WO1998022148A1 - Agents de contraste et ligands pour imagerie a resonance magnetique (irm) - Google Patents

Agents de contraste et ligands pour imagerie a resonance magnetique (irm) Download PDF

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Publication number
WO1998022148A1
WO1998022148A1 PCT/US1997/016606 US9716606W WO9822148A1 WO 1998022148 A1 WO1998022148 A1 WO 1998022148A1 US 9716606 W US9716606 W US 9716606W WO 9822148 A1 WO9822148 A1 WO 9822148A1
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Prior art keywords
iii
composition
group
set forth
gadolinium
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PCT/US1997/016606
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English (en)
Inventor
Wei-Jun Peng
Daniel A. Aguilar
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Washington University
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Filing date
Publication date
Priority claimed from US08/752,763 external-priority patent/US5861138A/en
Priority claimed from US08/752,505 external-priority patent/US5861140A/en
Application filed by Washington University filed Critical Washington University
Publication of WO1998022148A1 publication Critical patent/WO1998022148A1/fr

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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
    • C07D213/60—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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • 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
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings
    • 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
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring

Definitions

  • 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.
  • nuclei under study in a sample e.g. protons
  • RF radio-frequency
  • These nuclei as they relax, subsequently emit RF at a sharp resonance frequency.
  • the resonance frequency of the nuclei depends on the applied magnetic field.
  • nuclei with appropriate spin when placed in an applied magnetic field B, expressed generally in units of gauss or Tesla [10 4 gauss]
  • 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.
  • an RF pulse of radiation will excite the nuclei and can be considered to tip the net magnetization 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.
  • the decay of the emitted radiation characterized by two relaxation times, i.e., T, the spin-lattice relaxation time or longitudinal relaxation time, that is, the time taken by the nuclei to return to equilibrium along the direction the externally applied magnetic field, and T 2 , the spin- spin relaxation time associated with the dephasing of the initially coherent precession of individual proton spins.
  • MRI may be capable of differentiating different tissue types in detecting diseases which induce physiochemical changes that may not be detected by X-ray or CT which are only sensitive to differences in the electron density of tissue.
  • T the relaxation times
  • T 2 the relaxation times
  • these relaxation times are influenced by the environment of the nuclei, (e.g., viscosity, temperature, and the like).
  • These two relaxation phenomena are essentially mechanisms whereby the initially imparted radio-frequency energy is dissipated to the surrounding environment.
  • the rate of this energy loss or relaxation can be influenced by certain other nuclei which are paramagnetic.
  • Chemical compounds incorporating these paramagnetic nuclei may substantially alter the T, and T 2 values for nearby protons.
  • the extent of the paramagnetic effect of a given chemical compound is a function of the environment.
  • paramagnetic species such as ions of elements with atomic numbers of 21 to 29, 42 to 44 and 58 to 70 have been found effective as MRI contrasting agents.
  • suitable ions include chromium(III), manganese(II), manganese(III), iron(II), iron(III), cobalt(II), nickel(II), copper(II), praseody ⁇ nium(III), neodymium(III), samarium(III), and ytterbium(III). Because of their very strong magnetic moments, 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 clearance from the body following the imaging procedure.
