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WO1995019185A1 - Ligands aza-macrobicycliques fonctionnalises pour des applications en imagerie - Google Patents

Ligands aza-macrobicycliques fonctionnalises pour des applications en imagerie Download PDF

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Publication number
WO1995019185A1
WO1995019185A1 PCT/US1995/000634 US9500634W WO9519185A1 WO 1995019185 A1 WO1995019185 A1 WO 1995019185A1 US 9500634 W US9500634 W US 9500634W WO 9519185 A1 WO9519185 A1 WO 9519185A1
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Prior art keywords
compound
alkyl
mixture
different
same
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PCT/US1995/000634
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English (en)
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Rebecca A. Wallace
T. Jeffrey Dunn
Dennis A. Moore
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Mallinckrodt Medical, Inc.
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Priority to AU16817/95A priority Critical patent/AU1681795A/en
Publication of WO1995019185A1 publication Critical patent/WO1995019185A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • This invention relates to magnetic resonance imaging (MRI) , X-ray imaging, and radiopharmaceuticals. More particularly the invention relates to methods and compositions for enhancing MRI, X-ray imaging, and radiopharmaceuticals.
  • contrast agents in diagnostic medicine is rapidly growing.
  • X-ray diagnostics for example, increased contrast of internal organs, such as the kidneys, the urinary tract, the digestive tract, the vascular system of the heart (angiography) , and so forth is obtained by administering a contrast agent which is substantially radiopaque.
  • MRI diagnostics increased contrast of internal organs and tissues may be obtained by administering compositions containing paramagnetic metal species which increase the relaxivity of surrounding protons.
  • ultrasound diagnostics improved contrast is obtained by administering compositions having acoustic impedances different than that of blood and other tissues.
  • the recently developed technique of MRI encompasses the detection of certain atomic nuclei utilizing magnetic fields and radio-frequency radiation. It is similar in some respects to X-ray computed tomography (CT) in providing a cross-sectional display of the body organ anatomy with excellent resolution of soft tissue detail. As currently used, the images produced constitute a map of the proton density distribution ,the relaxation times, or both, in organs and tissues.
  • CT computed tomography
  • the technique of MRI is advantageously non- invasive as it avoids the use of ionizing radiation.
  • the nuclei under study in a sample e.g. protons
  • RF radio-frequency
  • nuclei with appropriate spin when placed in an applied magnetic field (B, expressed generally in units of gauss or Tesla [10 4 gauss] ) align in the direction of the field.
  • B expressed generally in units of gauss or Tesla [10 4 gauss]
  • these nuclei precess at a frequency, f, of 42.6 MHz, at a field strength of 1 Tesla.
  • f a frequency
  • an RF pulse of radiation will excite the nuclei and can be considered to tip the net magnetization out of the field direction, the extent of this rotation being determined by the pulse duration and energy.
  • the nuclei "relax" or return to equilibrium with the magnetic field, emitting radiation at the resonant frequency.
  • paramagnetic species such as ions of elements with atomic numbers of 22 to 29, 42 to 44 and 58 to 70 have been found effective as MRI image contrasting agents.
  • suitable ions include chromiu (III) , manganese (II) , manganese (III) , iron(II) , iron(III), cobalt (II) , nickel (II), copper(II), praseodymium(III) , neodymium(III) , samarium(III) , and ytterbium(III) .
  • gadolinium(III) , terbium(III) , dysprosium(III) , holmium(III) and erbium(III) are preferred.
  • Gadolinium(III) ions have been particularly preferred as MRI contrasting agents.
  • paramagnetic ions have been administered in the form of complexes with organic complexing agents.
  • Such complexes provide the paramagnetic ions in a soluble, non- toxic form, and facilitate their rapid clearence from the body following the imaging procedure.
  • Gries et al. U.S. Patent 4,647,447, disclose complexes of various paramagnetic ions with conventional aminocarboxylic acid complexing agents.
  • a preferred complex disclosed by Gries et al. is the complex of gadolinium(III) with diethylenetriamine-pentaacetic acid (“DTPA”) .
  • Paramagnetic ions such as gadolinium(III) have been found to , form strong complexes with DTPA, ethylenediamine-tetraacetic acid (“EDTA”), and with tetraazacyclododecane-N,N' ,N" ,N"' - tetraacetic acid (“DOTA”) .
