Gadolinium chelate compounds for use in magnetic resonance imaging

Patent metadata

Field	Value
Publication number	US-10722601-B2
Application number	US-201816192185-A
Country	US
Kind code	B2
Filing date	Nov 15, 2018
Priority date	Jun 4, 2015
Publication date	Jul 28, 2020
Grant date	Jul 28, 2020

Abstract

A compound having the formula of tetragadolinium [4,10-bis(carboxylatomethyl)-7-{-3,6,12,15-tetraoxo-16-[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]-9,9-bis({[{2-[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propanoyl} amino)acetyl]amino}methyl)-4,7,11,14-tetraazaheptadecan-2-yl}-1,4,7,10-tetraazacyclo dodecan-1-yl]acetate wherein the stereochemistry at the chiral carbon of the four alanine substituents is selected from the group consisting of RRRR, SSSS, RSSS, RRSS, and RRRS stereoisomers, and racemic and diastereomeric mixtures of any thereof, or a tautomer, a hydrate, a solvate, or a salt thereof, or a mixture of same is described. The compounds may be used as an MRI contrast imaging agent.

First claim

The invention claimed is:

1. A compound comprising a formula according to formula (I):

wherein a stereochemistry at the chiral carbon of the four alanine substituents is selected from the group consisting of RRRR, SSSS, RSSS, RRSS, and RRRS stereoisomers, and racemic and diastereomeric mixtures of any thereof,
or a tautomer, a hydrate, a solvate, or a salt thereof, or a mixture of same.

2. The compound of claim 1 , wherein the compound has the formula:
Tetragadolinium [4,10-bis(carboxylatomethyl)-7-{(2R,16R)-3,6,12,15-tetraoxo-16-[4,7,10-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]-9,9-bis({[({(22R)-2-[4,7,10-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propanoyl}amino)acetyl]-amino}methyl)-4,7,11,14-tetraazaheptadecan-2-yl}-1,4,7,10-tetraazacyclododecan-1-yl]acetate,
or a tautomer, a hydrate, a solvate, or a salt thereof, or a mixture of same.

3. The compound of claim 1 , wherein the compound has the formula:
Tetragadolinium [4,10-bis(carboxylatomethyl)-7-{(2S,16S)-3,6,12,15-tetraoxo-16-[4,7,10-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]-9,9-bis({[({(22S)-2-[4,7,10-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propanoyl}amino)acetyl]-amino}methyl)-4,7,11,14-tetraazaheptadecan-2-yl}-1,4,7,10-tetraazacyclododecan-1-yl]acetate,
or a tautomer, a hydrate, a solvate, or a salt thereof, or a mixture of same.

4. The compound of claim 1 , wherein the compound has the formula:
Tetragadolinium [4,10-bis(carboxylatomethyl)-7-{(2R,16S)-3,6,12,15-tetraoxo-16-[4,7,10-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]-9,9-bis({[({(22S)-2-[4,7,10-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propanoyl}amino)acetyl]-amino}methyl)-4,7,11,14-tetraazaheptadecan-2-yl}-1,4,7,10-tetraazacyclododecan-1-yl]acetate,
or a tautomer, a hydrate, a solvate, or a salt thereof, or a mixture of same.

5. The compound of claim 1 , wherein the compound has the formula:
Tetragadolinium [4,10-bis(carboxylatomethyl)-7-{(2R,16R)-3,6,12,15-tetraoxo-16-[4,7,10-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]-9,9-bis({[({(22S)-2-[4,7,10-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propanoyl}amino)acetyl]-amino}methyl)-4,7,11,14-tetraazaheptadecan-2-yl}-1,4,7,10-tetraazacyclododecan-1-yl]acetate,
or a tautomer, a hydrate, a solvate, or a salt thereof, or a mixture of same.

6. The compound of claim 1 , wherein the compound has the formula:
Tetragadolinium [4,10-bis(carboxylatomethyl)-7-{(2S,16R)-3,6,12,15-tetraoxo-16-[4,7,10-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]-9,9-bis({[({(22R)-2-[4,7,10-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propanoyl}amino)acetyl]-amino}methyl)-4,7,11,14-tetraazaheptadecan-2-yl}-1,4,7,10-tetraazacyclododecan-1-yl]acetate,
or a tautomer, a hydrate, a solvate, or a salt thereof, or a mixture of same.

