High relaxivity gadolinium chelate compounds for use in magnetic resonance imaging

Patent metadata

Field	Value
Publication number	US-10975060-B2
Application number	US-201716463076-A
Country	US
Kind code	B2
Filing date	Nov 24, 2017
Priority date	Nov 28, 2016
Publication date	Apr 13, 2021
Grant date	Apr 13, 2021

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),

wherein:
R 1 represents, independently from each other, a hydrogen atom or a methyl group; and
R 2 represents, independently from each other, a substituent selected from the group consisting of:
C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 6 -hydroxyalkyl, (C 1 -C 3 -alkoxy)-(C 2 -C 4 -alkyl)-, 2-(2-methoxyethoxy)ethyl, 2-(2-ethoxyethoxy)ethyl, oxetan-3-yl, tetrahydro-2H-pyran-4-yl, and phenyl,
wherein said C 1 -C 6 -alkyl group is optionally substituted, identically or differently, with a phenyl group, wherein the phenyl group is optionally substituted, one, two, or three times, identically or differently, with a halogen atom or a group selected from:
C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, and C 1 -C 3 -alkoxy, and

wherein when R 2 represents phenyl, the phenyl is optionally substituted, one, two, or three times, identically or differently, with a halogen atom or a group selected from:
C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, and C 1 -C 3 -alkoxy;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

2. The compound according to claim 1 , wherein:
R 1 represents a hydrogen atom; and
R 2 represents a substituent selected from the group consisting of:
C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 4 -hydroxyalkyl, (C 1 -C 3 -alkoxy)-(C 2 -C 4 -alkyl)-, oxetan-3-yl, tetrahydro-2H-pyran-4-yl, and phenyl,
wherein said C 1 -C 6 -alkyl group is optionally substituted, identically or differently, with a phenyl group, wherein the phenyl group is optionally substituted, one, two, or three times, identically or differently, with a halogen atom or a group selected from:
C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, and C 1 -C 3 -alkoxy, and

wherein when R 2 represents phenyl, the phenyl is optionally substituted, one, two, or three times, identically or differently, with a halogen atom or a group selected from:
C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, and C 1 -C 3 -alkoxy;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

3. The compound according to claim 1 , wherein:
R 1 represents a hydrogen atom; and
R 2 represents a substituent selected from the group consisting of:
C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, (C 1 -C 3 -alkoxy)-(C 2 -C 4 -alkyl)-, and phenyl,
wherein said C 1 -C 6 -alkyl group is optionally substituted, identically or differently, with a phenyl group, wherein the phenyl group is optionally substituted, one, two, or three times, identically or differently, with a halogen atom or a group selected from:
C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, and C 1 -C 3 -alkoxy, and

wherein when R 2 represents phenyl, the phenyl is optionally substituted, one, two, or three times, identically or differently, with a halogen atom or a group selected from:
C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, and C 1 -C 3 -alkoxy;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

4. The compound according to claim 1 , wherein:
R 1 represents a hydrogen atom; and
R 2 represents a substituent selected from the group consisting of:
C 1 -C 4 -alkyl, C 3 -C 5 -cycloalkyl, (C 1 -C 2 -alkoxy)-(C 2 -C 3 -alkyl)-, and phenyl,
wherein said C 1 -C 4 -alkyl group is optionally substituted, identically or differently, with a phenyl group, wherein the phenyl group is optionally substituted, one, two, or three times, identically or differently, with a halogen atom or a group selected from:
C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, and C 1 -C 3 -alkoxy, and

wherein when R 2 represents phenyl, the phenyl is optionally substituted, one, two, or three times, identically or differently, with a halogen atom or a group selected from:
C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, and C 1 -C 3 -alkoxy;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

5. The compound according to claim 1 , wherein:
R 1 represents a hydrogen atom; and
R 2 represents a substituent selected from the group consisting of:
methyl, ethyl, isopropyl, 2-methylpropyl, benzyl, cyclopropyl, cyclopentyl, 2-methoxyethyl, 2-ethoxyethyl, and phenyl,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