  • EDTA ethylenediamine-tetraacetic acid
  • DOTA tetraazacyclododecane-N,N' ,N" ,N"' - tetraacetic acid
  • Typical salts are sodium and N-methylglucamine. The administration of salts is attended by certain disadvantages. These salts can raise the in vivo ion concentration and cause localized disturbances in osmolality, which in turn, can lead to edema and other undesirable reactions.
  • the first three factors are thermodynamic in nature whereas the fourth involves chelate kinetics.
  • the first factor is the thermodynamic stability constant of the metal-ligand.
  • the thermodynamic stability constant indicates the affinity that the totally unprotonated ligand has for a metal.
  • the second factor is the conditional stability constant which takes into account the pH and is important when considering stability under physiological pH.
  • the selectivity of the ligand for the paramagnetic metal over other endogenous metal ions such as zinc, iron, magnesium and calcium is the third factor.
  • the present invention provides new and structurally diverse compositions comprising compounds of the general formula:
  • A is N-G or P-G; B is N or P; C is N or P; D is
  • R 1# R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 can be the same or different and are hydrogen, Ci-C o alkyl, or C 6 -C 10 aryl, optionally substituted by one or more hydroxy, Ci-C e alkyl, C ⁇ C,, hydroxyalkyl, Ci-C,, alkoxy, C 6 -C 10 aryl, C 6 -C 10 hydroxyaryl, C 6 -C 10 aryloxy, -C0 2 R 7 , -CON ⁇ , or -NR 10 R X1 groups; R 9 ,
  • compositions comprising complexes of the compounds with metal ions of the general formula
  • A is N-G or P-G; B is N or P; C is N or P; D is
  • N-G or P-G; E is N-G, P-G or C(R 6 ) - [CH(R 7 ) ] q -Y; G is -[CH(R 8 )] 1 - Y; Y is -C0 2 M, -OPO 3 HM, -P0 3 HM, -S0 3 M, -SM, -OM, or -CONHOM: R 1#
  • R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 can be the same or different and are hydrogen, alkyl, or C 6 -C 8 alkyl, C 6 -C 10 aryl, optionally substituted by one or more hydroxy, hydroxyalkyl, C ⁇ C B alkoxy, C 6 -C 10 hydroxyaryl, C 6 -C 10 aryloxy, - C0 2 R 9 , -CO Ri o R n , or NR ⁇ F ⁇ groups
  • R 9 , R 10 , and R 1X may be the same or different and are selected from the group consisting of hydrogen, C j -C ⁇ alkyl alkyl, C x -C 8 hydroxyalkyl and Ci-C 8 alkoxyalkyl;
  • R 10 and R X1 may form a 5 or 6 membered carbocyclic ring optionally containing singularly or in combination nitrogen, oxygen or sulfur; i, j, k, 1, m
  • compositions comprising the above formulas wherein M is a radioactive metal ion, a paramagnetic ion, or a metal ion capable of absorbing x-rays are also provided for use as radiopharmaceuticals, magnetic resonance imaging, and x-ray contrast agents, respectively.
  • Diagnostic compositions comprising the compounds of the invention are also provided. Methods of performing diagnostic procedures with compositions of the invention are also disclosed. The methods comprise administering to a patient an effective amount of the compositions of the invention and optionally subjecting the patient to an imaging procedure of imaging.
  • compositions of the invention are suitable for use with a variety of modalities including x-rays, magnetic resonance imaging and radiopharmaceuticals.
  • Biomolecule refers to all natural and synthetic molecules that play a role in biological systems. Biomolecules include hormones, amino acids, peptides, peptidomimetics, proteins, deoxyribonucleic acid (DNA) ribonucleic acid (RNA) , lipids, albumins, polyclonal antibodies, receptor molecules, receptor binding molecules, monoclonal antibodies and aptamers. Specific examples of biomolecules include insulins, prostaglandins, growth factors, liposomes and nucleic acid probes. Examples of synthetic polymers include polylysine, arborols, dendrimers, and cyclodextrins.
  • biomolecules include enhanced tissue targeting through specificity and delivery.
  • Coupling of the chelating moieties to biomolecules can be accomplished by several known methods (e.g., Krejcarek and Tucker Biochem. Biophys. Res. Comm. 30, 581 (1977); Hnatowich, et al. Science, 220, 613 (1983).
