EP0527131A1 - Chelants - Google Patents

Chelants

Info

Publication number
EP0527131A1
EP0527131A1 EP91902213A EP91902213A EP0527131A1 EP 0527131 A1 EP0527131 A1 EP 0527131A1 EP 91902213 A EP91902213 A EP 91902213A EP 91902213 A EP91902213 A EP 91902213A EP 0527131 A1 EP0527131 A1 EP 0527131A1
Authority
EP
European Patent Office
Prior art keywords
group
groups
formula
compound
salt
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.)
Withdrawn
Application number
EP91902213A
Other languages
German (de)
English (en)
French (fr)
Inventor
Joan F. Carvalho
Shaun P. Crofts
Scott M. Rocklage
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.)
Amersham Health Salutar Inc
Original Assignee
Nycomed Salutar Inc
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 Salutar Inc filed Critical Nycomed Salutar Inc
Publication of EP0527131A1 publication Critical patent/EP0527131A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray 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
    • A61K49/06—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
    • A61K51/0482—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 chelates from cyclic ligands, e.g. DOTA
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • 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

  • the present invention relates to certain novel chelating agents, in particular polyamines, and to their uses, especially their medical uses.
  • compositions as antidotes for poisonous heavy metal species and as diagnostic agents for the administration of metal species (e.g. ions or atoms) for diagnostic techniques such as X-ray, magnetic resonance imaging (MRI) or ultrasound imaging or scintigraphy.
  • metal species e.g. ions or atoms
  • diagnostic techniques such as X-ray, magnetic resonance imaging (MRI) or ultrasound imaging or scintigraphy.
  • Polyamine chelating agents for example aminopoly- (carboxylic acid or carboxylic acid derivative)
  • APCA chelating agents and their metal chelates
  • EP-A-71564 describes
  • paramagnetic metal chelates for which the chelatingagents are nitrilotriacetic acid (NTA),
  • N,N,N',N'-ethylenediamine-tetraacetic acid EDTA
  • N-hydroxyethyl-N,N',N'-ethylenediaminetriacetic acid HEDTA
  • DTPA N,N,N',N",N"- diethylenetriaminepentaacetic acid
  • N-hydroxyethyl-iminodiacetic 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 administration of that paramagnetic species.
  • the paramagnetic species e.g. Gd(III)
  • Gd DTPA 1,4,7,10- tetraazacyclododecanetetraacetic acid
  • each X independently represents an oxygen or sulphur atom or a group of formula NA, or
  • E represents COH, NR 2 , O or S
  • each A independently represents a hydrogen atom or a group (CR 2 R 3 ) p Y, (CR 2 R 3 ) n N[(CR 2 R 3 ) p Y] 2 or
  • each Y independently represents a group COZ, SO 2 Z, POZ 2 ,
  • each Z independently represents a group OR 2 or NR 2 R 2 ; each G is a 3 or 4 membered chain of carbon atoms and optionally a nitrogen, oxygen or sulphur atom; each J is a 2 or 3 membered chain of carbon atoms and optionally a nitrogen, oxygen or sulphur atom; each n is an integer of 2 to 4, preferably 2 or 3 or in a group (CR 2 R 3 ) n attached to a moiety R 1 which represents a hydrogen atom or a group R 4 n may also be zero or 1;
  • n is an integer of 3 to 8 , preferably 3 to 6;
  • p is an integer of 1 to 3, preferably 1;
  • each R 1 represents a hydrogen atom or a group R 4 or together both groups R 1 represent a carbon-carbon bond; each R 2 independently represents a hydrogen atom or a C 1-8 alkyl group optionally mono- or poly-substituted by hydroxyl or C 1-8 alkoxy groups or NR 2 R 2 may together represent a nitrogen-attached 5 to 7 membered saturated heterocyclic ring optionally containing as a further ring heteroatom a nitrogen, oxygen or sulphur atom and optionally substituted by a group R 4 ;
