Enhanced relaxivity monomeric and multimeric compounds

Abstract

Metal chelates capable of exhibiting an immobilized relativity between about 60 and 200 mM −1 s −1 /metal atom are useful as magnetic resonance imaging agents. Additionally, a compound which is useful as a metal-chelating ligand has the following formula: wherein Q is a 4- to an 8-membered carbocyclic ring which may be fully or partially saturated; t is an integer from 2 to 16; each R group is independently hydrogen, —OH, —CH 2 -A, —OCH 2 CH(OH)CH 2 -A or a functional group capable of forming a conjugate with a biomolecule, provided that at least two of the R groups are selected from —CH 2 -A or —OCH 2 CH(OH)CH 2 -A; and A is a moiety capable of chelating a metal atom.

What is claimed is:  
     
         1 . A compound of the following formula I:  
       
         
           
           
               
               
           
         
       
       wherein 
 each m, n, o and p is independently 1 or 2;  
 q is 0 or 1;  
 each G is independently —COOR″, —P(O)(OR″) 2 , —P(O)(OR″)(R″) or —C(O)N(R″) 2 ;  
 each R′ is independently hydrogen or alkyl, alkoxy, cycloalkyl, hydroxyalkyl or aryl, each of which is optionally substituted, or a functional group capable of forming a conjugate with a biomolecule or of forming a multimer of said compound of formula I;  
 each R″ is hydrogen;  
 each R 13  through R 20  is independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl or a functional group capable of forming a conjugate with a biomolecule or of forming a multimer of said compound of formula I;  
 or R 13  together with R 15 , and R 17  together with R 18  , independently form, together with the carbon atoms in the tetraazacyclododecane macrocycle to which they are attached, a fused fully or partially saturated non-aromatic cyclohexyl ring which may be unsubstituted or substituted by one or more halogen, alkyl, ether, hydroxy or hydroxyalkyl groups, and which may be further fused to a carbocyclic ring, or R 13  and R 15 , are each hydrogen and R 17 , together with R 18 , forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above, or R 13 , together with R 15 , forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above and R 17  and R 18  are hydrogen; provided that (a.) when G is always —COOR″ and (i.) R′, R″, R 14  and R 16  through R 20  are all hydrogen, then R 13  and R 15  are other than hydrogen; (ii.) R″ and R 13  through R 20  are all hydrogen, and m, n, o, p and q are each 1, then (CR′R′) is other than (CH 2 ) and (CHCH 3 ); (iii.) R′, R″, R 13 , R 14 , R 17  and R 20  are all hydrogen, then at least two of R 15 , R 16 , R 18  and R 19  are other than methyl; and (iv.) R″, R 16 , R 19  and R 20  are all hydrogen, and each (CR′R′) is independently (CHR′) or (CH 2 CHR′), then R 13  and R 15 , and R 17  and R 18 , are other than a fused ring; and (b.) when G is always —P(O)(OR″) 2 , —P(O)(OR″)(R″ ) or —C(O)N(R″) 2 , then at least one R′ or R 13  through R 20  is other than hydrogen;  
 or a salt or multimeric form thereof.  
 
     
     
         2 . A metal chelate, comprising a compound of  claim 1  complexed with a metal atom.  
     
     
         3 . The chelate of  claim 2 , wherein the metal is selected from atoms having an atomic number of 21 to 29, 42 or 57 to 83.  
     
     
         4 . The chelate of  claim 3 , wherein said metal is gadolinium.  
     
     
         5 . A compound of the following formula II:  
       
         
           
           
               
               
           
         
       
       wherein 
 Q is a 4- to an 8-membered carbocyclic ring which may be fully or partially saturated;  
 t is an integer from 2 to 16;  
 each R group is independently hydrogen, —OH, —CH 2 -A, —OCH 2 CH(OH)CH 2 -A or a functional group capable of forming a conjugate with a biomolecule, provided that at least two of the R groups are selected from —CH 2 -A or —OCH 2 CH(OH)CH 2 -A; and  
 A is a moiety capable of chelating a metal atom.  
 
