Contrast agents endowed with high relaxivity
AssigneeBracco Imaging S.P.A.
InventorsSilvio Aime, Matteo Galli, Luciano Lattuada, Pierfrancesco Morosini, Fulvio Uggeri, Kondareddiar Ramalingam
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Abstract
The present invention relates to a novel class of paramagnetic ion-based contrast agents of formula (I), wherein a chelating backbone moiety is highly functionalized by the presence of one or more polyhydroxylated chain, that show a pharmacokinetic profile analogous to that of the commonly used T1-general extravascular agents (NSA) but are further characterized by a higher relaxivity.
Claims20
1) A compound of formula (III) or (IIIa)
- wherein:
- R is, independently, H or a C2-C70 aminopolyol moiety comprising a straight or branched alkyl chain substituted by from 2 to 30 hydroxyl groups, said chain being optionally interrupted by one or more groups selected from —O—, —NH—, —N<, —CO—, —CONH—, —NHCO—, —CON< or >NCO—;
- and optionally substituted by one or more C4-C10 cyclic units;
- L is, independently, a direct bond or a divalent straight or branched linker moiety between R and the rest of the molecule, comprising at most 20 carbon atoms;
- v is a positive integer from 1 to 7;
- together with the corresponding protonated forms of the phosphonate (—PO3H2) and carboxy (—COOH) groups;
- or a physiologically acceptable salt of such ligand;
- with the proviso that at least one of the R groups is other than H.
12) A compound of formula (III) or (IIIa) according to any one of claims from 1 to 3 and any physiologically acceptable salt thereof, as a chelated complex with a bivalent or trivalent paramagnetic metal ion selected from Fe(2+), Fe(3+), Cu(2+), Cr(3+), Eu(3+), Dy(3+), La(3+), Yb(3+), Mn(2+), Mn(3+) and Gd(3+).
15) A process for the preparation of the compounds of formula (III) or (IIIa) according to any one of claims from 1 to 3, which process comprises:
- 1) preparation of the aminopolyol moiety R in a suitable form wherein the amino group involved in the coupling reaction with the rest of the molecule and the hydroxy groups can be suitably and independently protected or activated;
- 2) preparation of the linker L in a suitable form, in which any optional functional group being part of it can be independently and suitably protected or activated;
- 3) preparation of the backbone chelating moiety in a suitable form wherein any functional group, either involved or not in the metal coordination and covalent binding with the rest of the molecule, can be suitably and independently protected or activated;
- and, optionally, wherein the chelating moiety can be already complexed with the selected paramagnetic metal ion;
- 4) coupling of the chelating moiety with groups L and R, in any suitable order, upon cleavage of any selected protecting group and/or activation of any selected functional group, in any of the chelating moiety and L and R moieties;
- 5) cleavage of any protecting group and isolation of the compound of formula (III) or (IIIa);
- and, optionally
- 6) complexation of the compound of formula (III) or (IIIa) with the selected paramagnetic metal ion, followed by isolation of the chelated complex and/or the salt thereof.
Dependencies are inferred from the claim text.