Gadolinium chelate compounds for use in magnetic resonance imaging
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.
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-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,
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, and
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,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
7. A method of preparing a compound of general formula (I-d), the method comprising:
reacting a compound of formula 4,
in which has a structure:
where each group * represents a hydrogen atom or a salt thereof,
with a compound of general formula (III):
in which R 5 is a hydrogen atom or a methyl group, and LG represents an activating leaving group selected from the group consisting of pentafluorophenol, 4-nitrophenol, 1-hydroxypyrrolidine-2,5-dione, hydroxybenzotriazole, and 3H-[1,2,3]triazolo[4,5-b]pyridine-3-ol,
to afford a compound of general formula (I-d):
8. A method of imaging body tissue in a patient, comprising:
administering to the patient an effective amount of one or more compounds according to claim 1 in a pharmaceutically acceptable carrier, and
subjecting the patient to a magnetic resonance imaging procedure.
9. A compound of general formula (III):
in which R 5 is a hydrogen atom or a methyl group, and LG represents an activating leaving group selected from the group consisting of pentafluorophenol, hydroxybenzotriazole, and 3H-[1,2,3]triazolo[4,5-b]pyridine-3-ol.
10. The compound of claim 1 , wherein the compound is:
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, or
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
11. A compound of general formula (II), comprising:
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.
12. The compound of claim 11 , wherein the compound is selected from the group consisting of:
[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;
{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;
{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;
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;
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;
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;
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;
{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; and
[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,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
13. The compound of claim 1 , wherein the compound is:
[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, or
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.