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WO1991015467A1 - Agents chelateurs d'acide aminopolycarboxylique - Google Patents

Agents chelateurs d'acide aminopolycarboxylique Download PDF

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Publication number
WO1991015467A1
WO1991015467A1 PCT/EP1991/000675 EP9100675W WO9115467A1 WO 1991015467 A1 WO1991015467 A1 WO 1991015467A1 EP 9100675 W EP9100675 W EP 9100675W WO 9115467 A1 WO9115467 A1 WO 9115467A1
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chr
group
chelant
formula
metal
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PCT/EP1991/000675
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English (en)
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Pål RONGVED
Jo Klaveness
Harald Dugstad
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Cockbain, Julian, Roderick, Michaelson
Nycomed As
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Publication of WO1991015467A1 publication Critical patent/WO1991015467A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/547—Chelates, e.g. Gd-DOTA or Zinc-amino acid chelates; Chelate-forming compounds, e.g. DOTA or ethylenediamine being covalently linked or complexed to the pharmacologically- or therapeutically-active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/228—Host-guest complexes, clathrates, chelates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
    • C07F13/005—Compounds without a metal-carbon linkage
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • Aminopolycarboxylic acid chelating agents The present invention relates to chelating agents, more particularly aminopolycarboxylic acid chelants, and metal chelates thereof and the use of such chelating agents and chelates in diagnostic imaging, radiotherapy or heavy metal detoxification.
  • metal ions for radiotherapy or diagnostic imaging e.g. X-ray, magnetic resonance imaging (MRI), ultrasound or scintigraphy.
  • diagnostic imaging e.g. X-ray, magnetic resonance imaging (MRI), ultrasound or scintigraphy.
  • APCAs are well known as particularly effective chelants and are described in a wide range of publications, for example in US-A-2407645 (Bersworth), EP-A-71564 (Schering), EP-A-130934
  • EP-A-71564 describes
  • paramagnetic metal chelates for which the chelating agent is nitrilotriacetic acid (NTA),
  • EDTA N,N,N',N'-ethylenediaminetetraacetic acid
  • HEDTA N,N,N',N",N"-diethylenetriamine-pentaacetic 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
  • DOTA 1,4,7,10-tetraazacyclododecanet'etraacetic acid
  • Salutar Inc in for example US-A-4687659, has proposed the use as MRI contrast agents of chelates of paramagnetic metal ions and bisamides of DTPA, in particular DTPA-bismethylamide.
  • the invention provides chelants of formula I (X-CHR 1 ) 2 N-(CHR 1 ) n -A-(CHR 1 ) m -N(CHR 1 -X) 2 (I)
  • A(CHR 1 ) m represents a carbon nitrogen bond
  • each X which may be the same or different, represents a carboxyl group or a derivative thereof or a group R 1 ; each R 1 which may be the same or different, represents a hydrogen atom or an alkoxy group or an alkyl or alkoxy group mono or poly substituted by hydroxy and/or alkoxy groups; and
  • n, m and p are each 2,3 or 4 , preferably 2; with the provisos that in at least two CHR 1 X moieties X is a carboxyl group or a derivative thereof, that at least one group X, and preferably at least 2, is of formula CONR 2 R 3 where R 2 represents a hydrogen atom or an alkyl group optionally mono- or polysubstituted by hydroxy and/or alkoxy groups and R 3 represents an alkoxyalkyl group optionally mono- or polysubstituted by hydroxy and/or alkoxy groups and that where R 3 represents an
  • R 2 represents other than a hydrogen atom, a methoxy or methoxyethyl group or at least one R 1 group in a (CHR 1 X), (CHR 1 ) m , (CHR 1 ) n or (CHR 1 ) p moiety is other than hydrogen, preferably a hydrophilic group and especially preferably an R 1 in a backbone moiety (CHR 1 ) m , (CHR 1 ) n or (CHR 1 ) p is a hydrophilic group and particularly
  • R 2 represents an alkoxyalkyl or hydroxyalkyl group
  • each group CHR 1 X in the compounds of formula I is other than a methyl group
  • (CHR 1 ) p moiety is a hydrophilic group, then at least one