     
     
         6 . A compound of  claim 5  wherein A is  
       
         
           
           
               
               
           
         
         each m, n, o and p is independently 1 or 2;  
         q is 0 or 1;  
         each G is independently —COOR″, —P(O)(OR″) 2 , —P(O)(OR″)(R″) or —C(O)N(R″) 2 ;  
         each R′ is independently hydrogen or alkyl, alkoxy, cycloalkyl, hydroxyalkyl or aryl, each of which is optionally substituted, or a functional group capable of forming a conjugate with a biomolecule or of forming a multimer;  
         each R″ is hydrogen;  
         each R 13  through R 20  is independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl or a functional group capable of forming a conjugate with a biomolecule or of forming a multimer of said compound of the formula I;  
         or R 13  together with R 15 , and R 17  together with R 18 , independently form, together with the carbon atoms in the tetraazacyclododecane macrocycle to which they are attached, a fused fully or partially saturated non-aromatic cyclohexyl ring which may be unsubstituted or substituted by one or more halogen, alkyl, ether, hydroxy or hydroxyalkyl groups, and which may be further fused to a carbocyclic ring, or R 13  and R 15  are each hydrogen and R 17 , together with R 18 , forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above, or R 13 , together with R 15 , forms a fused fully or partially saturated non-aromatic cyclohexyl ring as defined above and R 17  and R 18  are hydrogen; provided that (a.) when G is always —COOR″ and (i.) R′, R″, R 14  and R 16  through R 20  are all hydrogen, then R 13  and R 15  are other than hydrogen; (ii.) R″ and R 13  through R 20  are all hydrogen, and m, n, o, p and q are each 1, then (CR′R′) is other than (CH 2 ) and (CHCH 3 ); (iii.) R′, R″, R 13 , R 14 , R 17  and R 20  are all hydrogen, then at least two of R 15 , R 16 , R 18  and R 19  are other than methyl; and (iv.) R″, R 16 , R 19  and R 20  are all hydrogen, and each (CR′R′) is independently (CHR′) or (CH 2 CHR′), then R 13  and R 15 , and R 17  and R 18 , are other than a fused ring; and (b.) when G is always —P(O)(OR″) 2 , —P(O)(OR″)(R″) or —C(O)N(R″) 2 , then at least one R′ or R 13  through R 20  is other than hydrogen;  
         or a salt or multimeric form thereof.  
       
     
     
         7 . A compound of  claim 5 , wherein A is  
       
         
           
           
               
               
           
         
         each R′ is independently hydrogen, alkyl, alkoxy, hydroxyalkyl, aryl, aralkyl or arylalkoxy;  
         each R″ is hydrogen; and  
         each n is 1 or 2.  
       
     
     
         8 . A compound of  claim 5  wherein  
       
         
           
           
               
               
           
         
         is  
         
           
             
             
                 
                 
             
           
         
         each R 1  through R 12  group is independently hydrogen, —OH, —CH 2 -A, —OCH 2 CH(OH)CH 2 -A or a functional group capable of forming a conjugate with a biomolecule;  
         at least two of R 1  through R 12  are selected from —CH 2 -A or —OCH 2 CH(OH)CH 2 -A; and  
         R 8  and R 9  taken together may additionally form the group —O—[C(RR)]—O— where each R is independently hydrogen or alkyl, or R 8  and R 9  taken together may form  
         
           
             
             
                 
                 
             
           
         
       
     
     
         9 . A compound of  claim 6  wherein  
       
         
           
           
               
               
           
         
         is a compound of the formula  
         
           
             
             
                 
                 
             
           
         
         wherein  
         each R 1  through R 12  group is independently hydrogen, —OH, —CH 2 -A, —OCH 2 CH(OH)CH 2 -A or a functional group capable of forming a conjugate with a biomolecule;  
         at least two of R 1  through R 12  are selected from —CH 2 -A or —OCH 2 CH(OH)CH 2 -A; and  
         R 8  and R 9  taken together may additionally form the group —O—[C(RR)]—O— where each R is independently hydrogen or alkyl, or R 8  and R 9  taken together may form  
         