  • Gries et al. U.S. Pat. No. 4,647,447, disclose complexes of various paramagnetic ions with conventional aminocarboxylic acid complexing agents.
  • a preferred complex disclosed by Gried 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").
  • DTPA ethylenediamine-tetraacetic acid
  • EDTA ethylenediamine-tetraacetic acid
  • DOTA tetraazacyclododecane- N,N',N",N'"-tetraacetic acid
  • the gadolinium complex of DTPA has a net charge of -2
  • the gadolinium complex of EDTA or DOTA has a net charge of -1
  • both are generally administered as soluble salts.
  • Typical salts are sodium and N-methylglucamine. The administration of salt 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.
  • U.S. 4,001,323 discloses water-soluble non-ionizing hydroxy-containing amide derivatives of 2,4,6-triiodoisophthalic acid for use as radiopaque materials.
  • U.S. 4,250, 113 discloses new amides as X-ray contrast agents.
  • U.S. 4,647,447 discloses new paramagnetic contrast agents.
  • U.S. 4,687,659 discloses homologs of diamide-DTPA-paramagnetic compounds as contrast agents for MR imaging.
  • U.S. 4,719,098 discloses enteral contrast medium useful for nuclear magnetic resonance imaging.
  • U.S. 4,885,363 discloses 1 -substituted- 1 ,4,7-triscarboxymethyl- 1,4,7, 10- tetraazacyclododecane useful when complexed with a paramagnetic metal atom as MR imaging agents.
  • U.S. 4,916,246 discloses paramagnetic chelates useful for NMR imaging.
  • U.S. 4,957,939 discloses sterile pharmaceutical compositions of gadolinium chelates useful as enhancing NMR imaging.
  • U.S. 5,405,601 discloses functionalized tripodal ligands for imaging applications.
  • Kametani, T., Tetrahedron. 1970, 26, 5753 discloses a general synthesis of ligands. All of the above cited prior art and any other references mentioned herein are incorporated herein by reference in their entirety.
  • the present invention provides novel compositions of matter having the formula
  • 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 subjecting the patient to an imaging procedure.
  • compositions of matter having the formula in: 1, m and n are independently 0 or 1
  • R is C or N
  • R 2 is N, 0, or S
  • R 3 is C
  • R 5 is selected from the group consisting of
  • M is a suitable metal ion such as a metal ion of the lanthamide series having an atomic number of 57 - 70, or of a transition metal of an atomic number of 21 - 29, 42, or 44.
  • M is selected from the group consisting of chromium(III), manganese(II), iron(III), iron(II), cobalt(II), nickel(II), copper(II), praseodymium(III), neodymium(III), samarium(III), ytterbium(III), gadolinium(III), terbium(III), dysprosium(III), holmium(III), erbium(III), lanthamium(III), gold(III), lead(II), bismuth(III), and europium(III).
  • 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-1-hydroxymethyl-ethyl.
  • R, - R 8 and M have the same definition as in formula (I) above.
  • Examples of compounds falling within formula la include:
  • R 2 , R 4 - R 8 , and M have the same definition as set forth in formula (la).
  • compositions formed by the ligands and central metal ions enumerated above may be further complexed 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.
  • the compositions of the present invention can also be employed for delivery of either radiopharmaceuticals or heavy metals for X-ray contrast into the body.
  • the complexed metal ion (M) must be radioactive.
  • Radioisotopes of the elements technetium, rhenium, indium, gallium, copper, ytterbium, samarium and holmium are suitable.
  • the complexed metal ion (M) must be able to absorb adequate amounts of the X-rays.
  • These metal ions are generally referred to as radiopaque.
  • Suitable elements for use as the radiopaque metal ion include lead, bismuth, gadolinium, dysprosium, holmium and praseodymium.
  • compositions of the present invention can be formulated into 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 1.0 M 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 0.1M to about 0.5M.
  • Such solutions also may contain pharmaceutically acceptable buffers and, optionally, electrolytes such as sodium chloride.
  • parenteral dosages will range from about 0.001 to about 1.0 mmol of paramagnetic ion complex per kg of patient body weight.