6. The compound according to claim 1 , wherein the compound is selected from the group consisting of:
Tetragadolinium [4,10-bis(carboxylatomethyl)-7-{3,13-dimethyl-8,8-bis({[(methyl {[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetyl }amino) acetyl]amino}methyl)-2,5,11,14-tetraoxo-15-[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]-3,6,10,13-tetraazapentadec-1-yl }-1,4,7,10-tetraazacyclododecan-1-yl]acetate,
Tetragadolinium [4,10-bis(carboxylatomethyl)-7-{3,13-diethyl-8,8-bis({[(ethyl{[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetyl}amino)acetyl]amino}-methyl)-2,5,11,14-tetraoxo-15-[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclo -dodecan-1-yl]-3,6,10,13-tetraazapentadec-1-yl}-1,4,7,10-tetraazacyclododecan-1-yl]acetate,
Tetragadolinium {4,10-bis(carboxylatomethyl)-7[15-(2-methoxyethyl)-10,10-bis{({[(2-methoxyethyl){[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]-acetyl}amino]acetyl}amino)methyl]-7,13,16-trioxo-5-{[4,7,10-tris(carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-1-yl]acetyl}-2-oxa-5,8,12,15-tetraazaheptadecan-17-yl]-1,4,7,10-tetraazacyclododecan-1-yl}acetate,
Tetragadolinium {4,10-bis(carboxylatomethyl)-7-[16-(2-ethoxyethyl)-11,11-bis[({[(2-ethoxyethyl){[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1yl]-acetyl}amino]acetyl}amino)methyl]-8,14,17-trioxo-6-{[4,7,10-tris(carboxylatomethyl) -1,4,7,10-tetraazacyclododecan-1-yl]acetyl}-3-oxa-6,9,13,16-tetraazaoctadecan-18-yl]-1,4,7,10-tetraazacyclododecan-1-yl}acetate,
Tetragadolinium [4,10-bis(carboxylatomethyl)-7-{3,13-diisopropyl-8,8-bis({[(isopropyl -{[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetyl}amino)acetyl]-amino}methyl)-2,5,11,14-tetraoxo-15-[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraaza -cyclododecan-1-yl]-3,6,10,13-tetraazapentadec-1-yl}-1,4,7,10-tetraazacyclododecan-1-yl]acetate,
Tetragadolinium {4,10-bis(carboxylatomethyl)-7-[3-isobutyl-8,8-bis({[(isobutyl{[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetyl}amino)acetyl]amino}-methyl)-15-methyl-2,5,11-trioxo-13-{[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraaza -cyclododecan-1-yl]acetyl}-3,6,10,13-tetraazahexadec-1-yl]-1,4,7,10-tetraazacyclododecan -1-yl}acetate,
Tetragadolinium [4,10-bis(carboxylatomethyl)-7-{3,13-dicyclopropyl-8,8-bis({[(cyclopropyl{[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetyl}amino)acetyl]amino}methyl)-2,5,11,14-tetraoxo-15-[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]-3,6,10,13-tetraazapentadec-1-yl}-1,4,7,10-tetraazacyclododecan-1-yl]acetate,
Tetragadolinium [4,10-bis(carboxylatomethyl)-7-{3,13-dicyclopentyl-8,8-bis({[(cyclopentyl{[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetyl}amino)acetyl]amino}methyl)-2,5,11,14-tetraoxo-15-[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]-3,6,10,13-tetraazapentadec-1-yl}-1,4,7,10-tetraazacyclododecan-1-yl]acetate,
Tetragadolinium [4,10-bis(carboxylatomethyl)-7-{2,5,11,14-tetraoxo-3,13-diphenyl-8,8-bis({[(phenyl{[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetyl}-amino)acetyl]amino}methyl)-15-[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclo -dodecan-1-yl]-3,6,10,13-tetraazapentadec-

Assignees

• Bayer Pharma AG

Inventors

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

Classifications

• C07D403/14 Primary

  containing three or more hetero rings · CPC title

• C07D257/02 Primary

  not condensed with other rings · CPC title

• A61K49/124

  dendrimers, dendrons, hyperbranched compounds · CPC title

• A61K49/106 Primary

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