Classifications

• • 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
  • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
  • C07D213/40—Acylated substituent nitrogen atom
• • 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
  • 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
  • C07C237/10—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 nitrogen atoms not being part of nitro or nitroso groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
  • C07D211/56—Nitrogen atoms
  • C07D211/58—Nitrogen atoms attached in position 4
• • 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
  • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
  • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2602/00—Systems containing two condensed rings
  • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
  • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
  • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

• 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, and in particular as hepatobiliary contrast agents.
• 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),
• DTPA N-hydroxyethylimino-diacetic acid
• 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 the paramagnetic species.
• EP-A-71564 was the dimeglumine salt of GdDTPA, the use of which as an MRI contrast agent has recently received much attention.
• 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.
• Salutar suggested that for imaging of the liver chelates of DTPA-bis (higher alkyl-amides) might be used.
• EHPG ethylene-bis-(2-hydroxyphenyl glycine)
• HBED bis (2-hydroxybenzyl)-ethylenediamine diacetic acid
• benzo- and dibenzo-DTPA triaza and tetraaza
• GdBOPTA in which the chelant BOPTA has a DTPA structure with one N 3 carboxymethyl replaced by a 2-benzyloxy-1-carboxy-ethyl group.
• GdBOPTA has been described by Vittadini et al in CMR '89, MR19 as a liver-specific MRI contrast agent.
• hydrophilic groupings such as hydroxyl and alkoxy groups.
• n 0 or 1
• R 1 is a group NR 11 R 14 where R 11 is a hydroxyl or alkoxy group or a group -L-Cy or -O-L-Cy, and R 14 is a hydrogen atom, an alkyl group or a group -L-Cy, and the other group R 1 is a hydroxyl group or a group NR 11 R 14 ;
• L is a bond or a straight-chain or branched saturated or unsaturated alkylene group optionally interrupted by a carbocyclic or heterocyclic saturated or unsaturated group and optionally attached to the Cy group by a peptide or carbonyl link and optionally substituted by further Cy groups or by aminocarbonyl, acyl or acylamino groups; and Cy is a cyclic lipophilic group, eg a carbocyclic or heterocyclic saturated or unsaturated group itself optionally carrying one or more fused carbocyclic or heterocyclic saturated or unsaturated rings and optionally substituted by halogen atoms
• alkyl or alkylene moieties in the compounds of the invention preferably contain up to 10, particularly preferably up to 6, carbon atoms.
• the lipophilic Cy groups and the other cyclic rings in the compounds of formula I are
• rings particularly preferably mono or polycyclic groups containing 5 to 7 ring members in each ring, the rings if heterocyclic containing up to 3, preferably 1 or 2 , non-adjacent ring heteroatoms selected from O, N and S.
• Preferred such rings include benzene, pyridine,
• pyrimidine pyrazine, 1,3-oxazine, 1,4-oxazine, 1,3-thiazine, 1,4-thiazine, pyrrole, imidazole, 1,3-oxazole, 1,3-thiazole, furan, thiophene, piperidine, piperazine, morpholine, perhydro-1,4-thiazine and pyrrolidine.
• lipophilic Cy groups include groups of formula la to Ie
• R 3 to R 8 is each independently a bond or a
• linker moiety L is conveniently a branched or linear alkylene chain, eg such that LCy is of formula
• each R 10 is a hydrogen atom, an alkyl group, an optionally esterified carboxyl group or a group Cy, at least one and preferably only one being a group Cy, and one or more CHR 10 moieties may optionally be replaced by a 5-7 membered saturated homo or heterocyclic ring.
• the carboxyl groups in the compounds of formula I may, for example, be in the form of carboxylate salt groups, for example groups of formula -COOMt (where Mt 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).
• Mt + is a cation deriving from an organic base, for example meglumine.
• the number of the ion-forming carboxyl 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 -COOH or -COOMt groups.
• the metal chelate will be formed as a neutral species, a form preferred since the osmotic pressures in
