Gadolinium bearing PCTA-based contrast agents

Patent metadata

Field	Value
Publication number	US-10973934-B2
Application number	US-201916766619-A
Country	US
Kind code	B2
Filing date	Aug 6, 2019
Priority date	Aug 6, 2018
Publication date	Apr 13, 2021
Grant date	Apr 13, 2021

Abstract

The present invention relates to the RRR/SSS pair of enantiomers of the of Gd(PCTA-tris-glutaric acid), the single enantiomers of the pair, the pharmaceutically acceptable salts thereof, their amide derivatives, and compositions comprising at least 50% of these compounds.

First claim

The invention claimed is:

1. An isomeric mixture of Gd(PCTA-tris-glutaric acid) of formula

comprising at least 50% of
[(αR,α′R,α″R)-α,α′,α″-tris(2-carboxyethyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetato(3-)-κN3,κN6,κN9,κN15,κO3,κO6,κO9]-gadolinium having the formula Ia (enantiomer RRR):

and [(αS,α′S,α″S)-α,α′,α″-tris(2-carboxyethyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15), 11,13-triene-3,6,9-triacetato(3 9]-gadolinium having the formula Ib (enantiomer SSS):

or a pharmaceutically acceptable salt thereof.

2. The isomeric mixture of claim 1 wherein the pharmaceutically acceptable salt is with (i) a cation of an inorganic base selected from an alkali-earth metal, alkaline-earth metal, potassium, sodium, calcium and magnesium, or of (ii) an organic base selected from ethanolamine, diethanolamine, morpholine, glucamine, N-methylglucamine, and N,N-dimethylglucamine or of (iii) an amino acid selected from lysine, arginine and ornithine or with (iv) an anions of inorganic acids selected from halo acids, chlorides, bromides and iodides, or of (v) other suitable ions selected from acetate, succinate, citrate, fumarate, maleate and oxalate.

3. An isomeric mixture of an amide derivative of Gd(PCTA-tris-glutaric acid) having the formula (II B)
F′(NR 1 R 2 ) 3   (II B)

in which:
F′ is an isomeric mixture of a Gd(PCTA-tris-glutaric acid) residue of formula III,

said isomeric mixture of Gd(PCTA-tris-glutaric acid) residue comprising at least 50% of a RRR enantiomer residue of formula IIIa:

and a SSS enantiomer residue of formula IIIb:

and each of the three —NR 1 R 2 groups is bound to an open bond of a respective carboxyl moiety (.) of F′;
R 1 is H or a C 1 -C 6 alkyl, optionally substituted by 1-4 hydroxyl groups; and
R 2 is a C 1 -C 6 alkyl optionally substituted by 1-4 hydroxyl groups.

4. The isomeric mixture according to claim 3 comprising at least 50% of an amide derivative selected from the group consisting of: [(αS,α′S,α″S)-α,α′,α″-tris[3-[(2(S),3-dihydroxypropyl)amino]-3-oxopropyl]-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15), 11,13-triene-3,6,9-triacetato(3-)-κN3,κN6,κN9,κN15,κO3,κO6,κO9]-gadolinium (isomer SSS-SSS); [(αS,α′S,α″S)-α,α′,α″-tris[3-[(2(R),3-dihydroxypropyl)amino]-3-oxopropyl]-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15), 11,13-triene-3,6,9-triacetato(3-)-κN3,κN6,κN9,κN15,κO3,κO6,κO9]-gadolinium (isomer SSS-RRR); [(αR,α′R,α″R)-α,α′,α″-tris[3-[(2(R),3-dihydroxypropyl)amino]-3-oxopropyl]-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetato(3-)-κN3,κN6,κN9,κN15,κO3,κO6,κO9]-gadolinium (isomer RRR-RRR); [(αR,α′R,α″R)-α,α′,α″-tris[3-[(2(S),3-dihydroxypropyl)amino]-3-oxopropyl]-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15), 11,13-triene-3,6,9-triacetato(3-)-κN3,κN6,κN9,κN15,κO3,κO6,κO9]-gadolinium (isomer RRR-SSS); and mixtures thereof.

5. The isomeric mixture according to claim 3 in which in the formula (II B) F′ comprises at least 60% of the mixture of RRR and SSS enantiomer residues.

6. A pharmaceutical composition comprising the isomeric mixture according to claim 1 in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.

7. A pharmaceutical composition comprising an isomeric mixture of an amide derivative of formula (II B) according to claim 3 in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients.

8. The pharmaceutical composition according to claim 7 in which in the formula (II B) R 1 is H and R 2 is —CH 2 CH(OH)CH 2 OH.

9. The isomeric mixture according to claim 3 in which in the formula (II B) F′ comprises at least 70% of the RRR and SSS enantiomers residues.

10. The isomeric mixture according to claim 3 in which in the formula (II B) F′ comprises at least 80% of the RRR and SSS enantiomers residues.

11. The isomeric mixture according to claim 3 in which in the formula (II B) F′ comprises at least 90% of the RRR and SSS enantiomers residues.

12. The isomeric mixture according to claim 3 , wherein R 2 is a C 1 -C 3 alkyl substituted by one or two hydroxyl groups.

13. The isomeric mixture according to claim 3 wherein, in the formula (II B), R 1 is H and R 2 is C 1 -C 3 alkyl substituted by one or two hydroxyl groups.

14. The isomeric mixture according to claim 13 wherein, in the formula (II B), R 1 is H and R 2 is —CH 2 CH(OH)CH 2 OH.

15. The pharmaceutical composition according to claim 7 in which in the formula (II B) F′ comprises at least 70% of the RRR and SSS enantiomers residues.

16. The isomeric mixture of claim 2 wherein the pharmaceutically acceptable salt is with a cation of an inorganic base selected from potassium, sodium, calcium and magnesium.

Assignees

• Bracco Imaging Spa

Inventors

• Napolitano Roberta
• Lattuada Luciano
• Baranyai Zsolt
• Guidolin Nicole
• Marazzi Giuseppe

Classifications

• C07F5/003

  without C-Metal linkages · CPC title

• A61K49/108

  the metal complex being Gd-DOTA · CPC title

• C07D471/08 Primary

  Bridged systems · CPC title

• A61K49/106 Primary

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