  • each R 3 independently represents a hydrogen atom or a C 1-8 alkyl or C 1-8 alkoxy group optionally mono or poly substituted by hydroxy or C 1-8 alkoxy groups;
  • each R 4 independently represents a hydrogen atom, a halogen atom, a hydroxyl group, an optionally mono- or poly-hydroxylated C 1-8 alkyl, C 1-8 alkoxy, (C 1-8 alkoxy)-C 1-8 alkyl or poly(C 1-8 alkoxy)-C 1-8 alkyl group, a sulphonate group or a group (CR 2 R 3 ) Y or two groups R 4 on the same ring represent a (CR 2 R 3 ) n-1 [X(CR 2 R 3 ) n ] m-1 (CR 2 R 3 ) n-1 group in which case the said ring may be saturated; with the provisos that at least 2 Y groups, preferably at least 3, are present, that where both groups R 1 together form a bond, m is 4 or 5, all n are 2, one X is
  • heterocyclic group or both R groups together represent a bond and two (CR 2 R 3 ) p Y groups together represent a
  • R 1 groups represent a bond
  • m is 6 or greater and two X groups separated by at least two other X groups are oxygen or sulphur atoms, and preferably that where m is 3 or 4, all n are 2, one X is
  • R 2 , R 3 or R 4 is other than hydrogen or a chelate complex or salt thereof.
  • alkyl In the compounds of the invention, alkyl or
  • alkylene moieties in groups R 1 to R 4 may be straight chained or branched and
  • substituents may themselves optionally be substituted by hydroxyl or alkoxy groups, this may be monosubstitution or polysubstitution and, in the case of polysubstitution, alkoxy or hydroxyl
  • substituents may be carried by alkoxy substituents.
  • the compounds of the invention incorporate one or more hydrophilic R 1 to R 4 groups, these are preferably straight-chained or branched moieties having a carbon atom content of from 1 to 8, especially preferably 1 to 6, carbon atoms.
  • the hydrophilic groups may be alkoxy, polyalkoxy,
  • hydroxylated alkoxyalkyl polyhydroxylated alkoxyalkyl, hydroxylated polyalkoxyalkyl, or polyhydroxylated polyalkoxyalkyl groups. More preferably however they will be monohydroxyalkyl or polyhydroxyalkyl groups.
  • hydrophilic groups serve to increase the hydrophilic groups
  • the compounds of formula I should contain at least 1, conveniently from 1 to 4, and preferably 1, 2 or 3 such hydrophilic groups.
  • hydrophilic groups the compounds of the invention may thus include for example hydroxymethyl,
  • Particularly preferred compounds of formula I according to the invention include those of monocyclic structure containing at least 6 ring heteroatoms, those of fused bicyclic structure containing at least two ring heteroatoms in the smaller ring, and those of fused tricyclic or higher polycyclic structure.
  • the aromatic groups comprised by X groups preferably are pyridine, pyrazine, pyrrole, furan, phenol, pyrimidine or
  • thiophene rings especially pyridine rings.
  • E is COH, e.g. where X comprises a phenol group, it is especially preferred that an electron withdrawing R 4 substituent (e.g. a lower alkyl or halogen such as chlorine or methyl) should be present on the ring, preferably at the para position to the hydroxyl group.
  • R 4 substituent e.g. a lower alkyl or halogen such as chlorine or methyl
  • adjacent X groups preferably do not both comprise such aromatic groups.
  • adjacent X groups preferably do not both comprise such aromatic groups.
  • piperazine or 1,4-diazacycloheptane rings, especially piperazin-1,4-diyl groups.
  • one, two or three X groups should comprise such aromatic groups, the remaining X groups, or all but one remaining X group being
  • groups X comprising no ionizing group Y should be non-adjacent particularly that they should adopt opposed positions in macrocyclic chelants, e.g. as the 1st and 5th X groups in an 8 X ring.
  • Particularly preferred compounds of formula I include those of formulae lb and Ic
  • v 0,1,2,3 or 4 and X 2 is O or S).
  • W is CHR4 , NR 4 , O or S, where q is zero W preferably being CHR 4 .
