Contrast agents
AssigneeBracco Imaging S.P.A.
InventorsLuciano LATTUADA, Roberta NAPOLITANO, Valeria BOI, Massimo VISIGALLI, Silvio AIME, Giovanni Battista GIOVENZANA, Alberto FRINGUELLO MINGO
Life of this patent
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Abstract
The present invention relates to new class of functionalized polyazamacrocycles including at least one phosphonic or phosphinic group linked to a nitrogen atom of the macrocyclic cage, and capable of chelating paramagnetic metal ions, their chelated complexes with metal ions and the use thereof as contrast agents, particularly suitable for Magnetic Resonance Imaging (MRI) analysis.
Claims29
(canceled)
A compound according to claim 1 in which L in the formula (I) is a direct bond, and Z is a substituted phenyl, or a C1-C6 alkyl chain that is optionally interrupted by one or more groups selected from —O—, —NH— and —CO—, and is substituted by one or more groups selected from hydroxyl, carboxyl, halogen atoms, or by a group of formula —O—(CH2)m—Ar, —NHSO2R5, —NHC(O)NHR6, —NHC(O)OR7 or —NR8R9.
(canceled)
(canceled)
A compound according to claim 1 in which in the formula (I) Z is a macrocyclic residue of formula —W—G—W′—T, having the formula (IX)
- in which:
- L is an alkylene chain —(CH2)n— where n is an integer from 1 to 3;
- W and W′ represent, the same or different from each other, a divalent group selected from —O—, —SO2NH—, —NHSO2—, —CONH— and —NHCO—;
- G is a bifunctional residue selected from a phenylene (—C6H4—) and a C1-C5 linear or branched alkylene optionally interrupted by one or more oxygen atoms, and optionally substituted by one or more groups selected from hydroxyl, phenyl and carboxyl.
(canceled)
A compound according to claim 1 in which in the formula (I) one of Y1, Y2 and Y3 is a carboxyl of formula —COOR′ and the other two, independently from one another, are selected from —PO(OR′)2 and —PO(R4)(OR′).
A compound according to claim 1 in which in the formula (I) one of Y1, Y2 and Y3 is selected from —PO(OR′)2 and —PO(R4)(OR′) and the remaining two are carboxyls of formula —COOR′.
A compound according to claim 1 in which in the formula (I) R′ is H.
A compound of formula (I) according to claim 1 selected from the group consisting of:
- and the physiologically acceptable salt thereof.
A compound of formula (I) according to claim 1, in the form of a complex with a paramagnetic metal ion selected from the group consisting of Fe(2+), Fe(3+), Cu(2+), Cr(3+), Gd(3+), Eu(3+), Dy(3+). La(3+), Yb(3+) and Mn(2+), or of a physiologically acceptable salt thereof.
(canceled)
A compound of formula (I) according to claim 1, wherein the physiologically acceptable salt is with a cation of an inorganic base selected from an alkali or alkaline-earth metal selected from potassium, sodium, calcium or magnesium, or of an organic base selected from ethanolamine, diethanolamine, morpholine, glucamine, N-methylglucamine, N,N-dimethylglucamine or of an amino acid selected from lysine, arginine and omithine or, optionally, with an anions of inorganic acids selected from halo acids as well as of other suitable ions selected from acetate, succinate, citrate, fumarate, maleate or oxalate.
(canceled)
A process for the preparation of the compounds of formula (I) as defined in claim 1 comprising the following main steps:
- a) Obtaining a macrocyclic substrate 1 in a suitable protected form, e.g. in which the carboxylic groups of the substrate are protected as tert-butyl esters;
- b) Obtaining an alkylating molecule 2, in which any optional functional group(s) not involved with the coupling reaction with the substrate 1 is suitably protected;
- c) Coupling the protected substrate 1 with the alkylating molecule 2, to give the desired compound of formula (I) in a suitably protected form or, alternatively, an intermediate thereof 3;
- d) Optionally converting the intermediate obtained at the step c) of the process in the suitably protected compound of formula (I);
- e) Removing any protecting group and isolating the cheating ligand of formula (I);
- and
- f) Complexing the obtained ligand with a suitable paramagnetic metal ion and isolating the chelate complex, or the salt thereof.
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(canceled)
A compound according to claim 1 in which in the formula (I) R1, R2 and R3 are H.
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Dependencies are inferred from the claim text.