  • X, R 2 and/or R 3 group is hydroxylated, particularly preferably at, at least, the terminal (omega) carbon.
  • alkyl or alkylene moieties in the compounds of the invention preferably contain up to 8, particularly preferably up to 6, carbon atoms.
  • 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.
  • the R 1 groups may be alkoxy, polyalkoxy, hydroxyalkoxy,
  • hydroxypolyalkoxyalkyl or polyhydroxypolyalkoxyalkyl groups but more preferably they will be
  • hydrophilic R 1 groups serve to increase the
  • the compounds of formula I should contain from 1 to 4 hydrophilic R 1 groups.
  • the compounds of 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-hydroxyethyl, methoxymethyl, ethoxymethyl, 2-hydroxyethoxymethyl, methoxyethoxymethyl, (2-hydroxy- ethoxy) ethyl, etc groups.
  • R 2 groups may be a hydrogen atom, or alkyl, hydroxyalkyl,
  • hydroxypolyalkoxyalkyl or polyhydroxypolyalkoxyalkyl groups and the R 3 groups may be hydroxyalkoxyalkyl, polyhydroxyalkoxyalkyl, hydroxypolyalkoxyalkyl or polyhydroxypolyalkoxyalkyl groups.
  • alkyl and alkylene moieties having up to 4 carbon atoms are especially preferred. Examples of such groups include hydroxymethyl, 2-hydroxyethyl,
  • the carboxyl derivatives which may be represented by the groups X in the compounds of formula I may include for example, amide groups, ester groups and carboxylate salt groups, for example groups of formulae
  • CONR 11 2 (where each R 11 , which may be the same or different, i .s a group R 2 or R 3 ; or. NR 11 2 is a nitrogen attached 5 to 7 membered heterocyclic ring optionally containing a nitrogen, oxygen or sulphur atom as a further ring heteroatom and optionally substituted by one or more hydroxy and/or R 1 groups), COOR 12 (where R 12 is a hydrogen atom or an optionally hydroxylated, optionally alkoxylated alkyl group) and -COOM (wherein
  • M + is a monovalent cation or a fraction of a polyvalent cation, for example an ammonium or substituted ammonium ion or a metal ion, for example an alkali metal or alkaline earth metal ion). Particularly preferably, M + is a cation deriving from an organic base, for example meglumine.
  • the number of the ion-forming X groups in the compounds of formula I be chosen to equal the valency of the metal species to be chelated by the compound of formula I.
  • the chelating agent of formula I preferably contains three ion-forming X groups, for example -COOH or -COOM. In this way, the metal chelate will be formed as a neutral species, a form preferred since the osmotic pressures in
  • R 2' is an alkyl group, particularly a C 1 -3 alkyl group, and R 3 is as hereinbefore defined, in particular a hydroxyalkoxyalkyl group, particularly one in which the alkyl or alkylene moieties contain 1 to 3 carbons.
  • the terminal amine nitrogens each carry one group CHR 1 X in which X represents an amide group CONR 2 R 3 .
  • one or more of the remaining X groups in the molecule may represent a tertiary amide of formula -NR 11 where each R 11 represents an alkyl, hydroxyalkyl or optionally hydroxylated alkoxyalkyl group or NR 2 11 represents a nitrogen-attached
  • heterocyclic group as mentioned above, e.g. a group
  • Particularly preferred compounds according to the invention include the chelants of formula II
  • the other is a hydrogen atom or a hydroxy (C 1-4 ) alkyl
  • R 2 R 3 NCOCH 2 (HOOCCH 2 )NCH 2 CH 2 N(CH 2 COOH) CH 2 CH 2 N(CH 2 COOH) CH 2 CONR 2 R 3
  • R 2 R 3 NCOCH 2 (HOOCCH 2 )NCH 2 CH 2 N(CH 2 COOH) CH 2 CHN(CH 2 COOH) CH 2 CONR 2 R 3
  • R 2 R 3 NCOCH 2 (HOOCCH 2 ) NCHCH 2 N ( CH 2 COOH) CH 2 CHN ( CH 2 COOH) CH 2 CONR 2 R 3
  • metal chelates and salts thereof are also particularly useful as metal chelates and salts thereof.
  • the chelant compounds of the invention may be any organic compound that has a wide range of properties.
  • the chelant compounds of the invention may be any organic compound that has a wide range of properties.
  • the invention provides a process for the preparation of compounds of formula I, said process comprising at least one of the following steps: i) reacting a corresponding amine to introduce a CHR 1 X moiety at an amine nitrogen;