  • CONCHR 4 CHR 4 W(CHR 4 ) CHR 4 , CONHR 2" or CONR 2" 2 (where R 2" is an alkyl or mono or poly hydroxyalkyl group, for example a C 1 -6 alkyl group optionally carrying 1, 2, 3 or 4 hydroxyl groups). Particularly preferably, in the case where R 1 are not bonds terminal X groups will comprise an aromatic heterocyclic group.
  • the compounds of formula I can conveniently form salts or chelates in which Y represents -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).
  • M + is a cation deriving from an organic base, for example meglumine or lysine.
  • M + is a cation deriving from an organic base, for example meglumine or lysine.
  • the number of the ion-forming groups Y in the compounds of formula I be chosen to egual the valency of the metal species to be chelated by the compound formula I.
  • the compound of formula I preferably contains three or six ion-forming Y groups, for example -COOH (or -COOM).
  • the metal chelate will be formed as a neutral species, a form preferred since the osmolalities in concentrated solutions of such compounds are low and since their toxicities relative to their ionic analogues are significantly reduced.
  • each R 2 represents a hydrogen atom or a mono- or poly-hydroxylated alkyl group
  • Y represents a group of formula COZ
  • Z represents a hydroxyl group or a group NHR 2 ) and metal chelates and salt thereof.
  • Especially preferred compounds according to the invention include those of the following formulae Im to
  • R 2 " is hydrogen or methyl
  • R 6 is a carboxymethyl group or derivative thereof, e.g. CH 2 COOH
  • each R 4" may also represent a C 1-4 hydroxyalkyl group) and the metal chelates and the salts thereof.
  • Particularly preferred compounds according to the invention include those of formulae Ij to lo wherein R 6 is CH 2 COOH and the chelates, e.g. with Gd 3+ , and salts thereof.
  • the invention also provides a process for the preparation of the compounds of the invention, said process comprising one or more of the following steps:
  • R 1' to R 3' are as defined for R 1 to R 3 or are protected R 1 to R 3 groups, and X' is a group X or a protected group X with the proviso that at least one X ' group is of formula NH or (CR 2' R 3 ' ) p NH 2 ) with a compound of formula III
  • LV-(CR 2' R 3 ' ) p -Y' (III) (where Y' is a group Y or a protected group Y, R 2' and R 3' are as hereinbefore defined and Lv is a leaving group for example a halogen atom, e.g. bromine or chlorine or a tosylate group) and if necessary
  • the compounds of formula II are known from the literature or may be prepared in a number of ways using techniques known from the literature or analogous to literature described techniques. Thus for example such compounds may be prepared by condensing mono or
  • R 2 , R 3 , and R 4' are as defined for R 2 to R 4 or are protected R 2 to R 4 groups and R 12 is hydrogen, an amine protecting group or a group (CR 2' R 3' ) n-1 COR 3' ) with a linking molecule of formula V
  • R 2' and R 3' are as hereinbefore defined, mid-chain X" groups, if any are groups X' and end of chain X" groups are oxygen, sulphur or ring nitrogen atoms or, preferably, NH groups) followed if necessary by removal of any protecting groups and if necessary by reduction.
  • the compounds of formula II may also be prepared by activating starting compounds of formula V, e.g. by tosylation, and condensing the product with a mono or bifunctional heterocyclic compound of formulae VI or VII
  • R 13 is hydrogen, an amine protecting group or a group (CR 2' R 3, ) Lv)
  • linear or cyclic compounds of formula II can be prepared using the following reaction schemes.
  • group may be prepared by condensing a linear compound having active groups at each end with a compound of formula
  • the active linear compound of formula XII may of course be prepared by other routes, e.g.
