Gadolinium chelate compounds for use in magnetic resonance imaging

Patent metadata

Field	Value
Publication number	US-10137209-B2
Application number	US-201615578687-A
Country	US
Kind code	B2
Filing date	May 30, 2016
Priority date	Jun 4, 2015
Publication date	Nov 27, 2018
Grant date	Nov 27, 2018

Abstract

The present invention relates to a new class of high relaxivity extracellular gadolinium chelate complexes, to methods of preparing said compounds, and to the use of said compounds as MRI contrast agents.

First claim

The invention claimed is:

1. A compound of general formula (I), comprising 4, 5, 6, 7 or 8 gadolinium [4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl] groups,

in which:
represents a group selected from:

in which * on the A group indicates a point of attachment of the A group with R 1 ;
R 1 represents, independently from each other, a hydrogen atom or a substituent group selected from:

R 3 ,

in which * on the substituent group indicates a point of attachment of the substituent group with A group,
with the proviso that zero or only one of the R 1 groups present in the compound represent a hydrogen atom;
n represents an integer of 3 or 4;
R 2 represents, independently from each other, a hydrogen atom or a methyl group;
R 3 represents a group selected from:

in which * on the R 3 group indicates a point of attachment of the R 3 group with a nitrogen on the A group or the substituent group;
R 4 represents, independently from each other, a hydrogen atom or a methyl group; and
R 5 represents, independently from each other, a hydrogen atom or a methyl group;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

2. The compound of claim 1 , wherein the compound comprises 4, 5, or 6 gadolinium [4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl] R 3 groups, and wherein:
represents a group selected from:

in which * on the A group indicates a point of attachment of the A group with R 1 .

3. The compound of claim 1 , wherein the compound comprises 4, 5, or 6 gadolinium [4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl] R 3 groups, and wherein:
represents a group selected from:

in which * on the A group indicates a point of attachment of the A group with R 1 ;
R 2 represents a hydrogen atom;
R 3 represents a group selected from:

in which * on the R 3 group indicates a point of attachment of the R 3 group with a nitrogen on the A group or the substituent group; and
R 4 represents a hydrogen atom;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

4. The compound of claim 1 , wherein the compound comprises 4, 5, or 6 gadolinium [4,7,10-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl] R 3 groups, and wherein:
represents a group selected from:

in which * on the A group indicates a point of attachment of the A group with R 1 ;
R 2 represents a hydrogen atom;
R 3 represents a group selected from:

in which * on the R 3 group indicates a point of attachment of the R 3 group with a nitrogen on the A group or the substituent group;
R 4 represents a hydrogen atom; and
R 5 represents a methyl group;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

5. The compound of claim 1 , wherein the compound is selected from the group consisting 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-tetraazacyclododecan-1-yl]acetate,
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({[({(2R)-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,
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({[({(2S)-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,
Hexagadolinium 2,2′,2″,2′″,2″″,2′″″,2″″″,2′″″″,2″″″″,2′″″″″,2″″″″″,2′″″″″″,2″″″″″″,2′″″″″″″,2″″″″″″″, 2′″″″″″″″,2″″″″″″″″,2′″″″″″″″″-(1,4,7-triazonane-1,4,7-triyltris{carbonyl-1,4-diazepane-6,1,4-triylbis[(2-oxoethane-2,1-diyl)imino(1-oxopropane-1,2-diyl)-1,4,7,10-tetraazacyclododecane-10,1,4,7-tetrayl]}) octadecaacetate,
Tetragadolinium 2,2′,2″,2′″,2″″,2′″″,2″″″,2′″″″,2″″″″,2′″″″″,2″″″″″,2′″″″″″-{1,4,7,10- tetraazacyclododecane-1,4,7,10-tetrayltetrakis[(2-oxoethane-2,1-diyl)imino(1-oxopropane-1,2-diyl)-1,4,7,10-tetraazacyclododecane-10,1,4,7-tetrayl]}dodecaacetate,
Hexagadolinium 2,2′,2″,2′″,2″″,2′″″,2″″″,2′″″″,2″″″″,2′″″″″,2″″″″″,2′″″″″″,2″″″″″″,2′″″″″″″,2″″″″″″″, 2′″″″″″″″,2″″″″″″″″,2′″″″″″″″″-{3,7,10-triazatricyclo[3.3.3.0 1,5 ]undecane-3,7,10-triyltris[carbonyl-(3,6,11,14-tetraoxo-4,7,10,13-tetraazahexadecane-8,2,15-triyl)di-1,4,7,10-tetraazacyclododecane-10,1,4,7-tetrayl]}octadecaacetate,
Tetragadolinium 2,2′,2″,2′″,2″″,2′″″,2″″″,2′″″″,2″″″″,2′″″″″,2″″″″″,2′″″″″″-(3,7,9-triazabicyclo-[3.3.1]nonane-3,7-diylbis{carbonyl-1,4-diazepane-6,1,4-triylbis[(2-oxoethane-2,1-diyl)-1,4,7,10-tetraazacyclododecane-10,1,4,7-tetrayl]})dodecaacetate,
Tetragadolinium [4,10-bis(carboxylatomethyl)-7-{2,5,11,14-tetraoxo-15-[4,7,10-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]-8,8-bis({[({[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetyl}amino)acetyl]amino}methyl)-3,6,10,13-tetraazapentadec-1-yl}-1,4,7,10-tetraazacyclododecan-1-yl]acetate, and
Tetragadolinium {4,10-bis(carboxylatomethyl)-7-[2-oxo-2-({3-({[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetyl}amino)-2,2-bis[({[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetyl}amino)methyl]propyl}amino)ethyl]-1,4,7,10-tetraazacyclododecan-1-yl}acetate,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

6. The compound of claim 1 , wherein the compound is selected from the group consisting 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-tetraazacyclododecan-1-yl]acetate,
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({[({(2R)-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-tetr

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

• C07D257/02 Primary

  not condensed with other rings · CPC title

• A61K49/10

  Organic compounds · CPC title

• C07C229/16

  to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids · CPC title

• A61K49/105 Primary

  the metal complex being Gd-DTPA · CPC title

• A61K49/108

  the metal complex being Gd-DOTA · CPC title