  • a reactive moiety present in one of the R groups is coupled with a second reactive group located on the biomolecule.
  • a nucleophilic group is reacted with an electrophilic group to form a covalent bond between the biomolecule and the chelate.
  • nucleophilic groups include amines, anilines, alcohols, phenols, thiols and hydrazines.
  • suitable alkyl groups for use with the invention include methyl, ethyl, propyl, isopropyl, butyl, cyclohexyl, heptyl and octyl.
  • Suitable alkoxy groups include methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy and octoxy.
  • Hydroxyalkyl groups suitable for use with the invention include both mono and poly hydroxyalkyls such as hydroxyethyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 2,3,4- trihydroxybutyl, tris (hydroxymethyl)methyl and 2-hydroxy-l- hydroxymethyl-ethyl .
  • Suitable alkoxyalkyl groups include methoxymethyl, 2, 3-dimethoxypropyl, tris (methoxymethyl)methyl, and 2-methoxy-1-methoxymethyl-ethyl.
  • Examples of suitable compounds of the invention are 4, 7, 13-tris (carboxymethyl) -1, 4, 7, 10, 13-pentaazabicyclo [8.5.2] pentadecane; 4, 7, 12-tris (carboxymethyl) -12-methyl-1, 4, 7, 10-tetraazabicyclo [8.3.2] -pentadecane; 5, 8, 15- tris (carboxymethyl) -1, 5, 8, 12, 15- pentaazabicyclo [10.5.2] nonadecane; and 4, 1 ,. 13- tris (mercaptoethyl) -1, 4, 7, 10, 13-pentaazabicyclo [8.5.2]pentadecane.
  • Complexes of the novel ligands or compounds of the invention with one or more central metal ions or metal ion equivalents such as paramagnetic metals praseodymium(III) , neodymium(111) , samarium(III) , ytterbium(III) terbium(III) , dysprosium(III) , holmium(III) , erbium(III), iron(II), iron(III), manganese (II) , manganese (III) , gadolinium(III) , chromium(III) , cobalt(II) and nickel(II) are useful for enhancing magnetic resonance images.
  • paramagnetic metals praseodymium(III) , neodymium(111) , samarium(III) , ytterbium(III) terbium(III) , dysprosium(III) , holmium(III)
  • novel complexes of the invention are relatively or substantially nontoxic and therefore useful for enhancing magnetic resonance images by favorably altering relaxation times T x and T 2 and affording improved contrast between normal and diseased tissues or organs.
  • the preferred complexes of the invention are those formed from the above ligands and iron(II), iron(III), manganese (II) , manganese (III) and gadolinium(III) as the central metal ion or ions.
  • the complexes formed may be neutral, ionic, cationic, or zwitterionic in nature, or they may be negatively charged.
  • the neutral complexes are generally preferred and generally appear to exhibit relatively lower toxicity as compared to ionic or negatively charged complexes.
  • the negatively charged complexes formed by the ligands and central metal ions enumerated above may be further co plexed with one or more cations of an inorganic or organic base which are physiologically tolerated.
  • cations for further complexing include sodium, potassium, calcium, and salts of N-methylglucamine, and diethanolamine.
  • Examples of preferred compounds of the invention and one or more central metal ions include 4, 7, 13-tris (carboxymethyl) -1, 4, 7, 10, 13- pentaazabicyclo[8.5.2]pentadecane, gadolinium (III) complex;
  • compositions of the invention can also be employed for delivery of either radiopharmaceuticals or heavy metals for x-ray contrast into the body.
  • the complexed metal ion For use in diagnostic and therapeutic radiopharmaceuticals the complexed metal ion must be radioactive. Radioisotopes of the elements technetium, rhenium, indium, gallium, copper, yttrium, samarium and holmium are suitable.
  • the complexed metal ion must be able to absorb adequate amounts of the X-rays. These metal ions are generally refered to as radioopaque. Suitable elements for use as the radioopaque metal ion include lead, bismuth, gadolinium, dysprosium, holmium and praseodymium.