  • macrocyclic chelants i.e. compounds wherein two R 4 groups on a cyclic X group together represent a group (CR 2 R 3 ) n-1 [X(CR 2 R 3 ) n ] m-1 (CR 2 R 3 ) n-1 - can be prepared for example by a condensation equivalent to those of the schemes above using a tetrafunctional precursor for the cyclic X group and bifunctional co-reagents. It may be desirable to utilize aromatic tetrafunctional precursors and subsequently to reduce the product, e.g. by high pressure catalytic hydrogenation.
  • compounds of formula II may be prepared by the following scheme:
  • step (a) To introduce a (CR 2 R 3 ) Y group onto a compound of formula II using the precedure of step (a) may be effected in an aqueous, preferably basic, medium, for example by using a halocarboxylic acid Hal(CR 2' R 3' ) p -
  • Amide derivatives of formula I may be produced from the oligo acids by methods analogous to those of
  • EP-A-250358 or of EP-A-299795 Furthermore hydrophilic substituents on the skeleton of the linear or cyclic chelants of formula I may be introduced by methods analogous to those of EP-A-299795.
  • Chelants of formula I may be used as the basis for bifunctional chelants or for polychelant compounds, that is compounds containing several independant chelant groups, by substituting for one Y or R 1 to R 4 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 to produce a bifunctional-polychelant.
  • 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 to produce a bifunctional-polychelant.
  • Such macromolecular derivatives of the compounds of formula I and the metal chelates and salts 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 al. (see Biochemical and Biophysical Research
  • Salt and chelate formation may be performed in a conventional manner.
  • the chelating agents of the formula I 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 a heavy metal atom or ion 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,
  • the chelated metal species is especially Gd, Dy and Yb.
  • the chelated metal species is especially Gd, Dy and Yb.
  • the metal conveniently being a transition metal or a lanthanide, preferably having an atomic number of 21-29, 42, 44 or 57-71.
  • Gd, Dy, Ho, Cr, Mn or Fe are especially preferred and Gd 3+ , Mn 2+ and Dy 3+ are particularly preferred.
  • Chelates of ions of these metals specifically listed above with chelants of formula I (defined as above with the exclusion of the second proviso) or their salts with physiologically tolerable counterions are particularly useful for the diagnostic imaging procedures mentioned herein and they and their use are deemed to fall within the scope of the invention and references to chelates of compounds of formula I herein are consequently to be taken to include such chelates.
  • 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 For use in scintigraphy and radiotherapy, the chelated metal species must of course be radioactive and any conventional complexable radioactive metal isotope, such as 99mTc or 111 In for example, may be used.
  • the chelating agent may be in the form of a metal chelate with for example 153 Sm, 67 Cu or 90 Y.
  • the chelating agent For use in detoxification of heavy metals, the chelating agent must be in weak complex or 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 (e.g. calcium) cation or an anion deriving from an inorganic or organic acid.
  • a physiologically acceptable counterion for example an ammonium, substituted ammonium, alkali metal or alkaline earth metal (e.g. calcium) cation or an anion deriving from an inorganic or organic acid.
  • meglumine salts are particularly preferred.
  • the present invention provides a diagnostic or therapeutic composition
  • a metal chelate whereof the chelating entity is the residue of a compound of formula I 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 a weak complex or salt with a physiologically acceptable counterion, together with at least one pharmaceutical or veterinary carrier or excipient, or adapted for