• the compounds of the invention contain two -L-Cy groups and particularly preferred compounds according to the invention include the chelants of formula II
• R 15 is hydrogen or methyl and R 13 is a group selected from benzyl, 2-phenyl-ethyl, 1-phenyl-ethyl, pyrid-4-yl, pyrid-3-yl, pyrid-2-yl, 3- morpholino-propyl, N-benzyl-piperidin-4-yl and indanyl groups and iodinated such groups), and the metal
• the chelant compounds of the invention may be prepared by amidation, eg analogously to EP-A-130934 (Schering) and US-A-4687659 (Salutar) of EDTA or DTPA or an activated or protected derivative thereof (eg an acid anhydride or bisanhydride) with an amine compound of formula III
• R 11 ' and R 14 ' are groups R 11 and R 14 as hereinbefore defined or protected such groups), followed where necessary 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
• the compounds may be prepared in two or more stages, in the first reacting DTPA, EDTA or a derivative thereof to introduce one or two NR 11 " R 14 " groups (where one of R 11 " and R 14 " is a group R 11 ' or R 14 ' and the other is a Cy-free analogues of R 11 ' or R 14 ') and in a second stage to introduce the Cy groups, eg by a peptide condensation reaction.
• the amidation reactions are preferably performed in the liquid phase.
• a solution of the amine in a solvent such as water, dipolar aprotic solvents, such as acetonitrile, N-methylpyrrolidone, N-methylmorpholine, dimethylformamide, dimethylacetamide, dimethyl 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,
• reaction mixture is stirred under a 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 100oC or less
• the reaction mixture can eventually be
• the bisamide chelants may be prepared by amidation as follows: a) the amine of formula III is dissolved in a dry polar aprotic solvent, e.g. acetonitrile or chloroform, in a ratio of about 1:10 w:v amine: solvent.
• a dry polar aprotic solvent e.g. acetonitrile or chloroform
• the product may be purified as follows: the precipitate from a) is dissolved in deionized water, and if necessary the pH is adjusted to 8-10 using dilute NaOH. The pH is then adjusted to 3-3.5 with dilute HC1, and the precipitate is collected by filtration.
• 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 a hydrogen atom or hydroxyl 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 macromelecular 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 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 , Mn and Dy 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 detoxification 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.
• 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 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 administration.
• diagnostic agent of the invention may conveniently be admi .ni.stered in amounts of from 10-3 to 3 mmol of the metal species per kilogram of body weight, e.g. about 1 mmol Gd/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, especially the liver, 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.
• 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 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
• 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.
• EDTA-bis (anhydride) 1.0 g (3.9 mmol) was gradually added to a stirred solution of 1-phenylethylamine 0.9 g (7.8 mmol) in dried acetonitrile (40 ml) at ambient
• the crude solid was dissolved in 20 ml water to which was added 1N NaOH to bring the pH to 10.
• DTPA-bis(anhydride) 1.0 g (2.8 mmol) was gradually added to a stirred solution of 2-phenylethylamine 0.68 g (5.6 mmol) in dried chloroform (85 ml) at ambient
• DTPA-bis (anhydride) 1.0 g (2.8 mmol) was gradually added to a stirred solution of 2-aminomethylpyridine 0.61 g (5.6 mmol) in dried chloroform at ambient temperature. The stirred solution was left for 42 hours at ambient temperature. The precipitate formed was isolated by filtration and dried.
• DTPA-bis (anhydride) 1.0 g (2.8 mmol) was gradually added to a stirred solution of 4-amino-1-benzylpiperidine 1.07 g (5.6 mmol) in dried chloroform (85 ml) at ambient temperature. The solution was then heated to reflux temperature. The solution was refluxed with stirring overnight under a nitrogen atmosphere. The solution was then evaporated until 25-30 ml remained. Subsequently ether (120ml) was added, and the precipitate was
• DTPA-bis (anhydride) 0.88 g (2.48 mmol) was gradually added to a stirred solution of 2-aminoindane 0.66 g (4.955 mmol) in dried acetonitrile (40 ml) at ambient temperature. The solution was heated to reflux