  • Examples of preferred compounds for radiopharmaceuticals are 4, 7, 13-tris (carboxymethyl) -1, 4, 7, 10, 13- pentaazabicyclo[8.5.2]pentadecane, yttrium(III) complex; 4, 7, 12-tris (carboxymethyl) -12-methyl-1, 4, 7, 10- tetraazabicyclo [8.3.2] -pentadecane, indium(III) complex; 5, 8, 15-tris (carboxymethyl) -1, 5, 8, 12, 15- pentaazabicyclo[10.5.2]nonadecane, gallium(III) complex; and 4, 7, 13-tris (mercaptoethyl) -1, 4, 7, 10, 13- pentaazabicyclo[8.5.2]pentadecane, indium(III) complex.
  • Examples of preferred compounds for x-ray contrast are 4, 7, 13-tris (carboxymethyl) -1, 4, 7, 10, 13- pentaazabicyclo[8.5.2]pentadecane, holmium(III) complex; 4, 7, 12-tris (carboxymethyl) -12-methyl-1, 4, 7, 10- tetraazabicyclo[8.3.2] -pentadecane, gadolinium(III) complex; 5, 8, 15-tris (carboxymethyl) -1, 5, 8, 12, 15- pentaazabicyclo[10.5.2]nonadecane, dysprosium(III) complex; and 4, 7, 13-tris (mercaptoethyl) -1, 4, 7, 10, 13- pentaazabicyclo[8.5.2]pentadecane, bismuth (III) complex.
  • compositions of the invention can be formulated into therapeutic or diagnostic compositions for enteral or parenteral administration.
  • These compositions contain an effective amount of the paramagnetic ion complex along with conventional pharmaceutical carriers and excipients appropriate for the type of administration contemplated.
  • parenteral formulations advantageously contain a sterile aqueous solution or suspension of from about 0.05 to about 1.0M of a paramagnetic ion complex according to this invention.
  • Parenteral compositions may be injected directly or mixed with a large volume parenteral composition for systemic administration.
  • Preferred parenteral formulations have a concentration of paramagnetic ion complex of about 0.IM to about 0.5M.
  • Such solutions also may contain pharmaceutically acceptable buffers and, optionally, electrolytes such as sodium chloride.
  • compositions may advantageously contain a slight excess (e.g., from about 0.01 to about 15.0 mole % excess) of a complexing agent or its complex with a physiologically acceptable, non-toxic cation.
  • physiologically acceptable, non-toxic cations include calcium ions, magnesium ions, copper ions, zinc ions, salts of n-methylglucamine and diethanolamine, and the like. Generally, calcium ions are preferred.
  • Formulations for enteral administration may vary widely, as is well-known in the art.
  • such formulations are liquids which include an effective amount of the paramagnetic ion complex in aqueous solution or suspension.
  • Such enteral compositions may optionally include buffers, surfactants, thixotropic agents, and the like.
  • Compositions for oral administration may also contain flavoring agents and other ingredients for enhancing their organoleptic qualities.
  • the diagnostic compositions are administered in doses effective to achieve the desired enhancement of the image. Such doses may vary widely, depending upon the particular paramagnetic ion complex employed, the organs or tissues which are the subject of the imaging procedure, the imaging procedure, the imaging equipment being used, and the like.
  • compositions of the invention are used in the conventional manner.
  • the compositions may be administered to a patient, typically a warm-blooded animal, either systemically or locally to the organ or tissue to be imaged, and the patient then subjected to the imaging procedure.
  • Protocols for imaging and instrument procedures are found in texts such as Stark, D.D.; Bradley, W.G. Magnetic Resonance Imaging; Mosby Year Book: St. Louis, MO, 1992.
  • Radiopharmaceutical Imaging Procedures are found in Fred A. Mettler, Jr., M.D., M.P.H., Milton J. Guiberteau, M.D., Essentials of Nuclear Medicine Imaging, Grune and Stratton, Inc., New York, NY 1983) and E. Edmund Kim, M.S., M.D. and Thomas P. Haynie, M.D., (MacMillan Publishing Co. Inc., New York, NY 1987) .
  • a solution containing 18.2g (0.173mole) diethanolamine and 150mL (l.O ⁇ mole, 108.9g) triethylamine in 500mL dichloromethane is cooled in an ice-water bath.
  • a solution containing 108.6g (0.570mole) p- toluene-sulfonyl chloride in 200mL dichloromethane is added.
  • the rate of addition is such that the temperature of the reaction mixture does not exceed 5C.
  • the mixture is stored in 2L flask fitted with a CaCl 2 drying tube in a OC refrigerator overnight.