  • the diagnostic and therapeutic agents of the present invention may be formulated with conventional pharmaceutical or veterinary formulation aids, for example stablizers, antioxidants, osmolality adjusting agents, buffers, pH adjusting agents, etc. and may be in a form suitable for parenteral or enteral
  • compositions of the present invention may be in conventional
  • acceptable carrier media for example water for
  • 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,
  • DTPA-bisamide or non-complexed chelants of formula I or calcium chelate complexes (as for example calcium DTPA, CaNaDTPA-bisamide, calcium salts or chelates of chelants of formula I), or, optionally, additions (e.g., 1 to 50 mole percent) of 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
  • 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 1 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
  • the 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 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, ultrasound or scintigraphic image of at least a part said body.
  • 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 weak complex or 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 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, acetate or carbonate.
  • a solvent e.g. the sodium salt
  • an at least sparingly soluble compound of said metal for example a chloride, oxide, acetate 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 weak complex or salt with a
  • physiologically acceptable counterion together with at least one pharmaceutical or veterinary carrier or excipient.
  • ethanol/water (1/1) is placed in a 100 mL three neck round-bottom flask equipped with two addition funnels, pH electrode, thermometer, and stir bar.
  • NaOH 199 mg, 4.98 mmol
  • BrCH 2 CO 2 H 346 mg, 2.49 mmol
  • the solution of NaOH is added to the amine solution to bring the pH to 10.5.
  • the temperature is raised to 50°C and the
  • Chloroacetic acid (24 g; 254 mmol) in water (500 ml) was adjusted to pH 7 with NaOH solution. This was added dropwise to a solution of [12]N 4 (py) (15.00 g; 727 mmol) in water maintained at a temperature of 95°C. During the addition, the pH is maintained at pH 9-10 by the addition of 1N NaOH solution.
  • reaction mixture was adjusted to pH 3 using 1N HCl solution and concentrated to a solid.
  • N,N'-Bis(N-tosylaminoethyl)piperazine (4.0 g, 8.7 mmol) was dissolved in 200 ml of DMF, and Cs CO (6.0 g, 18.4 mmol) was added. The mixture was stirred under a nitrogen atmosphere at 110°C for 2 hours before
  • N,N-bis(tosyloxyethyl) amine (4.9 g, 8.6 mmol - prepared as described by Guerbet in EP-A-287465) in 80 ml of DMF was added dropwise over 0.5 hour. Stirring at 110°C was maintained for an additional 3 hours. The reaction mixture was evaporated to dryness. The resulting solid was stirred in CH 2 Cl 2 overnight. Undissolved material was filtered, and the solution was evaporated to
  • HBr in acetic acid (32% w/w, 82 ml) was added to a mixture of phenol (4.3 g, 46 mmol) and 4,7,10- tris(tosyl)-1,4,7,10,13-pentaazabicyclo[11.2.2]heptadecane (2.06 g, 3 mmol).
  • the solution was stirred at 70°C for 24 hours. The temperature was raised to 85°C, and stirring was continued for 5.5 hours. The solution was allowed to cool to ambient temperature.
  • Precipitated solid was collected and triturated with ether and cold ethanol. The solid was then dissolved in water and passed down a Dowex AGI-8X column. Water was removed. Drying of the solid overnight yielded 0.32 g
  • N, N''-bis(pyrid-2-yl- methyl) diethylenetriamine (23.6 g, 82.6 mmol) and diisopropylethylamine (53.4 g, 0.4 mol) in 1.2 L of methylene chloride at ambient temperature was added dropwise t-butylbromoacetate (50 g, 0.2 mol) in 300 mL of methylene chloride. After being stirred for 24 hours, the solution was evaporated to dryness and placed under vacuum for 2 hours to remove excess