  • Process step (i) may conveniently be performed by reacting a compound essentially of formula I but having at least one hydrogen atom or other readily displaceable group or moiety in place of a CHR 1 X moiety and
  • nucleophilically displaceable group such as a halogen atom, preferably a bromine atom; and R 1' and X", which are not both hydrogen atoms, are as defined for R 1 and X or are groups convertible thereto, for example by deprotection).
  • protecting groups conventional protecting groups may be used, for example groups such as are described by T.W. Greene in "Protective Groups in Organic Synthesis", John Wiley & Sons, 1981.
  • benzyl protecting groups which are stable over a wide pH range but are readily removed by hydrogenolysis as described by T.W. Greene.
  • Polyhydroxyalkyl groups may for example alternatively be protected in the form of cyclic polyether groups, for example as 2,2-dimethyl-1,3-dioxacyclopent-4-yl groups, as such cyclic polyether groups can be opened by acid hydrolysis to leave the unprotected polyhydroxyalkyl group.
  • introduction of a -CHR 1 X moiety may be effected by reacting an amine of formula VIII R N-(CHR 1' ) n -A"-(CHR 1' ) m -NR (VIII)
  • R 14 is a hydrogen atom or a CHR 1' X" group; X" and R 1' are as defined above; and A" is a group NR 14 or
  • n is a carbon nitrogen bond; with the provisos that at least one R 14 is a hydrogen atom or a readily displaceable group or NR is a cyclic
  • step (i) is particularly preferably effected by reacting a compound of formula VII (in which any hydroxyl moieties are protected) with bromoacetic acid or a derivative thereof, for example the lithium salt or an ester, followed by deprotection of the hydroxyl moieties and amidation.
  • HalCH 2 CHOHCH 2 OH or R 6 -O-CH 2 -CHHal-COOH wherein Hal is a halogen atom such as a bromine atom and R 6 is a
  • each R 1" is a protected R 1 group, e.g. a protected hydroxyalkyl group for example a -CH 2 -O-
  • 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" moieties are preferably in the form of cyclic polyethers.
  • Amidation of the corresponding carboxyl compounds to produce the compounds of formula I can be performed in a conventional manner, e.g. as described by Salutar in US-A-4687659 or by Schering in EP-A-130934.
  • a solution of the amine in a solvent such as water, dipolar aprotic solvents, such as acetonitrile, N-methylpyrrolidone, N-methylmorpholine,
  • sulfoxide, tetrahydrofuran and the like or mixtures thereof is prepared.
  • the anhydride is added in portions or optionally dissolved in a dipolar aprotic anhydrous solvent such as acetonitrile, N-methylpyrrolidone, N- methylmorpholine, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran and the like or mixtures thereof.
  • the reaction mixture is stirred under nitrogen atmosphere for a period ranging between 0.5 hour and 3 days, preferably between 1 hour and 24 hours.
  • the reaction temperatures generally range between about 0°C and 100°C, temperatures of about 20°C to 80°C being preferred.
  • solvents with a low boiling point 100°C or less
  • the reaction mixture is evaporated to dryness and the product is isolated.
  • a mixture of diethylether and chloroform may be added to precipitate the product.
  • Chelants of formula I may be used as the basis for bifunctional chelants or for polychelant compounds, that is compounds containing several independent chelant groups, by substituting for 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 itself be attached 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 itself be attached 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 itself be attached 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
  • Such macromolecular derivatives of the compounds of formula I and the salts and metal chelates thereof form a further aspect of the present invention.
  • macromolecule or backbone polymer may be effected by any of the conventional methods such as the carbodiimide method, the mixed anhydride procedure of Krejcarek et method, the mixed anhydride procedure of Krejcarek et al. (see Biochemical, and Biophysical Research
  • Formation of salts and chelates of the chelants of the invention may again be performed in a conventional manner.