  • the cold solution is filtered to remove the large amount of crystals which form (HNEt 3 +Cl-) and concentrated by evaporation in vacuo to a thick oil.
  • the oil is shaken with lOOOg ice and water and the precipitate which forms is collected by filtration.
  • the solid is dissolved in 300mL fresh dichloromethane and washed with 3xl50mL 1.ON HCl.
  • the organic layer is collected and dried with MgS0 4 . After removing the drying agent by filtration the solvent is removed by evaporation and the oil which forms is dissolved in a minimum of boiling methanol/ethyl acetate (20:1), ca. 250mL.
  • the residue is dissolved in IL 90% aqueous methanol and treated with 3.26g (86.3mmoles) NaBH 4 and refluxed for one hour. After cooling to room temperature the mixture is evaporated to dryness, redissolved in 200mL fresh methanol and evaporated again. The residue is dissolved in lOOmL water and the solution treated with 7.60g (31.6mmoles) sodium sulfide nonahydrate. The mixture is refluxed overnight. The mixture is cooled and filtered to remove the black precipitate. The filtrate is evaporated to an oil, slurried in dichloromethane and treated with MgS0 4 .
  • a slurry consisting of lg 5% Pd on C and 4.00g (5.60mmoles) 5,8,15-tris(benzylacetato) -1,5,8,12,15-pentaazabicyclo- [10.5.2]nonadecane in ethanol (95%) is shaken at 60psi H 2 overnight.
  • the catalyst is removed by filtration and the filtrate evaporated to leave 5, 8, 15-tris (carboxymethyl) - 1, 5, 8, 12, 15-pentaazabicyclo [10.5.2] nonadecane as a pale oil. Yield 2.21g (95%) .
  • Identity and purity of the product is confirmed by X R and 13 C nmr, and elemental analysis.
  • a slurry containing 2.00g (4.81mmoles) 5, 8, 15- tris (carboxymethyl) -1,5, 8, 12, 15- pentaazabicyclo [10.5.2] nonadecane and 1.74g (4.81mmoles) gadolinium oxide in lOOmL water is refluxed until the mixture is clarified. Water is removed by evaporation and the residue dissolved in a mixture of boiling acetonitrile:absolute ethanol:iso-propyl alcohol 3:3:4, filtered hot and allowed to stand.
  • the fractions are checked by tic, and appropriately combined.
  • the product 1,4-bis (2- (p- toluenesulfonamido)ethyl) -7- (p-toluenesulfonyl) -1,4,7- triazacyclononane, may be isolated by evaporation of solvent as a white powdery solid. Identity and purity of the product is confirmed by X H and 13 C nmr, and elemental analysis.
  • a mixture containing 22.Og (33.9mmoles) 1,4-bis(2- (p- toluenesulfonamido)ethyl) -7- (p-toluenesulfonyl) -1,4,7- triazacyclononane and 50mL concentrated sulfuric acid is allowed to stir overnight.
  • the mixture is cooled to OC and poured carefully into 500mL dry, cold diethyl ether.
  • the white solid which forms is collected by filtration and washed with cold ether. If the precipitate is tacky, or hygroscopic, the mother liquor of the diethyl ether-sulfuric acid slurry may be decanted, leaving the tacky residue.
  • the residue is dissolved in IL 90% aqueous methanol and treated with 3.26g (86.3mmoles) NaBH 4 and refluxed for one hour. After cooling to room temperature the mixture is evaporated to dryness, redissolved in 200mL fresh methanol and evaporated again. The residue is dissolved in lOOmL water and the solution treated with 7.60g (31.6mmoles) sodium sulfite nonahydrate. The mixture is refluxed overnight. The mixture is cooled and filtered to remove the black precipitate. The filtrate is evaporated to an oil, slurried in dichloromethane and treated with MgS0 4 .
  • a slurry consisting of lg 5% Pd on C and 6.50g (9.48mmoles) 4,7, 13-tris(benzylacetato) -1,4,7,10,13-pentazabicyclo- [8.5.2]heptadecane in ethanol (95%) is shaken at 60psi H 2 overnight.
  • the catalyst is removed by filtration and the filtrate evaporated to leave 4,7,13-tris(carboxymethyl) - 1,4, 7,10,13-pentazabicyclo[8.5.2]hepta-decane as a pale oil.
  • Identity and purity of the product is confirmed by X H and 13 C nmr, and elemental analysis.