  • step (b) The tris(t-butylcarboxymethyl)ester (24.89g, 0.1 mol) of step (b) was dissolved in a solution of 600 mL of methylene chloride containing 380 mL of trifluoroacetic acid. The solution was stirred for 48 hours, evaporated under reduced pressure and diluted with 50 mL of water. This solution was applied to 200 mL of AG50-X8 (H + form, 100-200 mesh) and after washing with water until
  • the product was eluted with 1N NH 4 OH. After removal of NH 4 OH solution, the product was taken up in 24 mL of water, and the solution was adjusted to pH 10 and then applied to AG1-X8 (acetate, 100-200 mesh). The column was washed with three bed volumes of water and the product eluted with 2 N HOAc to give 12.0 g (69%) of the title product after several lyophilizations.
  • the title compound is prepared by reaction of 2,6- diformyl-pyridine with 1,4-di(2-aminoethyl) piperazine by the method of scheme (G), followed by alkylation with bromoacetic acid.
  • the title compound is prepared by reaction of 2,6- diacetyl-pyridine with 1,4-di(2-aminoethyl)pipperazine by the method of scheme (G), followed by alkylation with bromoacetic acid.
  • the title compound is prepared by reaction of 2,6- diformyl-pyridine with 1,4-di(3-aminopropyl)piperazine by the method of scheme (G), followed by alkylation with bromoacetic acid.
  • the title compound is prepared by reaction of 2,6- diacetyl-pyridine with 1,4-di(3-aminopropyl)piperazine by the method of scheme (G), followed by alkylation with bromoacetic acid.
  • the tetraimine:bisimine/bisimidazolidine (3.00 g, 7.42 mmol) was added to a suspension of sodium borohydride (1.17 g, 31 mmol) in 100 mL of ethanol. The mixture was stirred for 1 hour at ambient temperature, refluxed for 0.5 hours, and then stirred overnight at ambient
  • Example 1 Example 1
  • 5 mL of a 100 mM aqueous solution of GdCl 3 are mixed thoroughly and the pH is adjusted to 6.9 with 1N NaOH to yield the title product.
  • T 1 and T 2 relaxivities of the chelate, in mM -1 s -1 measured in water at 10MHz and 37 °C were respectively 6.99 and 6.23.
  • Example 20 The title compound is prepared analogously to that of Example 16 by reaction of the chelant of Example 2 with MnCl 2 .
  • Example 20 The title compound is prepared analogously to that of Example 16 by reaction of the chelant of Example 2 with MnCl 2 .
  • N,N"-Bis(pyrid-2-yl-methyl)diethylenetriamine-N,N'N"- triacetic acid (2,8719 g, 6.25 mmol) (the compound of Example 6) and gadolinium oxide (1.1328 g, 3.125 mmol) were combined in 15 mL of water and heated at 95°C for 4 hours to provide a solution of the desired complex.
  • the title compound is prepared analogously to that of Example 16 by reaction of the chelant of Example 6 with CaCl 2 .
  • composition comprising GdBis(py) DTTA and CaNa
  • Example 23 The compounds of Examples 20 and 21 are admixed in a 95:5 (by weight) ratio and dispersed in water for injections to a Gd content of 400 mM.
  • Example 23 The compounds of Examples 20 and 21 are admixed in a 95:5 (by weight) ratio and dispersed in water for injections to a Gd content of 400 mM.
  • the title chelate is prepared analogously to that of Example 16 by reaction of the chelant of Example 7 with GdCl 3 .
  • the title chelate is prepared analogously to that of Example 16 by reaction of the chelant of Example 8 with MnCl 2 .
  • the title chelate is prepared analogously to that of Example 16 by reaction of the chelant of Example 9 with MnCl 2 .
  • Example 27 The title chelate is prepared analogously to that of Example 16 by reaction of the chelant of Example 10 with MnCl 2 .
  • Example 27 The title chelate is prepared analogously to that of Example 16 by reaction of the chelant of Example 10 with MnCl 2 .
  • the title chelate is prepared analogously to that of Example 16 by reaction of the chelant of Example 11 with MnCl 2 .