  • the chelating agents of the present invention are particularly suitable for use in detoxification or in the formation of metal chelates, chelates which may be used for example in or as contrast agents for in vivo or in vitro magnetic resonance (MR), X-ray or ultrasound diagnostics (e.g. MR imaging and MR spectroscopy), or scintigraphy or in or as therapeutic agents for
  • Salts or chelate complexes of the compounds of the invention containing heavy metal ions are particularly useful in diagnostic imaging or therapy. Especially preferred are salts or complexes with metals of atomic numbers 20-32, 42-44, 49 and 57 to 83, particularly Gd, Dy and Yb.
  • the chelated metal ion is particularly suitably a
  • paramagnetic ion the metal conveniently being a
  • transition metal or a lanthanide preferably having an atomic number of 21-29, 42, 44 or 57-71.
  • Metal chelates in which the metal species is Eu, Gd, Dy, Ho, Cr, Mn or Fe are especially preferred and Gd 3+ , Mn 2+ and Dy 3+ are particularly preferred.
  • the paramagnetic metal species is conveniently non-radioactive as
  • 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 be used.
  • the chelating agent may be in the form of a metal chelate with for example 67 Cu, 153 Sm or 90 Y.
  • the chelating agent For use in detaxification of heavy metals, 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.
  • the metal chelate carries an overall charge, such as is the case with the prior art Gd DTPA, it will conveniently be used in the form of a salt with a physiologically acceptable counterion, for example an ammonium, substituted ammonium, alkali metal or alkaline earth metal cation or an anion deriving from an
  • meglumine salts are particularly preferred.
  • the present invention provides a diagnostic or therapeutic agent comprising a metal chelate, whereof the chelating entity is the residue of a compound of formula I or salt thereof, together with at least one pharmaceutical or veterinary carrier or excipient, or adapted for formulation
  • the present invention provides a detoxification agent comprising a chelating agent according to the invention in the form of salt with a physiologically acceptable counterion, 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 diagnostic and therapeutic agents of the present invention may be formulated with conventional pharmaceutical or veterinary formulation aids, for example stabilizers, antioxidants, osmolality adjusting agents, buffers, pH adjusting agents, etc. and may be in a form suitable for parenteral or enteral
  • agent of the present invention may be in a conventional
  • compositions such as a tablet, capsule, powder, solution, suspension, dispersion, syrup, suppository, etc; however, solutions, suspensions and dispersions in physiologically acceptable carrier media, for example water for injections, will generally be preferred.
  • the compounds according to the invention may therefore be formulated for administration using
  • Suitable additives include, for example, physiologically
  • biocompatible buffers as for example, tromethamine hydrochloride
  • additions e.g., 0.01 to 10 mole
  • chelants such as, for example, DTPA, a DTPA-bisamide or non-complexed chelants of formula I
  • calcium chelate complexes as for example calcium DTPA, CaNaDTPA-bisamide, calcium salts or chelates of chelants of formula I
  • additions e.g., 1 to 50 mole percent
  • calcium of sodium salts for example, calcium chloride, calcium ascorbate, calcium gluconate or calcium lactate combined with metal chelate complexes of chelants formula I and the like.
  • a small amount of soluble chelate may be mixed with one or more of the inactive ingredients traditionally present in oral solutions and/or
  • the most preferred mode for administering metal chelates as contrast agents is parenteral, e.g.,
  • parenterally administrable forms e.g., intravenous solutions
  • Suitable vehicles include aqueous vehicles customarily used for administering parenteral solutions such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium
  • solutions can contain preservatives, antimicrobial agents, buffers and antioxidants conventionally used for parenteral solutions, excipients and other additives which are compatible with the chelates and which will not interfere with the manufacture, storage or use of products.