  • a flask is charged with 60.Og (375mmoles) 1-hydroxymethyl- l,4,4-trimethyl-3,5-dioxocyclohexane, 127.5g (411mmoles) triphenylphosphite, and 35mL (79.8g, 562mmoles) iodomethane.
  • the mixture is heated under gentle reflux until the temperature of the refluxing liquid rises from ca. 75C to ca. 130C.
  • Volatiles are removed from the mixture by evaporation in vacuo and the residue is taken up in diethyl ether.
  • the dark solution is slurried with 35g charcoal and refluxed on a steam bath. The mixture is filtered and solvent removed in vacuo.
  • a slurry consisting of 22.7g (164mmoles) K 2 C0 3 and 26.lg (67.2mmoles) 1,4-bis (trimethethylsilylethylsulfonyl) -1,4- diazabutane in 150mL dry dmf is heated to 60C.
  • a solution of 40g (74.7mmoles) 1- (benzylcarboxymethyl) -1, 1-bis (tosyloxymethyl)ethane in 200mL dry dmf.
  • the addition is complete the mixture is allowed to stir an additional 24 hours, with heat. After cooling the mixture to room temperature, the volatiles are removed by rotary-evaporation. The residue is shaken with 500g ice and the mixture filtered.
  • the solid collected is wash with distilled water until the filtrate is neutral pH.
  • the solid is dried on the filter with suction.
  • the solid is dissolved in a minimum of boiling methanol, filtered hot and allowed to cool to effect crystallization of l,5-bis(2- trimethylsilylethylsulfonyl) -3- (benzylcarboxymethyl) -3-methyl- 1, 5-diazacycloheptane. Identity and purity of the product is confirmed by H and 13 C nmr, and elemental analysis.
  • the residue is dissolved in lOOmL 95% ethanol and 3.80g (16.0mmoles) nickel (II) chloride hexahydrate is added. The mixture is heated to reflux for two hours, then allowed to cool. Then solvent is removed by evaporation in vacuo and the residue redissolved in 95% aqueous methanol. To this solution is added 2.32g (16.0mmoles) 40% aqueous glyoxal. The mixture is refluxed overnight. After removing the solvent by evaporation, the residue is dissolved in 500mL 90% aqueous methanol and treated with 1.20g (31.7mmoles) NaBH 4 and refluxed for one hour.
  • the mixture is filtered to remove the drying agent and the filtrate evaporated to leave 12- (benzylcarboxymethyl) -12-methyl-1,4, 7, 10-tetra- azabicyclo [8.3.2]pentadecane as an oil. Identity and purity of the product is confirmed by l U and 13 C nmr, and elemental analysis.
  • the catalyst is removed by filtration and the filtrate evaporated to leave 4, 7,12- tris (carboxymethyl) -12-methyl-1,4, 7, 10-tetraaza- bicyclo [8.3.2]pentadecane as a pale oil. Identity and purity of the product is confirmed by H and 13 C nmr, and elemental analysis.
  • a slurry containing l.OOg (2.50mmoles) 4,7,12- tris (carboxymethyl) -12-methyl-l, ,7,10-tetraaza- bicyclo[8.3.2]pentadecane and 0.50g (1.38mmoles) gadolinium oxide in lOOmL water is refluxed until the mixture is clarified. Water is removed by evaporation and the residue dissolved in a mixture of boiling acetonitrile:absolute ethanol:iso-propyl alcohol 3:3:4, filtered hot and allowed to stand.

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Abstract

La présente invention fournit de nouvelles compositions, présentant des structures diverses, comprenant les composés de la formule générale (I), où A correspond à N-G ou P-G; B correspond à N ou P; C correspond à N ou P; D correspond à N-G ou P-G; E correspond à N-G, P-G ou C(R6)-(CH(R7))q-X; G correspond à -(CH(R8)i-X; X correspond à -CO2H, -OPO3H2, PO3H2, -SO3H, -SH, -OH, ou -CONHOH; R1, R2, R3, R4, R5, R6, R7 et R8 peuvent être égaux ou différents et correspondent à de l'hydrogène, C1-C8 alkyle, ou C6-C10 aryle, éventuellement substitués par un ou plusieurs hydroxy, C1-C8 alkyle, C1-C8 hydroxyalkyle, C1-C8 alcoxy, C6-C10 aryle, C6-C10 hydroxyaryle, C6-C10 aryloxy, ou des groupes -C02R7, -CONR10R11, ou -NR10R11; R9, R10 et R11 peuvent être égaux ou différents et sont choisis dans le groupe se composant d'hydrogène, C1-C8 alkyle, C1-C8 hydroxyaryle et C1-C8 alcoxyalkyle; R10 et R11 peuvent former un anneau carbocyclique à 5 ou 6 éléments contenant éventuellement de l'azote, de l'oxygène ou du soufre, séparément ou combinés; i, j, k, l, m, n et q peuvent être égaux ou différents et correspondent à un nombre compris entre zéro et 5 environ. Des procédés d'imagerie utilisant des compositions selon la présente invention sont également décrits.
