Complex of gadolinium and a chelating ligand derived from a diastereoisomerically enriched PCTA and preparation and purification process
Inventors
le Greneur, Soizic • CHÉNEDÉ, Alain • Cerf, Martine • Petta, Myriam • MARAIS, EMMANUELLE • François, Bruno • Robic, Caroline • LOUGUET, Stéphanie
Assignees
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Publication Number
US-11590246-B2
Publication Date
2023-02-28
Expiration Date
Abstract
The present invention relates to a complex of formula (II) constituted of at least 90% of a diastereoisomeric excess comprising a mixture of isomers II-RRR and II-SSS of formulae: The present invention also relates to a process for preparing and purifying said complex of formula (II), and also to a composition comprising said complex.
Core Innovation
The invention relates to gadolinium complexes for MRI, providing a diastereoisomerically enriched complex of formula (II) comprising a mixture of isomers II-RRR and II-SSS with diastereoisomeric excess. The disclosed diastereoisomer families arise from asymmetric carbons, with isomers identified by UHPLC/HPLC, including iso1–iso4 and isoD. The enrichment concept is based on conversion via an intermediate hexaacid gadolinium complex of formula (I) to enrich an isomeric family and ultimately to achieve enrichment toward iso4 in the complex of formula (II).
The composition concept combines the enriched complex of formula (II) with a free macrocyclic ligand to achieve very low free gadolinium concentrations, stated as less than 1 ppm (m/v). A free macrocyclic ligand, exemplified by free DOTA, is used with an explicitly defined free macrocyclic ligand content relative to the complex, enabling the low free gadolinium level in the context of improved complex stability. The document further frames the relevance to nephrogenic systemic fibrosis (NSF) and gadolinium deposition and contrasts macrocyclic versus linear GBCA.
The document also describes preparation and purification of gadolinium DOTA-based complexes in which diastereoisomeric enrichment is obtained for complexes of formula (II), including a mixture of isomers II-RRR and II-SSS having a diastereoisomeric excess of at least 80% and higher. It teaches purification of the diastereoisomer-enriched complex using ion-exchange resin(s) and ultrafiltration to remove impurities, including 3-amino-1,2-propanediol and dicoupled impurities, and reports isolation of the complex in solid form with purity and diastereoisomeric excess ranges.
Claims Coverage
The partial claims provided include two independent composition claims, each requiring a complex of formula (II) with a specified diastereoisomeric excess, together with a free macrocyclic ligand and a very low free gadolinium concentration. Across the independent claims, the key inventive features are: (i) diastereoisomerically enriched formula (II) complex, (ii) the presence of a free macrocyclic ligand, and (iii) a free gadolinium concentration of less than 1 ppm (m/v) with a specified free ligand-to-complex level, with one claim further requiring DOTA as the free macrocyclic ligand.
Diastereoisomerically enriched complex of formula (II)
A composition comprising a complex of formula (II) having a diastereoisomeric excess of at least 80% or at least 90% of a mixture of isomers II-RRR and II-SSS.
Free macrocyclic ligand with very low free gadolinium
A composition comprising a free macrocyclic ligand, wherein the composition has a concentration of free gadolinium of less than 1 ppm (m/v), and wherein the composition comprises from 0.002 to 0.4 mol/mol % of free macrocyclic ligand relative to the complex of formula (II).
DOTA as the free macrocyclic ligand
A composition comprising a free macrocyclic ligand being DOTA, wherein the composition has a concentration of free gadolinium of less than 1 ppm (m/v), and wherein the composition comprises from 0.002 to 0.4 mol/mol % of DOTA relative to the complex of formula (II).
Overall, the independent claims define compositions that pair a highly diastereoisomerically enriched complex of formula (II) with a free macrocyclic ligand, while requiring free gadolinium below 1 ppm (m/v) and a specified free ligand-to-complex level. One claim further restricts the free macrocyclic ligand to DOTA.
Stated Advantages
Improved thermodynamic stability and kinetic inertia versus other iso groups.
Very low free gadolinium concentration, stated as less than 1 ppm (m/v).
The low free gadolinium level is presented in the context of reducing risks associated with nephrogenic systemic fibrosis (NSF) and gadolinium deposition.
Endotoxin-removal advantage.
Documented Applications
MRI using gadolinium complexes with diastereoisomerically enriched complex of formula (II).
Contextual relevance to nephrogenic systemic fibrosis (NSF) and gadolinium deposition.
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