New gadolinium chelate compounds for use in magnetic resonance imaging

Abstract

An aqueous pharmaceutical composition including 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-tetraazacyclododecan-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.

We claim: 
     
         1 . An aqueous pharmaceutical composition comprising:
 a tetrameric gadolinium compound dissolved in water,   wherein the tetrameric gadolinium compound comprises four 1,4,7,10-tetraazacyclododecan-1-yl units complexed with four gadolinium (III) ions, and   wherein 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 aqueous pharmaceutical composition of  claim 1 , 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. 
     
     
         3 . The aqueous pharmaceutical composition of  claim 1 , wherein the tetrameric gadolinium compound has 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 in water ranges from 10.8 to 11.7 L mmol −1 s −1  at 1.41 T measured at 37° C. 
     
     
         4 . The aqueous pharmaceutical composition of  claim 1 , wherein 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. 
     
     
         5 . The aqueous pharmaceutical composition of  claim 4 , 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. 
     
     
         6 . The aqueous pharmaceutical composition of  claim 1 , wherein the tetrameric gadolinium 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 a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a mixture of same. 
     
     
         7 . The aqueous pharmaceutical composition of  claim 1 , wherein the tetrameric gadolinium compound has a structure selected from the group consisting of:
 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; and   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,   or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a mixture of any thereof.   
     
     
         8 . An aqueous pharmaceutical composition comprising:
 a tetrameric gadolinium compound dissolved in water,   wherein the tetrameric gadolinium compound comprises four 1,4,7,10-tetraazacyclododecan-1-yl units complexed with four gadolinium (III) ions, and   wherein 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.   
     
     
         9 . The aqueous pharmaceutical composition of  claim 8 , 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. 
     
     
         10 . The aqueous pharmaceutical composition of  claim 8 , wherein the tetrameric gadolinium compound has the r 1  relaxivity value in human plasma ranges from 10.4 to 11.8 L 25 mmol −1 s −1  and the r 2  relaxivity value in human plasma ranges from 13.1 to 14.7 L mmol −1 s −1  at 1.41 T measured at 37° C. 
     
     
         11 . The aqueous pharmaceutical composition of  claim 8 , wherein 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. 
     
     
         12 . The aqueous pharmaceutical composition of  claim 11 , 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. 
     
     
         13 . The aqueous pharmaceutical composition of  claim 8 , wherein the tetrameric gadolinium 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 a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a mixture of same. 
     
     
         14 . The aqueous pharmaceutical composition of  claim 8 , wherein the tetrameric gadolinium compound has a structure selected from the group consisting of:
 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; and   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,   or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a mixture of any thereof.   
     
     
         16 . A method of imaging body tissue in a patient, the method comprising:
 administering to the patient an effective amount of an aqueous pharmaceutical composition comprising:
 a tetrameric gadolinium compound dissolved in water, 
 wherein the tetrameric gadolinium compound comprises four 1,4,7,10-tetraazacyclododecan-1-yl units complexed with four gadolinium (III) ions, and 
 wherein 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.; and 
   subjecting the patient to a magnetic resonance imaging procedure.   
     
     
         17 . The method of  claim 16 , wherein the effective amount of the aqueous pharmaceutical composition comprises an amount of the aqueous pharmaceutical composition sufficient to provide from 0.1 mmol Gadolinium per kilogram body weight (100 μmol Gd/kg bw) to 0.3 mmol Gadolinium per kilogram body weight (300 μmol Gd/kg bw) to the patient. 
     
     
         18 . The method of  claim 16 , 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. 
     
     
         19 . The method of  claim 16 , wherein the tetrameric gadolinium 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 a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a mixture of same. 
     
     
         20 . The method of  claim 16 , wherein the tetrameric gadolinium compound has a structure selected from the group consisting of:
 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; and   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,   or a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a mixture of any thereof.