PCT/US1995/000634 1994-01-14 1995-01-13 Ligands aza-macrobicycliques fonctionnalises pour des applications en imagerie WO1995019185A1 (fr)

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US08/182,243 1994-01-14

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WO1997020841A3 (fr) * 1995-12-04 1997-12-11 Schering Ag Nouveaux composes macrobicycliques, leur procede de fabrication et agents pharmaceutiques les renfermant
US6218351B1 (en) 1998-03-06 2001-04-17 The Procter & Gamble Compnay Bleach compositions
US6306812B1 (en) 1997-03-07 2001-10-23 Procter & Gamble Company, The Bleach compositions containing metal bleach catalyst, and bleach activators and/or organic percarboxylic acids
US6387862B2 (en) 1997-03-07 2002-05-14 The Procter & Gamble Company Bleach compositions
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US6608015B2 (en) 1997-03-07 2003-08-19 Procter & Gamble Company Bleach compositions
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US6673333B1 (en) 2000-05-04 2004-01-06 Research Corporation Technologies, Inc. Functional MRI agents for cancer imaging
US6713045B1 (en) 1995-06-02 2004-03-30 Research Corporation Technologies, Inc. Targeted magnetic resonance imaging agents for the detection of physiological processes
US6906189B2 (en) 1997-03-07 2005-06-14 Procter & Gamble Company Catalysts and methods for catalytic oxidation
US7354568B1 (en) 1997-10-27 2008-04-08 California Institute Of Technology Magnetic resonance imaging agents for the detection of physiological agents

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6713045B1 (en) 1995-06-02 2004-03-30 Research Corporation Technologies, Inc. Targeted magnetic resonance imaging agents for the detection of physiological processes
WO1997020841A3 (fr) * 1995-12-04 1997-12-11 Schering Ag Nouveaux composes macrobicycliques, leur procede de fabrication et agents pharmaceutiques les renfermant
US6566318B2 (en) 1997-03-07 2003-05-20 Christopher Mark Perkins Bleach compositions containing metal bleach catalyst, and bleach activators and/or organic percarboxylic acids
US6387862B2 (en) 1997-03-07 2002-05-14 The Procter & Gamble Company Bleach compositions
US6399557B2 (en) 1997-03-07 2002-06-04 The Procter & Gamble Company Bleach compositions containing metal bleach catalyst, and bleach activators and/or organic percarboxylic acids
US6306812B1 (en) 1997-03-07 2001-10-23 Procter & Gamble Company, The Bleach compositions containing metal bleach catalyst, and bleach activators and/or organic percarboxylic acids
US6608015B2 (en) 1997-03-07 2003-08-19 Procter & Gamble Company Bleach compositions
US6906189B2 (en) 1997-03-07 2005-06-14 Procter & Gamble Company Catalysts and methods for catalytic oxidation
US7125832B2 (en) 1997-03-07 2006-10-24 Procter & Gambel Company Bleach compositions
US7354568B1 (en) 1997-10-27 2008-04-08 California Institute Of Technology Magnetic resonance imaging agents for the detection of physiological agents
US6218351B1 (en) 1998-03-06 2001-04-17 The Procter & Gamble Compnay Bleach compositions
US6673333B1 (en) 2000-05-04 2004-01-06 Research Corporation Technologies, Inc. Functional MRI agents for cancer imaging
US6656450B2 (en) 2000-07-17 2003-12-02 California Institute Of Technology, Inc. Macrocyclic magnetic resonance imaging contrast agents
WO2002026267A3 (fr) * 2000-09-25 2003-04-03 Procter & Gamble Compositions ameliorant les images irm

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