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Nanotechnology (AREA)
  • Physics & Mathematics (AREA)
  • Radiology & Medical Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biophysics (AREA)
  • Optics & Photonics (AREA)
  • Medical Informatics (AREA)
  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Biotechnology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Acoustics & Sound (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Solid-Sorbent Or Filter-Aiding Compositions (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP91902213A 1990-01-19 1991-01-18 Chelants Withdrawn EP0527131A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB909001245A GB9001245D0 (en) 1990-01-19 1990-01-19 Compounds
GB9001245 1990-01-19

Publications (1)

Publication Number Publication Date
EP0527131A1 true EP0527131A1 (en) 1993-02-17

Family

ID=10669570

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91902213A Withdrawn EP0527131A1 (en) 1990-01-19 1991-01-18 Chelants

Country Status (10)

Country Link
EP (1) EP0527131A1 (no)
JP (1) JPH05506426A (no)
AU (1) AU7060291A (no)
CA (1) CA2074171A1 (no)
FI (1) FI923286A (no)
GB (1) GB9001245D0 (no)
HU (1) HUT61306A (no)
IE (1) IE910189A1 (no)
NO (1) NO922849L (no)
WO (1) WO1991010645A2 (no)

Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5334371A (en) * 1988-07-20 1994-08-02 Schering Aktiengesellschaft Marcocyclic polyaza bicyclo compounds containing 5 or 6 membered rings, and method for MRI
FR2644785B1 (fr) * 1989-03-24 1991-07-05 Guerbet Sa Nouveaux ligands macrocycliques azotes, procede de preparation, complexes metalliques formes par ces ligands et composition de diagnostic les contenant
US5367080A (en) * 1990-11-08 1994-11-22 Sterling Winthrop Inc. Complexing agents and targeting radioactive immunoreagents useful in therapeutic and diagnostic imaging compositions and methods
CA2072934C (en) * 1991-07-19 2007-08-28 Karl William Aston Manganese complexes of nitrogen-containing macrocyclic ligands effective as catalysts for dismutating superoxide
US5428139A (en) * 1991-12-10 1995-06-27 The Dow Chemical Company Bicyclopolyazamacrocyclophosphonic acid complexes for use as radiopharmaceuticals
HUT67602A (en) * 1991-12-10 1995-04-28 Dow Chemical Co Process for producing bicyclo-polyaza-macrocyclo-carboxylic acid complexes, their conjugates and contrast materials containing them
WO1994026313A1 (en) * 1993-05-06 1994-11-24 The Dow Chemical Company Bicyclopolyazamacrocyclocarboxylic acid complexes, their conjugates, processes for their preparation, and use as contrast agents
MX9207168A (es) * 1991-12-10 1993-12-01 Dow Chemical Co Composiciones orales para inhibir la formacion de placa y de calculos.
AU3246893A (en) * 1991-12-10 1993-07-19 Dow Chemical Company, The Bicycloazamacrocyclophosphonic acid, conjugates, contrast agents and preparation
US5739294A (en) * 1991-12-10 1998-04-14 The Dow Chemical Company Bicyclopol yazamacrocyclophosphonic acid complexes for use as contrast agents
WO1993021957A1 (en) * 1992-05-07 1993-11-11 Sterling Winthrop Inc. Complexing agents and targeting immunoreagents
JPH08509976A (ja) * 1993-05-06 1996-10-22 ザ・ダウ・ケミカル・カンパニー コントラスト剤として使用するためのビシクロポリアザマクロシクロホスホン酸、それらの錯体および複合体ならびにそれらの製造方法
WO1994026315A1 (en) * 1993-05-06 1994-11-24 The Dow Chemical Company Bicyclopolyazamacrocyclocarboxylic acid complexes, their conjugates, processes for their preparation, and use as radiopharmaceuticals
WO1994026755A1 (en) * 1993-05-06 1994-11-24 The Dow Chemical Company Bicyclopolyazamacrocyclophosphonic acid complexes, a process for their preparation, and their conjugates, for use as radiopharmaceuticals
US5476644A (en) * 1994-04-13 1995-12-19 Sterling Winthrop Inc. Cyclic triamine chelating agents
US6207826B1 (en) 1995-03-27 2001-03-27 Isis Pharmaceuticals, Inc. Macrocyclic compounds having nitrogen-containing linkages
US6107482A (en) 1995-03-27 2000-08-22 Isis Pharmaceuticals, Inc. Nitrogenous macrocyclic compounds
US6525041B1 (en) 1995-06-06 2003-02-25 Pharmacia Corporation Manganese or iron complexes of nitrogen-containing macrocyclic ligands effective as catalysts for dismutating superoxide
AU6722496A (en) * 1995-08-17 1997-03-12 Monsanto Company Methods of diagnostic image analysis using metal complexes of nitrogen-containing macrocyclic ligands
AU6896796A (en) 1995-08-17 1997-03-12 Monsanto Company Methods of diagnostic image analysis using bioconjugates of metal complexes of nitrogen-containing macrocyclic ligands
GB9702978D0 (en) * 1997-02-13 1997-04-02 Ciba Geigy Compounds
US6214817B1 (en) 1997-06-20 2001-04-10 Monsanto Company Substituted pyridino pentaazamacrocyle complexes having superoxide dismutase activity
EP3527079A1 (en) 2006-10-12 2019-08-21 Galera Labs, LLC Methods of treating oral mucositis
US20090208421A1 (en) * 2008-02-19 2009-08-20 Dominique Meyer Process for preparing a pharmaceutical formulation of contrast agents
WO2013048965A1 (en) 2011-09-26 2013-04-04 Galera Therapeutics, Llc Methods for treatment of diseases
ES2626582T5 (es) * 2013-04-26 2022-10-07 Guerbet Sa Formulación de producto de contraste y su procedimiento de preparación asociado
MX2018001605A (es) 2015-08-11 2018-09-26 Galera Labs Llc Complejos de anillos macrocíclicos de pentaaza que poseen biodisponibilidad oral.
GB201610738D0 (en) 2016-06-20 2016-08-03 Ge Healthcare As Chelate compounds
IL295620B2 (en) 2017-04-13 2024-01-01 Galera Labs Llc Cancer immunotherapy combined with a macrocyclic ring pentase complex