  • the diagnostic or therapeutic agent comprises a chelate or salt of a toxic metal species, e.g. a heavy metal ion
  • a chelate or salt of a toxic metal species e.g. a heavy metal ion
  • the diagnostic agent of the present invention if in solution, suspension or dispersion form, will generally contain the metal chelate at concentration in the range l micromole to 1.5 mole per litre, preferably 0.1 to 700mM.
  • the diagnostic agent may however be supplied in a more concentrated form for dilution prior to administration.
  • diagnostic agent of the invention may conveniently be administered in amounts of from 10 -3 to 3 mmol of the metal species per kilogram of body weight, e.g. about 1 mmol Dy/kg bodyweight.
  • the dose of the contrast agent should generally be higher and for scintigraphic examination the dose should generally be lower than for MR examination.
  • conventional dosages may be used for radiotherapy and detoxification.
  • the present invention provides a method of generating an image of the human or non-human animal body, which method comprises
  • the present invention provides a method of radiotherapy practised on the human or non-human animal body, which method comprises
  • the present invention provides a method of heavy metal detoxification
  • a chelating agent according to the invention in the form of a salt with a physiologically acceptable counterion.
  • the present invention also provides the use of the compounds, especially the metal chelates, according to the
  • the present invention provides a process for the preparation of the metal chelates of the invention which process comprises admixing in a solvent a chelant 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 chelant of formula I or a salt 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
  • 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 acid from a) is taken up in methanol saturated with ammonia and stirred overnight at ambient temperature.
  • 6-Carboxymethyl-3,9-bis[N-methyl-(5-hydroxy-3- oxapentylcarbamoylmethyl)]-3,6,9-triazaundecane diacid (0.50 g, 0.84 mmol) was dissolved in water (10 ml).
  • a neutral suspension of bismuth(III) hydroxide is prepared by neutralisation of a solution of bismuth (III) chloride (0.12 g, 0.37 mmol, 4 ml) with sodium
  • Example 2 6-Carboxymethyl-3,9-bis[N-methyl-(5-hydroxy-3- oxapentylcarbamoyImethyl)]-3,6,9-triazaundecane diacid (1.79 g, 3 mmol) (Example 2) was dissolved in water (15 ml). The pH was adjusted to 7 by careful addition of 1 M sodium hydroxide, water was added to 20 ml, the solution was filtered and filled into a 20 ml vial. The vial was autoclaved.
  • the solution contained 0.15 mmol of the trisodium salt of 6-carboxymethyl-3,9-bis[N-methyl-(5-hydroxy-
  • the solution is for treatment of acute or chronic poisoning by heavy metals such as lead.
  • 6-carboxymethyl-3,9-bis(5-hydroxy-3-oxapentylcarbamoyImethyl)-3,6,9-triazaundecane diacid is for scintigraphic examination of organs such as the brain and kidneys.
  • the chelate is also useful for the study of kidney function.
  • Example 18 Preparation of a solution containing the sodium salt of the zinc(II) chelate of 6-carboxymethyl-3,9-bis- (5-hydroxy-3-oxapentylcarbamoyImethyl)-3,6,9- triazaundecane diacid 6-Carboxymethyl-3,9-bis(5-hydroxy-3-oxapentylcarbamoyImethyl)-3,6,9-triazaundecane diacid (1.14 g, 2 mmol) (Example 1) and zinc(II) carbonate (0.25 g, 2 mmol) were refluxed for 12 hours in water (15 ml). The mixture was cooled to ambient temperature, the pH was adjusted to 6 by careful addition of 1 M sodium
  • the solution is for the treatment of acute or chronic poisoning by heavy metals or radioactive metals such as Plutonium.
  • Example 19
  • 6-carboxymethyl-3,9-bis(5-hydroxy-3-oxapentylcarbamoyImethyl)-3,6,9-triazaundecane diacid (7.22 g, 10 mmol) (Example 9) was added, water was added to 20 ml, the solution was filtered and filled into a 20 ml vial. The vial was autoclaved.
  • the solution contained 0.5 mmol of gadolinium (III) chelate of 6-carboxymethyl-3,9-bis(5-hydroxy-3- oxapentylcarbamoyImethyl)-3,6,9-triazaundecanediacid per ml.

