Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Patent
1994-11-01
1998-10-06
Burn, Brian M.
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
564153, 564156, 424 944, 424 9452, C07C23746
Patent
active
058178732
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to compounds which can be used as contrast media for X-ray radiology.
The present invention relates more especially to compounds which can be used as contrast media displaying a long residence in the vascular compartment.
There is still a need for this type of product at the present time.
In effect, the traditional ionic or nonionic media customarily used, such as triiodinated derivatives of isophthalic acid, are very rapidly extravasated. The time available for obtaining an image of the vascular compartment of sufficient quality is thus very short.
To remedy this drawback, it has been proposed to repeat the injections of traditional contrast media. This approach entails, however, an increase in doses and a higher risk of adverse side effects. It also results in a greater cost of examinations of the vascular compartment.
Contrast media displaying a long residence in the vascular compartment for X-ray radiology have, moreover, been proposed; they are all based on the principle of attachment of a number of iodinated molecules to a high molecular weight polymer.
In this way, the contrast medium is excreted slowly by glomerular filtration and remains confined in the vascular compartment, at least for a certain time.
There may be mentioned, in this connection, EP-354 836 and EP-344,202 describing compounds possessing a dextran type backbone onto which iodinated phenyl groups are grafted, EP 436,316 describing compounds with polyacrylamide backbone onto which iodinated phenyl groups are grafted or alternatively U.S. Pat. No. 5,019,370 describing compounds having a polyacrylate or polyamide backbone.
The major drawback of the products of the prior art lies, however, in the polydispersity of the molecular weight of the polymers used, such as dextran or polylyine, or resulting from the copolymerization of the acrylamide type monomers used.
This polydispersity has several drawbacks: in the first place, the low molecular weight components of the iodinated polymer are excreted rapidly and no longer contribute to the concentration which is useful for obtaining the vascular image.
In addition, extravasation of the low molecular weight polymers into the interstitial compartment decreases the contrast at the interface between the vascular and interstitial compartments, and results in an image of insufficient quality.
Lastly, the high molecular weight components of the iodinated polymer are eliminated only very slowly via the kidneys or by uptake by the reticuloendothelial system, and may generate undesirable anaphylactoid reactions.
Hence the compounds proposed hitherto do not permit the confinement of a contrast medium in the vascular compartment, or its biocompatibility, to be controlled in a precise manner.
Polyiodinated compounds comprising up to 3 phenyl rings are, moreover, known from FR 2,272,640.
These compounds are not, however, described as being capable of displaying a long residence in the vascular compartment.
The objective of the present invention is to provide compounds which can be used as contrast media for X-ray radiology which do not possess the drawbacks of the compounds of the prior art while displaying a good residence time in the vascular compartment.
The subject of the invention is polyiodinated compounds with a single molecular weight having a molecular concentration of iodine of greater than approximately 20% by weight, and in particular greater than approximately 30% by weight, containing at least 9 iodine atoms and having a molecular weight above 2000 and below approximately 50,000, and in particular above 2000 and below approximately 20,000, characterized in that they have either a zero overall electrical charge or at least two anionic charges, and in that they persist in the vascular compartment at a value equal to at least approximately 30% by weight of the injected dose in a subject five minutes after intravascular administration in the said subject.
Single molecular weight is understood, in the context of the present invention, to mean a molecular weight which
REFERENCES:
Article entitled: "Polymers with Controlled Molecular Architecture: Control of Surface Functionality in the Synthesis of Dendritic Hyperbranched Macromolecules using the Convergent Approach"; J. Chem. Soc. Perkin Trans. 1991; pp. 1059-1076; Karen L. Wooley, Craig J. Hawker and Jean M. J. Frechet.
Article entitled: Starburst Dendrimers: Molecular-Level Control of Size, Shape, Surface Chemistry, Topology, and Flexibility from Atoms to Macroscopic Matter; Angew. Chem. Int. Ed. Engl. 29 (1990) 138-175; pp. 138-175; Donald A. Tomalia, Adel M. Naylor, and William A. Goddard III.
Chambon Catherine
le Greneur Soizic
le Lem Gael
Meyer Dominique
Simonot Christian
Burn Brian M.
Guerbet S.A.
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