Dimeric contrast agents

Patent metadata

Field	Value
Publication number	US-10407412-B2
Application number	US-201616060754-A
Country	US
Kind code	B2
Filing date	Dec 12, 2016
Priority date	Dec 10, 2015
Publication date	Sep 10, 2019
Grant date	Sep 10, 2019

Abstract

The present invention relates to new class of dimeric macrocycles 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.

First claim

The invention claimed is:

1. A compound having the following formula (II)

in which:
m is 1, 2, 3, 4, 5, or 6;
n is 1 or 2; and
R 2 is a C 5 -C 12 polyol comprising 4-11 hydroxyl groups, or a physiologically acceptable salt thereof.

2. The compound according to claim 1 in which the polyol is selected from the group consisting of pentyl-polyols comprising 4 hydroxyl groups on a C 5 alkyl chain; hexyl-polyols comprising from 4 to 5 hydroxyl groups on a C 6 alkyl chain; and heptyl-polyols comprising from 4 to 6 hydroxyl groups on a C 7 alkyl chain.

3. The compound according to claim 1 in which the polyol is selected from the group consisting of a pentyl-tetraol of formula

and a hexyl-pentaol of formula

4. The compound according to claim 1 of formula

5. A chelated complex of a compound according to claim 1 with two paramagnetic metal ions 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 a physiologically acceptable salt thereof.

6. The chelated complex according to claim 5 , wherein the paramagnetic metal ions are Gd 3+ ions.

7. The compound according to claim 1 , wherein the physiologically acceptable salt is with a cation of (i) an inorganic base selected from an alkali metal and alkaline-earth metal, (ii) an organic base selected from ethanolamine, diethanolamine, morpholine, glucamine, N-methylglucamine, and N,N-dimethylglucamine or (iii) an amino acid selected from lysine, arginine and ornithine.

8. The chelated complex according to claim 5 , wherein the physiologically acceptable salt is with a cation of (i) an inorganic base selected from an alkali metal and alkaline-earth metal, (ii) an organic base selected from ethanolamine, diethanolamine, morpholine, glucamine, N-methylglucamine, and N,N-dimethylglucamine or (iii) an amino acid selected from lysine, arginine and ornithine.

9. A method of MR imaging comprising:
administering the chelated complex as defined in claim 5 to a patient;
submitting the patient to a radiation frequency selected to excite non-zero proton spin nuclei of the chelated complex; and
recording a MR signal from said nuclei.

10. A pharmaceutical composition comprising:
a chelated complex of claim 5 and
at least one of a pharmaceutically acceptable carrier, a diluent an excipient and combinations thereof.

Assignees

• Bracco Imaging Spa

Inventors

• Boi Valeria
• Napolitano Roberta
• Lattuada Luciano

Classifications

• C07D257/02 Primary

  not condensed with other rings · CPC title

• A61K49/122

  dimers of complexes or complex-forming compounds · CPC title

• C07D403/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K49/108

  the metal complex being Gd-DOTA · CPC title

• A61K49/105

  the metal complex being Gd-DTPA · CPC title