7. The compound of claim 1 , wherein the compound is a racemic mixture of compounds, and wherein the stereochemistry of the racemic mixture is selected from the group consisting of: RRRR and SSSS stereoisomers; and RSSS and SRRR stereoisomers.

8. The compound of claim 1 , wherein the compound is a diastereomeric mixture of two or more of RRRR, SSSS, RSSS, SRRR, and RRSS stereoisomers.

9. A compound comprising a formula according to formula (II):

wherein a stereochemistry at the chiral carbon of the four alanine substituents is selected from the group consisting of RRRR, SSSS, RSSS, RRSS, and RRRS stereoisomers, and racemic and diastereomeric mixtures of any thereof,
or a tautomer, a hydrate, a solvate, or a salt thereof, or a mixture of same.

10. The compound of claim 9 , wherein the compound has the formula:
{4,10-bis(carboxymethyl)-7-[(2R,16R)-3,6,12,15-tetraoxo-16-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]-9,9-bis({[({(22R)-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propanoyl}amino)acetyl]amino}methyl)-4,7,11,14-tetraazaheptadecan-2-yl}-1,4,7,10-tetraazacyclododecan-1-yl}-acetic acid,
or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

11. The compound of claim 9 , wherein the compound has the formula:
{4,10-bis(carboxymethyl)-7-[(2S,16S)-3,6,12,15-tetraoxo-16-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]-9,9-bis({[({(22S)-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propanoyl}amino)acetyl]amino}methyl)-4,7,11,14-tetraazaheptadecan-2-yl}-1,4,7,10-tetraazacyclododecan-1-yl}-acetic acid,
or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

12. The compound of claim 9 , wherein the compound has the formula:
{4,10-bis(carboxymethyl)-7-[(2S,16S)-3,6,12,15-tetraoxo-16-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]-9,9-bis({[({(22R)-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propanoyl}amino)acetyl]amino}methyl)-4,7,11,14-tetraazaheptadecan-2-yl}-1,4,7,10-tetraazacyclododecan-1-yl}-acetic acid,
or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

13. The compound of claim 9 , wherein the compound has the formula:
{4,10-bis(carboxymethyl)-7-[(2S,16R)-3,6,12,15-tetraoxo-16-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]-9,9-bis({[({(22R)-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propanoyl}amino)acetyl]amino}methyl)-4,7,11,14-tetraazaheptadecan-2-yl}-1,4,7,10-tetraazacyclododecan-1-yl}-acetic acid,
or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

14. The compound of claim 9 , wherein the compound has the formula:
{4,10-bis(carboxymethyl)-7-[(2R,16S)-3,6,12,15-tetraoxo-16-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]-9,9-bis({[({(22S)-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propanoyl}amino)acetyl]amino}methyl)-4,7,11,14-tetraazaheptadecan-2-yl}-1,4,7,10-tetraazacyclododecan-1-yl}-acetic acid,
or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

15. A method of imaging body tissue in a patient, comprising:
administering to the patient an effective amount of one or more compounds having a formula according to Formula (I) according to claim 1 in a pharmaceutically acceptable carrier; and
subjecting the patient to a magnetic resonance imaging procedure.

16. The method of claim 15 , wherein less than 0.5% of the one or more compounds are present in the patient seven days after the administration.

Assignees

• Bayer Pharma AG

Inventors

• Berger Markus
• Lohrke Jessica
• Hilger Christoph-Stephan
• Jost Gregor
• Frenzel Thomas
• Suelzle Detlev
• Platzek Johannes
• Panknin Olaf
• Pietsch Hubertus

Classifications

• A61K49/108

  the metal complex being Gd-DOTA · CPC title

• A61K49/106 Primary

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

• A61K49/105 Primary

  the metal complex being Gd-DTPA · CPC title

• A61K49/10

  Organic compounds · CPC title

• C07D257/02 Primary

  not condensed with other rings · CPC title