690A (en) 1990-08-13
JPH04502919A (ja) 1992-05-28

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