  • Preferred parenteral dosages generally range from about 0.01 to about 0.5 mmol of paramagnetic ion complex per kg of patient body weight.
  • Enteral dosages generally range from about 0.5 to about 100 mmol, preferably from about 1.0 to about 10.0 mmol, preferably from about 1.0 to about 20.0 mmol of paramagnetic ion complex per kg of patient body weight.
  • compositions of the present 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 NMR 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, N.T. 1983) and E. Edmund Kim, M.S., M.D. and Thomas P. Haynie,
  • R - R 14 , 1, m, and n are the same as set forth in formula (I) above, and M" is Na, Li, K, NH 4 ffi , or MgBr.
  • a class of compounds (ligands) falling within formula (X) above are
  • novel ligands and the novel ligand-metal complexes of the present invention are prepared from substituted aromatic heterocycles ("SAH") which are generally commercially available from Aldrich Chemical Company (Milwaukee).
  • SAH substituted aromatic heterocycles
  • the SAH have the general formula:
  • R, - R 3 and R ⁇ - R 8 , and m are defined above.
  • R 10 and R u are defined below.
  • Rg - R 8 are the same as defined above and are protected if incompatible with the reaction conditions.
  • both R 10 and R n can be halogen (such as Br) and then a halogen lithium exchange reaction is carried out at low temperature (e.g. from about -100°C to about -20°C) to generate a monolithium reagent, which is then coupled with a linking reagent such as POCl 3 , PC1 3 , or methyl chloroformate, to link three units of SAH to form a capping mode ligand in one or two steps as shown in Scheme 2.
  • a linking reagent such as POCl 3 , PC1 3 , or methyl chloroformate
  • R 10 is first protected by converting it to an oxazoline under amidation conditions as shown in Scheme 1, then, the amide is thus subjected to ring closure conditions to form the oxazoline.
  • a halogen lithium exchange reaction is then carried out at low temperature to form a monolithium reagent which is coupled with a linking agent such as POCl 3 , PC1 3 or methyl chloroformate, to link three units of SAH.
  • the carboxylic acid groups are then regenerated as shown in Scheme 1 by cleaving the oxazoline.
  • the coupling reaction with the linking reagent is carried out by refluxing the SAH with the linking reagent in a solvent in the presence of a base. In this case, the SAH is used in excess.
  • the final step in the overall synthesis for preparing the ligand-metal complex is reaction of the novel ligand with a solution containing the metal ion in the form of a compound which, for example, may be the acetate form, e.g. Gd(OAc) 3 . Pressures and temperatures are not critical.
  • the mole ratio of ligand to metal (atom) is about 1 :1.
  • GdTCPM GdTCPM The following specific examples are supplied for the purpose of better illustrating the invention. These examples are not intended, however, to limit or restrict the scope of the invention in any way and should not be construed as providing conditions, parameters, or values which must be utilized exclusively in order to practice the present invention.
  • 5-Bromofuric acid 50 g, 0.262 mol
  • a three neck Schlenk flask equipped with a thermocouple temperature probe and a condenser, which was sealed with a stopper.
  • the setup was evacuated with high vacuum for 30 minutes and then refilled with nitrogen.
  • Thionyl chloride 250 ml was added by removing the temperature probe temporarily.
  • the stopper on the condenser was replaced with a T-joint, which was connected on one end to nitrogen and the other end to a NaOH/H 2 0 trap.
  • An empty trap should also be placed between the T joint and the base trap to prevent the base from being sucked into the reaction flask in the event of a pressure drop in the reaction flask.
  • the amide (30 g, 0.114 mol) obtained from Example 1 was charged into a 250 ml Schlenk flask equipped with an addition funnel and a stir bar. The setup was evacuated for 30 minutes and refilled with nitrogen. SOCl 2 (30 ml, 47.6g) was added into the addition funnel. A
  • T-joint connected to nitrogen on one end and a base trap on the other end, was used to cap the addition funnel with a gentle flow of nitrogen through the T-joint.
