Complex of gadolinium and a chelating ligand derived from a diastereoisomerically enriched PCTA and preparation and purification process

Patent metadata

Field	Value
Publication number	US-11590246-B2
Application number	US-202017423638-A
Country	US
Kind code	B2
Filing date	Jan 17, 2020
Priority date	Jan 17, 2019
Publication date	Feb 28, 2023
Grant date	Feb 28, 2023

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.

First claim

The invention claimed is:

1. A composition comprising:
1) A complex of formula (II) below:

having a diastereoisomeric excess of at least 80% of a mixture of isomers II-RRR and II-SSS of formulae:

and

and
2) 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).

2. The composition of claim 1 , wherein the composition comprises from 0.01 to 0.3 mol/mol % of free macrocyclic ligand relative to the complex of formula (II).

3. The composition of claim 1 , wherein the complex of formula (II) has a diastereoisomeric excess of at least 90%.

4. The composition of claim 1 , wherein the degree of purity of the complex of formula (II) is greater than 95% evaluated by chromatography.

5. The composition of claim 1 , wherein the degree of purity of the complex of formula (II) is greater than 97% evaluated by chromatography.

6. The composition of claim 1 , wherein the complex of formula (II) has a diastereoisomeric excess of at least 92%.

7. The composition of claim 1 , wherein the complex of formula (II) has a diastereoisomeric excess of at least 94%.

8. The composition of claim 1 , wherein the isomers II-RRR and II-SSS are present in the mixture in a ratio of between 60/40 and 40/60.

9. The composition of claim 1 , wherein the composition has a concentration of complex of formula (II) of between 0.01 and 1.5 mol·L −1 .

10. The composition of claim 1 , wherein the composition has a concentration of complex of formula (II) of between 0.2 and 0.7 mol·L −1 .

11. The composition of claim 1 , wherein the composition has a concentration of complex of formula (II) of between 0.3 and 0.6 mol·L −1 .

12. The composition of claim 1 , wherein the free macrocyclic ligand is selected from the group constituted of DOTA, NOTA, DO3A, BT-DO3A, HP-DO3A, PCTA, DOTA-GA and derivatives thereof.

13. The composition of claim 1 , wherein the free macrocyclic ligand is DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid).

14. The composition of claim 1 , wherein the pH of the composition is between 4.5 and 8.5.

15. The composition of claim 1 , wherein the pH of the composition is between 6.5 and 8.

16. The composition of claim 1 , wherein the composition further comprises a buffer selected from the group consisting of lactate, tartrate, malate, maleate, succinate, ascorbate, carbonate, Tris (Tris(hydroxymethyl)aminomethane), HEPES (2-[4-(2-hydroxyethyl)-1-piperazine]ethanesulfonic acid), MES (2-morpholinoethanesulfonic acid) buffers and mixtures thereof.

17. The composition of claim 1 , wherein the composition further comprises a buffer being Tris (Tris(hydroxymethyl)aminomethane).

18. A composition comprising:
1) A complex of formula (II) below:

having a diastereoisomeric excess of at least 90% of a mixture of isomers II-RRR and II-SSS of formulae:

and

and
2) 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).

19. The composition of claim 18 , wherein the composition has a concentration of complex of formula (II) of between 0.3 and 0.6 mol·L −1 .

20. The composition of claim 18 , wherein the composition further comprises a buffer being Tris (Tris(hydroxymethyl)aminomethane) and has a pH between 6.5 and 8.

Assignees

• Guerbet Sa

Inventors

• Le Greneur Soizic
• Chénedé Alain
• Cerf Martine
• Petta Myriam
• Marais Emmanuelle
• François Bruno
• Robic Caroline
• Louguet Stéphanie

Classifications

• A61K49/106 Primary

  the complex-forming compound being cyclic, e.g. DOTA · CPC title

• A61K49/08

  characterised by the carrier · CPC title

• C07F5/003 Primary

  without C-Metal linkages · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D471/08 Primary

  Bridged systems · CPC title