Lanthanide complexes, preparation and uses thereof
View Patent ↗The invention relates to compounds, to the complexes they form with a lanthanide, and to the use of the complexes for fluorescence marking or NMR imaging. The complex consists of an Ln ion and a ligand R 2 —C(X—R 1 )(R 3 )—NR 4 R 5 . R 1 is a functional group, X is a single bond or a hydrocarbon-based chain consisting of at least one alkylene or alkenylene group optionally comprising at least one hetero atom or an arylene. R 2 is an anionic group A 2 or a C 1 -C 4 alkylene or alkenylene group bearing at least one such group A 2 and optionally comprising at least one hetero atom. R 3 is H or a C 1 -C 5 alkylene or alkenylene group optionally containing at least one hetero atom, and optionally bearing at least one anionic group A 3 . R 4 is a substituent with light-absorbing properties that forms chelate rings with Ln. R 5 is a substituent that forms chelate rings with Ln.
1. A process for preparing a lanthanide complex comprising reacting a compound of formula (I)
with a compound comprising a lanthanide cation,
wherein in the compound of formula (I):
R 1 is a functional group capable of reacting with the functions present on proteins, antibodies or on mineral or organic materials;
X represents a single bond or a hydrocarbon-based chain consisting of at least one group chosen from alkylene groups and alkenylene groups optionally comprising at least one hetero atom, and from arylene groups;
R 2 is a group A 2 that is anionic at neutral pH or an alkylene or alkenylene group containing from 1 to 4 carbon atoms and bearing at least one such group A 2 , said alkylene or alkenylene group optionally comprising at least one hetero atom in the chain;
R 3 represents H or an alkylene or alkenylene group containing from 1 to 5 carbon atoms and optionally containing at least one hetero atom in the chain, said group optionally bearing at least one group A 3 that is anionic at neutral pH;
R 4 is chosen from the groups corresponding to the formula —(C) n —C—Z 1 —C—C—Z 2 —C—A 4 in which n is equal to 1 or 2, Z 1 and Z 2 represent, independently of each other, a hetero atom chosen from O and N, at least one being a nitrogen atom forming part of an aromatic heterocycle with the two carbon atoms surrounding it, and A 4 is a group that is anionic at neutral pH, in which the atom bearing the anionic charge is in the γ position relative to Z 2 ; and
R 5 is chosen from the groups defined for R 4 or from groups corresponding to the formula —C—C—E 1 —C—C—E 2 —C—A 5 in which E 1 and E 2 represent, independently of each other, a hetero atom chosen from O and N, and A 5 is a group that is anionic at neutral pH, in which the atom bearing the anionic charge is in the γ position relative to E 2 .
2. The process as claimed in claim 1 , wherein the compound comprising a lanthanide cation is selected from the group consisting of lanthanide halide hydrates, lanthanide nitrate hydrates, lanthanide carbonates and lanthanide triflates.
3. The process as claimed in claim 1 , wherein the reaction is performed in solution in a solvent selected from the group consisting of water, methanol, ethanol and acetonitrile.
4. The process as claimed in claim 1 , wherein compound of formula (I) is reacted with the lanthanide ion precursor in a mixture of methanol and water at a pH ranging from 3 to 5, for a time of between 10 minutes and 24 hours, at a temperature of between 25° C. and 80° C., and the pH of the solution is then adjusted to 7.0 and the methanol is evaporated off.
5. A complex obtained via a process as claimed in claim 1 , wherein the complex comprises a lanthanide ion Ln complexed with a ligand corresponding to a compound of formula (I).
6. The complex as claimed in claim 5 , wherein the lanthanide ion is selected from the group consisting of from europium, terbium, samarium, dysprosium, erbium, ytterbium, neodymium and gadolinium ions.
7. The complex as claimed in claim 5 , wherein the substituent R 4 of the compound of formula (I) is —C—C—Z 1 —C—C—Z 2 —C—A 4 , the 3 chelate rings being formed between the lanthanide cation and, respectively:
the N atom bearing R 4 and R 5 , Z 1 and the carbon atoms that separate them;
Z 1 , Z 2 and the two carbon atoms that separate them;
the end segment Z 2 —C—A 4 .
8. The complex as claimed in claim 7 , wherein the substituent R 5 is of the same type as the substituent R 4 .
9. The complex as claimed in claim 7 , wherein the substituent R 5 is of the type —C—C—E 1 —C—C—E 2 —C—A 5 , three 5-membered chelate rings being formed between the lanthanide cation and, respectively:
the N atom bearing R 4 and R 5 , E 1 and the two carbon atoms that separate them;
E 1 , E 2 and the two carbon atoms that separate them;
the end segment E 2 —C—A 5 .
10. A process for the quantitative or qualitative analysis of a compound, comprising: covalently bonding to said compound a marker consisting of a complex as claimed in claim 8 , and detecting or quantifying the presence of the marked compound by means of the luminescence properties of the marker.
11. The process as claimed in claim 10 , wherein the complex is a europium, terbium, samarium or dysprosium complex.
12. The process as claimed in claim 10 , wherein the substituent R 1 of the complex is selected from amino, thio and carboxyl groups or from maleimido, N-succinimidyl ester and isothiocyano groups.
13. A relaxation agent for nuclear magnetic resonance, consisting of a complex as claimed in claim 5 .
14. The relaxation agent as claimed in claim 13 , wherein the complex is a gadolinium, europium or dysprosium complex.
15. The relaxation agent as claimed in claim 13 , wherein the complex is a complex in which the substituent R 1 is selected from amino, thio and carboxyl groups or from maleimido, N-succinimidyl ester and isothiocyano groups.