  • SOCl 2 was then added to the reaction flask and stirring started. Reaction started immediately, generating bubbles. The addition took about 10 minutes.
  • the solution was stirred for an additional 30 minutes and then poured into 150 ml of dry ether to precipitate the product. The white precipitate was filtered, washed with 50 ml of ether and air dried. The white powder was then stirred in 40 ml of 20% NaOH water solution for 30 minutes. Ether (150 ml) was then added and stirring continued. All the solid dissolved in about 10 minutes.
  • a reaction flask was equipped with a mechanical stirrer, nitrogen purge, internal temperature probe, and two equalizing addition funnels.
  • the flask was charged with diethyl ether (450 mL) and 2,6-dibromopyridine (55.8 g, 0.235 mol, MW 237, 5 equiv) and the resultant slurry was cooled to -75 °C with agitation.
  • One addition funnel was charged with n-butyllithium solution in hexane (120 mL, 1.6 M, 0.192 mol, 4 equiv) and the butyllithium was added to the reaction mixture with agitation at such a rate that the internal reaction temperature was maintained at -70 to -75 °C.
  • reaction temperature was maintained at -75 °C for an additional 30 - 60 min.
  • the second addition funnel was charged with diethyl ether (50 mL) and phosphorus trichloride (6.6 g, 0.048 mol, MW 137.3, 1.00 equiv).
  • the phosphorus trichloride solution was added to the reaction mixture with agitation at such a rate that the internal reaction temperature was maintained at -70 to -75 °C.
  • reaction temperature was maintained at -75 °C for an additional 30 - 60 min.
  • the reaction was quenched by the dropwise addition of methanol (6 mL) at -75 °C.
  • a flask was equipped with a reflux condenser, agitator, nitrogen purge and heat source.
  • the flask was charged copper (I) cyanide (20.27 g, 0.226 mol, MW 89.5, 5.4 equiv) in dry pyridine (120 mL).
  • a reaction flask was equipped with a reflux condenser, agitator and a nitrogen purge.
  • reaction mixture was concentrated by evaporation at below 60 °C and the residue was treated several times with chloroform (2 x 50 mL) followed by concentration to azeotropically remove water to afford 20.2 g of crude product as a brown solid.
  • 2,6-Dibromopyridine 38 g, 0.16 mol.
  • a 1 liter, 4-neck flask equipped with a stir bar, a temperature probe, a gas inlet w/stopcock, a septum( wired onto center neck), and an addition funnel (125 ml).
  • Dry ether 400 ml was added to the flask and methyl chloroformate (6.8 g, 0.07 mol.) in 40 ml ether was charged into the addition funnel.
  • the flask was taken out of the glovebox to a bench and placed under N 2 atmosphere.
  • BBPK (10 g, 0.029 mole) (Example 13) and 75 ml ether was charged into a 250 ml 2-neck Schlenk flask equipped with a stir bar, a septum, and a temperature probe adapter.
  • 2,6-dibromopyridine (7.13 g, 0.03 mol) and 75 ml ether was charged into another 250 ml Schlenk flask equipped with an addition funnel containing n-butyllithium (18.75 ml, 0.03 mol, 1.6 M in hexanes) and a temperature probe adapter.
  • a solution was prepared under nitrogen containing TBPM (4.0 g, 8.0 mmol) (Example 14), Pd(PPh 3 ) 4 (0.46 g, 0.4 mmol) (Example 14), NEt 3 (8.0 g, 79 mmol), methanol (8.0 g, 250 mmol) and toluene (150 ml).
  • This solution was transferred into a 300 ml stainless steel Pan- reactor which was purged with nitrogen. The reactor was purged three times with carbon monoxide (CO), pressurizing to 500 psi and then releasing the pressure. It was then pressurized to 500 psi with CO, heated to 100°Cand stirred at 500 RPM. The reaction was run for 72 hours.
  • CO carbon monoxide
  • Example 16 NaTCPM (1.00 g, 2.2 mmol) (Example 16) was dissolved in 100 ml of deionized water in a reaction flask. Gd(OAc) 3 XH 2 O (34.3% Gd; FW, 458; 0.90 g, 2.0 mmol), dissolved in 50 ml of deionized water was added dropwise with stirring. A white precipitate was obtained at the end of the addition. The volume was reduced to 20 ml and precipitate was filtered, washed with water, and dried to yield 0.92 g, 85% GdTCPM. Karl Fisher Water analysis determined that there were four molecules of water per molecule of GdTCPM.

