IP Library › Granted Patent US 11,491,245

Granted Patent B2

US 11,491,245 · App. 16/947,272 · Granted Nov 8, 2022

Gadolinium chelate compounds for use in magnetic resonance imaging

Inventors: Markus Berger (Berlin, DE); Jessica Lohrke (Berlin, DE); Christoph-Stephan Hilger (Berlin, DE); Gregor Jost (Berlin, DE); Thomas Frenzel (Berlin, DE); Detlev Suelzle (Berlin, DE); Johannes Platzek (Berlin, DE); Olaf Panknin (Berlin, DE); Hubertus Pietsch (Kleinmachnow, DE)

Assignee: BAYER PHARMA AKTIENGESELLSCHAFT

A61K49/106 C07D257/02

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Quick Facts

Patent No.: US 11,491,245
App. No.: 16/947,272
Granted: Nov 8, 2022
Kind: B2

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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.

Claims (54)

1. A tetrameric gadolinium compound comprising:

four 1,4,7,10-tetraazacyclododecan-1-yl units complexed with four gadolinium(III) ions, wherein the tetrameric gadolinium compound has a structure according to Formula 1-d or 1-e,

where R 4 and R 5 are each independently selected from H and CH 3 , and

is a tetraamine selected from

where R 2 is H and * indicates a point of attachment with each of the four 1,4,7,10-tetraazacyclododecan-1-yl units complexed with four gadolinium(III) ions,

wherein an aqueous solution of the tetrameric gadolinium compound has an r 1 relaxivity value of greater than 7.3 L mmol −1 s −1 in water and an r 2 relaxivity value of greater than 8.3 L mmol −1 s −1 in water at 1.41 T measured at 37° C.

2. The tetrameric gadolinium compound of claim 1 , wherein the r 1 relaxivity value in water ranges from 9.4 to 10.1 L mmol −1 s −1 and the r 2 relaxivity value ranges from 10.8 to 11.7 L mmol −1 s −1 in water at 1.41 T measured at 37° C.

3. The tetrameric gadolinium compound of claim 1 , wherein the aqueous solution of the tetrameric gadolinium compound has an r 1 relaxivity value of greater than 8.9 L mmol −1 s −1 in water at 3.0 T measured at 37° C.

4. The tetrameric gadolinium compound of claim 3 , wherein the r 1 relaxivity value in water ranges from 8.9 to 9.2 L mmol −1 s −1 at 3.0 T measured at 37° C.

5. The tetrameric gadolinium compound of claim 1 , wherein the tetrameric gadolinium compound has a structure 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-tetraaza cyclododecan-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-tetraaza cyclododecan-1-yl}acetate;

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({[({(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-tetraaza cyclododecan-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({[({(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-tetraaza cyclododecan-1-yl]acetate;

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({[({(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-tetraaza cyclododecan-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;

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 2,2′,2″,2′″,2″″,2′″″,2″″″,2′″″″,2″″″″,2′″″″″,2″″″″″,2′″″″″″-{1,4,7,10-tetraazacyclo- dodecane-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,

or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a mixture of same.

6. The tetrameric gadolinium compound of claim 5 , wherein the tetrameric gadolinium compound has a structure selected from the group consisting of:

or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a mixture of same.

7. A tetrameric gadolinium compound comprising:

four 1,4,7,10-tetraazacyclododecan-1-yl units complexed with four gadolinium(III) ions, wherein the tetrameric gadolinium compound has a structure according to Formula 1-d or 1-e,

where R 4 and R 5 are each independently selected from H and CH 3 , and

is a tetraamine selected from

where R 2 is H and * indicates a point of attachment with each of the four 1,4,7,10-tetraazacyclododecan-1-yl units complexed with four gadolinium(III) ions,

wherein an aqueous solution of the tetrameric gadolinium compound has an r 1 relaxivity value of greater than 9.7 L mmol −1 s −1 in human plasma and an r 2 relaxivity value of greater than 11.3 L mmol −1 s −1 in human plasma at 1.41 T measured at 37° C.

8. The tetrameric gadolinium compound of claim 7 , wherein the r 1 relaxivity value in human plasma ranges from 10.4 to 11.8 L mmol −1 s −1 and the r 2 relaxivity value ranges from 13.1 to 14.7 L mmol −1 s −1 in human plasma at 1.41 T measured at 37° C.

9. The tetrameric gadolinium compound of claim 7 , wherein the aqueous solution of the tetrameric gadolinium compound has an r 1 relaxivity value of greater than 10.1 L mmol −1 s −1 in human plasma at 3.0 T measured at 37° C.

10. The tetrameric gadolinium compound of claim 9 , wherein the r 1 relaxivity value in human plasma ranges from 10.1 to 11.4 L mmol −1 s −1 at 3.0 T measured at 37° C.

11. The tetrameric gadolinium compound of claim 7 , wherein the tetrameric gadolinium compound has a structure 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 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,

or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a mixture of same.

12. The tetrameric gadolinium compound of claim 11 , wherein the tetrameric gadolinium compound has a structure selected from the group consisting of:

or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a mixture of same.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 4, 2020

From: BERGER, MARKUS; LOHRKE, JESSICA; HILGER, CHRISTOPH-STEPHAN; JOST, GREGOR; FRENZEL, THOMAS; SUELZLE, DETLEV; PLATZEK, JOHANNES; PANKNIN, OLAF; PIETSCH, HUBERTUS

To: BAYER PHARMA AKTIENGESELLSCHAFT

Reel/Frame 054268/0206 →

Priority Claims (1)

EP 15170658 · Jun 4, 2015 · regional

Continuity (3)

Continuation 16192185 · Nov 15, 2018

Continuation 15578687

Related Publication 20200353104A1 · Nov 12, 2020

Cited By (1)

US 12,478,696