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Abstract

L'invention décrit des agents chélateurs d'acide aminopolycarboxylique, ainsi que leurs chélates métalliques, pouvant être utiles à la production d'agents destinés à la radiothérapie, à l'imagerie diagnostique ou à la détoxication de métaux lourds.
PCT/EP1991/000675 1990-04-09 1991-04-09 Agents chelateurs d'acide aminopolycarboxylique WO1991015467A1 (fr)

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GB9007967.4 1990-04-09
GB909007967A GB9007967D0 (en) 1990-04-09 1990-04-09 Compounds

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WO1991015467A1 true WO1991015467A1 (fr) 1991-10-17

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992017215A1 (fr) * 1990-03-28 1992-10-15 Nycomed Salutar, Inc. Milieux de contraste
US5482699A (en) * 1991-03-27 1996-01-09 Nycomed Salutar Inc. Multinuclear complexes for x-ray imaging
WO1997014413A1 (fr) * 1995-10-20 1997-04-24 Eastern Virginia Medical School Derives de chelate utilises comme protecteurs contre les lesions tissulaires
WO1998047858A1 (fr) * 1997-04-21 1998-10-29 Eastern Virginia Medical School Derives de chelates, utilises comme protecteurs contre les lesions tissulaires
WO2007082996A1 (fr) * 2006-01-17 2007-07-26 Wallac Oy Réactifs de marquage neutres et conjugués dérivés desdits réactifs
CN106008254A (zh) * 2016-05-27 2016-10-12 南京正大天晴制药有限公司 一种卡地酰胺钠的精制工艺
US20220072033A1 (en) * 2019-02-04 2022-03-10 Viktor Anatolievich MATKEVICH Acid-mineral composition for an enteral solution

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DE3324236A1 (de) * 1983-07-01 1985-01-10 Schering AG, 1000 Berlin und 4709 Bergkamen Neue komplexbildner
EP0130934B1 (fr) * 1983-07-01 1987-08-05 Schering Aktiengesellschaft Agents complexants, complexes et sels complexes
EP0263059A2 (fr) * 1986-09-26 1988-04-06 Schering Aktiengesellschaft Amides complexes
EP0299795A2 (fr) * 1987-07-16 1989-01-18 Nycomed As Acides aminopolycarboxyliques et leurs dérivés
US4826673A (en) * 1985-01-09 1989-05-02 Mallinckrodt, Inc. Methods and compositions for enhancing magnetic resonance imaging
WO1990001024A1 (fr) * 1988-07-19 1990-02-08 Mallinckrodt, Inc. Agents d'imagerie a resonance magnetique

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3324236A1 (de) * 1983-07-01 1985-01-10 Schering AG, 1000 Berlin und 4709 Bergkamen Neue komplexbildner
EP0130934B1 (fr) * 1983-07-01 1987-08-05 Schering Aktiengesellschaft Agents complexants, complexes et sels complexes
US4826673A (en) * 1985-01-09 1989-05-02 Mallinckrodt, Inc. Methods and compositions for enhancing magnetic resonance imaging
EP0263059A2 (fr) * 1986-09-26 1988-04-06 Schering Aktiengesellschaft Amides complexes
EP0299795A2 (fr) * 1987-07-16 1989-01-18 Nycomed As Acides aminopolycarboxyliques et leurs dérivés
WO1990001024A1 (fr) * 1988-07-19 1990-02-08 Mallinckrodt, Inc. Agents d'imagerie a resonance magnetique

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992017215A1 (fr) * 1990-03-28 1992-10-15 Nycomed Salutar, Inc. Milieux de contraste
US5482699A (en) * 1991-03-27 1996-01-09 Nycomed Salutar Inc. Multinuclear complexes for x-ray imaging
US5932190A (en) * 1991-03-27 1999-08-03 Nycomed Salutar, Inc. Multinuclear complexes for X-ray imaging
WO1997014413A1 (fr) * 1995-10-20 1997-04-24 Eastern Virginia Medical School Derives de chelate utilises comme protecteurs contre les lesions tissulaires
US6020373A (en) * 1995-10-20 2000-02-01 Eastern Virginia Medical School Chelate derivatives as protectors against tissue injury
WO1998047858A1 (fr) * 1997-04-21 1998-10-29 Eastern Virginia Medical School Derives de chelates, utilises comme protecteurs contre les lesions tissulaires
WO2007082996A1 (fr) * 2006-01-17 2007-07-26 Wallac Oy Réactifs de marquage neutres et conjugués dérivés desdits réactifs
CN106008254A (zh) * 2016-05-27 2016-10-12 南京正大天晴制药有限公司 一种卡地酰胺钠的精制工艺
CN106008254B (zh) * 2016-05-27 2018-08-21 南京正大天晴制药有限公司 一种卡地酰胺钠的精制工艺
US20220072033A1 (en) * 2019-02-04 2022-03-10 Viktor Anatolievich MATKEVICH Acid-mineral composition for an enteral solution
US12246035B2 (en) * 2019-02-04 2025-03-11 Viktor Anatolievich MATKEVICH Acid-mineral composition for an enteral solution

Also Published As

Publication number Publication date
GB9007967D0 (en) 1990-06-06
AU7664291A (en) 1991-10-30

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