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Abstract

L'invention a trait à des compositions de substances répondant aux formules (a) et (b). Dans la formule (a), les R, en l'occurrence de R1 à R14, M, l, m et n sont tels que définis dans le corps du descriptif et lesdites substances ont des applications en tant qu'agents de contraste pour IRM et dans la formule (b), les R, en l'occurrence de R1 à R14, M'', l, m et n sont tels que définis dans le corps du descriptif.
PCT/US1997/016606 1996-11-20 1997-09-12 Agents de contraste et ligands pour imagerie a resonance magnetique (irm) WO1998022148A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US08/752,763 1996-11-20
US08/752,505 1996-11-20
US08/752,763 US5861138A (en) 1996-11-20 1996-11-20 Ligands for MRI contrast agent
US08/752,505 US5861140A (en) 1996-11-20 1996-11-20 Tripodal paramagnetic contrast agents for MR imaging

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WO1998022148A1 true WO1998022148A1 (fr) 1998-05-28

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005042550A1 (fr) 2003-10-30 2005-05-12 Merck Patent Gmbh Complexes metalliques a ligands bipodes
DE102008015526A1 (de) 2008-03-25 2009-10-01 Merck Patent Gmbh Metallkomplexe
US7728137B2 (en) 2003-03-11 2010-06-01 Merck Patent Gmbh Metal complexes
US10233205B2 (en) 2015-08-07 2019-03-19 Auburn University Magnetic resonance imaging contrast agent capable of detecting hydrogen peroxide and reducing reactive oxygen species

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Publication number Priority date Publication date Assignee Title
WO1991012024A1 (fr) * 1990-02-12 1991-08-22 Hafslund Nycomed Innovation Ab Radicaux de triarylmethyle et utilisation de radicaux exempts de carbone inerte en irm
EP0494616A1 (fr) * 1991-01-07 1992-07-15 Byk Gulden Lomberg Chemische Fabrik Gmbh Agent de contraste pour le diagnostic RM
DE4320307A1 (de) * 1992-06-22 1993-12-23 Byk Gulden Lomberg Chem Fab Neue Eisenkomplexe

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
WO1991012024A1 (fr) * 1990-02-12 1991-08-22 Hafslund Nycomed Innovation Ab Radicaux de triarylmethyle et utilisation de radicaux exempts de carbone inerte en irm
EP0494616A1 (fr) * 1991-01-07 1992-07-15 Byk Gulden Lomberg Chemische Fabrik Gmbh Agent de contraste pour le diagnostic RM
DE4320307A1 (de) * 1992-06-22 1993-12-23 Byk Gulden Lomberg Chem Fab Neue Eisenkomplexe

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Title
A.J. AMOROSO ET AL.: "COMPLEXES OF THE PODAND LIGAND TRIS(3-(2-PYRIDYL)-PYRAZOL-1-YL)BORATE WITH LANTHANOIDS AND ACTINOIDS: RARE EXAMPLES OF ICOSAHEDRAL N12 COORDINATION", J. CHEM. SOC., CHEM. COMMUN., vol. 18, 1995, pages 1881 - 1882, XP002052426 *
D. L. WHITE ET AL.: "PREPARATION AND REACTIONS OF THE C3V LIGAND TRIS(2-PYRIDYL)METHANE AND ITS DERIVATIVES", INORG. CHEM., vol. 21, 1982, pages 3119 - 3122, XP002052425 *
H. ADOLFSSON ET AL.: "ENANTIOMERICALLY PURE C3-SYMMETRIC TRIPODAL PYRIDINE LIGANDS", J. CHEM. SOC., CHEM. COMMUN., 1992, pages 1054 - 1055, XP002052424 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7728137B2 (en) 2003-03-11 2010-06-01 Merck Patent Gmbh Metal complexes
WO2005042550A1 (fr) 2003-10-30 2005-05-12 Merck Patent Gmbh Complexes metalliques a ligands bipodes
US9029539B2 (en) 2003-10-30 2015-05-12 Merck Patent Gmbh Metal complexes with bipodal ligands
DE102008015526A1 (de) 2008-03-25 2009-10-01 Merck Patent Gmbh Metallkomplexe
DE102008015526B4 (de) 2008-03-25 2021-11-11 Merck Patent Gmbh Metallkomplexe
US10233205B2 (en) 2015-08-07 2019-03-19 Auburn University Magnetic resonance imaging contrast agent capable of detecting hydrogen peroxide and reducing reactive oxygen species

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