• EDTA-bis (anhydride) 1.0 g (3.9 mmol) was gradually added to a stirred solution of benzylamine 0.83 g (3.9 mmol) in dried chloroform (85 ml) at ambient temperature. The solution was heated to reflux temperature (70°C) and refluxed under a nitrogen atmosphere for 19 hours. The reaction mixture was subsequently cooled, and the precipitate formed was filtered off and dried.
• 1,4,7,10-Tetraaza-4,7-bis(carboxymethyl)-2,9-dioxo-1,10-bis(pyrid-2-yl) decane lg (3,9 mmol) EDTA-bis (anhydride) was gradually under stirring to acetonitrile (33 ml) heated to boiling. The mixture was refluxed for 1/2 h and 0.73g (1.1 mmol) 2-aminopyridine dissolved in 7 ml acetonitrile was
• DTPA-bis (anhydride) 1.0 g (2.8 mmol) was gradually added to a stirred solution of 4-amino-1-benzylpiperidine 1.07 g (5.6 mmol) in dried chloroform (100 ml) at ambient temperature. The stirred solution was left at ambient temperature for 66 hours. Then about 50% of the chloroform was evaporated off. Ether (50 ml) was then added, and the precipitate formed was filtered off and dried.
• DTPA-bis (anhydride) 1.0 g (3.9 mmol) was gradually added to a stirred solution of 4-amino-l-benzylpiperidine 1.48 g (7.8 mmol) in dried chloroform (85 ml) at ambient temperature. The stirred solution was left for 18 hours at ambient temperature. The solution was evaporated until 25-30 ml remained. Subsequently ether (2 ⁇ 100 ml) was added. The precipitate formed was isolated by filtration and dried.
• DTPA-bis (anhydride) 1.0 g (2.8 mmol) was gradually added to a stirred solution of N-(3-aminopropyl)morpholine 0.81 g (5.6 mmol) in dried chloroform (85 ml) at ambient temperature. The solution was stirred for 27 hours and then refluxed under a nitrogen atmosphere for 69 hours. The solution was evaporated until 25-30 ml remained.
• DTPA-bis (anhydride) 1.0 g (2.8 mmol) was gradually added to a stirred solution of 3-aminomethylpyridine 0.61 g (5.6 mmol) in dried acetonitrile (40 ml) at ambient temperature. The solution was stirred for 84 hours. The precipitate formed was isolated by filtration and dried.
• EDTA-bis (anhydride) 1.0 g (3.9 mmol) was gradually added to a stirred solution of 2-aminomethylpyridine 0.84 g (7.8 mmol) in dried chloroform (120 ml) at ambient temperature. The stirred solution was left for 16 hours at ambient temperature. The solution was evaporated until 25-30 ml remained. Subsequently ether (50 ml) was added. The precipitate formed was isolated by
• DTPA-bis (anhydride) (0.56 g, 1.56 mmol) was added in portions to a solution of H-Phe-OBzl-HCl (0.91 g, 3.12 mmol) and triethylamine (0.32 g, 3.12 mmol) in
• Triethylamine (0.57 g, 5.6 mmol), tryptophanmethylester (HCl) (1.43 g, 5.6 mmol) and DTPA-bis (anhydride) (1.000 g, 2.8 mmol) were dissolved in 100 ml chloroform. The mixture was refluxed in a nitrogen atmosphere for 3 days. Most of the chloroform was removed (20-30 ml left). 100 ml diethylether was added to the
• Lithium hydroxide (14.4 mg, 0.61 mmol) was dissolved in a 4.5 ml mixture of MeOH/H 2 O(3:1). 3,6,9,12-Tetraaza- 2,13,-bis(methyloxycarbonyl)-6,9-bis(carboxymethyl)- 4,11-dioxo-1,14-bis(indol-3-yl)tetradecane (60.0 mg, 8.7 ⁇ 10 -2 mmol) was added and the solution was stirred for 8 hours. Methanol was removed, 2 ml water was added and the pH was adjusted to 3.5 (0.5 M HCl). The solid product was collected and dried in vacuo for 12 hours. The identity of the product as the title compound was verified by 1 ⁇ . NMR.
• Lithium hydroxide (0.32 g, 13.4 mmol) was dissolved in a mixture of MeOH/H 2 O (3:1). 3,6,9,12,15-Pentaaza-2,16,-bis(methyloxycarbonyl)-6,9,12-tris(carboxymethyl)-4,14-dioxo-1,17-bis(indol-3-yl)heptadecane (1.33 g, 1.67 mmol) was added and the solution was stirred for 6 hours at ambient temperature. Methanol was evaporated and 10 ml water was added to the residual. The pH was adjusted to 3.5 with 0.5 M HCl. The solid product was collected by filtration and dried to give 18% product.

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• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

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• 1990
  • 1990-12-21 GB GB909027922A patent/GB9027922D0/en active Pending
• 1991
  • 1991-12-20 EP EP92901385A patent/EP0563145A1/en not_active Withdrawn
  • 1991-12-20 WO PCT/EP1991/002468 patent/WO1992011232A1/en not_active Application Discontinuation
  • 1991-12-20 CA CA002098712A patent/CA2098712A1/en not_active Abandoned
  • 1991-12-20 JP JP4501395A patent/JPH06504273A/ja active Pending

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