Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Patent
1995-05-30
1997-08-26
Kight, John
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
424 94, 424 942, 424 91, 534 16, A61K 4900, G01N 3100, G01N 3348
Patent
active
056608144
DESCRIPTION:
BRIEF SUMMARY
The chemistry of coordination compounds concerns metal complexes with suitable chelating agents, but many of its concepts can be extended to chemistry and biochemistry.
The use in medicine of a high number of chelating agents is well documented, for instance, as stabilizing agents for pharmaceutical preparations, as antidotes in case of ingestion of toxic metal species and as carriers for the administration of metal species (i.e. ions or atoms) through diagnostic techniques such as X-rays, nuclear magnetic resonance and scintigraphy.
Especially for NMR imaging, pharmaceutical paramagnetic compositions are now well known and more extensively investigated. They preferably contain complex chelating agents of bi- or trivalent metal ions with aminopolycarboxylic acid and/or their derivatives or analogues.
These compounds showed a good capacity of influencing proton relaxation times in NMR imaging, producing images of organs or tissues which, otherwise, couldn't be distinguished from the near regions,
Many of these contrast agents have already been suggested in literature and the following patent list can be cited as an example, even though indicative and partial: EP-A-71564 (Schering), EP-A-130934 (Schering), U.S. Pat. No. 4,615,879 (Runge), DE-A-3401052 (Schering), EP-A-230893 (Bracco), EP-A-185899 (Nycomed), EP-A-186947 (Nycomed) EP-A-165728 (Nycomed), U.S. Pat. No. 4,647,447 (Schering), U.S. Pat. No. 4826673 (Mallinckrodt), U.S. Pat. No. 4,639,365 (Sherry), EP-A-299795 (Nycomed), EP-A-258616 (Salutar), WO 8905802 (Bracco).
It has been now surprisingly found, and it is one of the objects of this invention, a method to improve the capacity of paramagnetic metal chelates of influencing proton relaxation time s during NMR imaging and thanks to it, a totally new class of compounds has been prepared, representing another characteristic object of this invention.
This method relies on the insertion in the same molecular structure of a paramagnetic substance and a X-ray opaque polyiodinated component.
The paramagnetic component comprises a paramagnetic metal ion and, as chelating part, the residue of a cyclic or acyclic aminopolycarboxylic acid, or of an aminopolyphosphonic, aminopolyphosphinic, aminopolysulfonic, aminopolysulfinic acid and/or derivatives or analogues. To this structure, a radiopaque residue, comprising at least an aromatic or heteroaromatic polyiodinated moiety, with radiopaque properties, can be bound, via known synthetic steps.
As a non-limiting example, the structure of the chelating component can be formed by the residue of one of the following chelating agents: EDTA (ethylenediaminotetraacetic acid), DTPA (U.S. Pat. No. 4,647,447: Schering), DTPA-bismethylamide (WO 8602841: Salutar); DOTA (DE-A-3401052: Schering), DO3A and MP-DO3A (EP-A-292689: Squibb), BOPTA (EP 230893: Bracco), DPDP (EP-A-290047: Salutar), DOTMA (Int. Jour. Rad/Appl and Instr, Pt. B, 15(1) 1988, 9-15), MCTA (EP-A-287465: Guerbet), EOB-DTPA (EP-A-40-5704: Schering), BT-DO3A (EP-A-448191: Schering), DTPA hydroxyalkyl amides (U.S. Pat. No. 4,826,673: Mallinckrodt and EP-A-130934: Schering) , as well as the macrocyclic chelating agents disclosed in EP-A-440606 (Bracco).
The iodinated component can be constituted by the residue of a known X-ray contrast agent, ionic and/or non-ionic, monomeric or dimeric, including a polyiodinated aromatic nucleus or two polyiodinated aromatic nuclei.
This residue can, for instance, preferentially belong to one of the following compounds (USAN and USP Dictionary of Drug Names, Ed. 1993): acetrizoic acid, diprotizoic acid, iobenzamic acid, iobutoic acid, iocarmic acid, iocetamic acid, iopanoic acid, iopronic acid, iothalamic acid, diatrizoic acid, iodoxamic acid, ioglycic acid, ioglycamic acid, iolidonic acid, iolixanic acid, iomorinic acid, ioprocemic acid, iosephamic acid, ioseric acid, iotetric acid, iotrizoic acid, iotroxic acid, ioxaglic acid, metrizoic acid, iodamide, iodipamide, iopamidol, iomeprol, iohexol, ioversol, metrizamide, iotrolan, iodecimol, iodixanol, ioglucol, ioglucomide, ioglun
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Anelli Pier Lucio
De Haen Christoph
Fedeli Franco
Murru Marcella
Uggeri Fulvio
Dibra S.p.A.
Jones Dameron L.
Kight John
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