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2751390A (en) * 1950-09-02 1956-06-19 Dow Chemical Co Di-pyridyl aliphatic alkylene polyamine poly acids
US4899755A (en) * 1985-05-08 1990-02-13 The General Hospital Corporation Hepatobiliary NMR contrast agents
CA1340527C (en) * 1988-05-31 1999-05-04 Lidia Vallarino Macrocyclic complexes of yttrium, the lanthanides and the actinides having peripheral coupling functionalities
DE3825040A1 (de) * 1988-07-20 1990-01-25 Schering Ag, 13353 Berlin 5- oder 6-ring- enthaltende makrocyclische polyaza-verbindungen, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische mittel
FR2644785B1 (fr) * 1989-03-24 1991-07-05 Guerbet Sa Nouveaux ligands macrocycliques azotes, procede de preparation, complexes metalliques formes par ces ligands et composition de diagnostic les contenant

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9110645A2 *

Also Published As

Publication number Publication date
HUT61306A (en) 1992-12-28
FI923286A0 (fi) 1992-07-17
GB9001245D0 (en) 1990-03-21
CA2074171A1 (en) 1991-07-20
NO922849L (no) 1992-09-04
HU9202347D0 (en) 1992-10-28
WO1991010645A2 (en) 1991-07-25
NO922849D0 (no) 1992-07-17
WO1991010645A3 (en) 1991-12-26
IE910189A1 (en) 1991-07-31
JPH05506426A (ja) 1993-09-22
FI923286A (fi) 1992-07-17
AU7060291A (en) 1991-08-05

Similar Documents

Publication Publication Date Title
EP0527131A1 (en) Chelants
US5322681A (en) Chelating compounds
US5650133A (en) Macrocyclic polyaza dichelates linked through ring nitrogens via an amide or ester functionality
US5348954A (en) Heterocyclic chelating agents
EP0722442B1 (en) Polyazacycloalkanes as dichelants
US5869651A (en) Hydrazide derivatives of polyamides and their medical use as chelating agents
US5556968A (en) Polyazamacrocycle chelating agents with amide linkages
KR100376950B1 (ko) 대환식킬레이트제,이들의킬레이트및진단분야에서의이의용도
KR20030022381A (ko) 극성 라디칼과의 퍼플루오로알킬 함유 착물, 이의 제조방법 및 용도
US5972307A (en) Dichelants
WO1991015467A1 (en) Aminopolycarboxylic acid chelating agents
WO1991015466A2 (en) Aminopolycarboxylic acid chelating agents
WO1990008134A1 (en) Chelating agent derivatives
AU646795C (en) Heterocyclic chelating agents
AU644627B2 (en) Chelating compounds
IE911182A1 (en) Chelating agents

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19920710

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

17Q First examination report despatched

Effective date: 19930625

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19980801