           
             
             
                 
                 
             
           
         
       
     
     
         10 . A compound of  claim 7 , wherein  
       
         
           
           
               
               
           
         
         is  
         
           
             
             
                 
                 
             
           
         
         each R 1  through R 12  group is independently hydrogen, —OH, —CH 2 -A, —OCH 2 CH(OH)CH 2 -A or a functional group capable of forming a conjugate with a biomolecule;  
         at least two of R 1  through R 12  are selected from —CH 2 -A or —OCH 2 CH(OH)CH 2 -A; and  
         R 8  and R 9  taken together may additionally form the group —O—[C(RR)]—O— where each R is independently hydrogen or alkyl, or R 8  and R 9  taken together may form  
         
           
             
             
                 
                 
             
           
         
       
     
     
         11 . A metal chelate, comprising a compound of  claim 5  complexed with a metal atom.  
     
     
         12 . A metal chelate, comprising a compound of  claim 6  complexed with a metal atom.  
     
     
         13 . A conjugate, comprising a compound of  claim 5  conjugated with a biomolecule.  
     
     
         14 . A metal chelate, comprising a conjugate of  claim 13  complexed with a metal atom.  
     
     
         15 . A method for diagnostic imaging, comprising the steps of administering to a host a compound of  claim 5 , which compound is complexed with a metal, and obtaining a diagnostic image of said host.  
     
     
         16 . The method of  claim 15 , wherein said image is a magnetic resonance image.  
     
     
         17 . A method for diagnostic imaging, comprising the steps of administering to a host a conjugate of  claim 13 , which conjugate is complexed with a metal, and obtaining a diagnostic image of said host.  
     
     
         18 . A compound selected from the group consisting of: 
 (1α,2α,4β,5β)-10,10′-[(1,2,4,5-Tetrahydroxy-1,4-cyclohexanediyl)bis(methylene)]bis[1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid];    (3aα,4α,5β,6α,7β,7aα)-10,10′10″,10″′-[[Hexahydro-2,2-dimethyl-1,3-benzodioxol-4,5,6,7-tetrayl]tetra(oxy)-tetra(2-hydroxy-3,1-propanediyl)]tetrakis[1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid];    3,4,5,6-Tetra-O-[2-hydroxy-3-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propyl]-myo-inositol;    (1α,2α,3α,4β,5α,6β)-10,10′-[(2,3,5,6-tetrahydroxy-1,4-cyclohexanediyl)bis(2-hydroxy-3,1-propanediyl)]-bis[1,4,7-10-tetraazacyclododecane-1,4,7-triacetic acid];    10 [[1,4-Dihydroxy-2,5-bis[2-hydroxy-3-[4,7,10-tris-(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]-propoxy]-4-[[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]methyl]cyclohexyl]methyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid;    [3aR-(3aα,3″aα,4β,4″β,5α,5″α,6β,6″b,7α,-7″α,7aα,7″aα)]-dodecahydro-4,4″,5,5″,6,6″,7,7″-octakis-[[2-hydroxy-3-[(4,7,10-tricarboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propyl]-oxy]dispiro-[1,3-benzodioxole-2,1′-cyclo-hexane-4′,2″-[1,3]-benzodioxole];    [2S-(2α,5α,8α,11α)]-2,5,8,11-Tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid;    [aR-(αR*,α′R*,α″R*,α′″R*,2S*,5S*,8S*,11S*)]-α,-α′,α″,a′″,2,5,8,11-Octamethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid;    [2S-(2R*,5R*,8R*,11R*)]-2,5,8,11,-Tetramethyl-1,4,7,10-tetraazacylcododecane-1,4,7-triacetic acid; and    10-(Phosphonomethyl)-1,4,7,10-tetraaza-cyclododecane-1,4,7-triacetic acid.    
     
     
         19 . A compound selected from the group consisting of: 
 (1α,2α,4β,5β)-10,10′-[(1,2,4,5-Tetrahydroxy-1,4-cyclohexanediyl)bis(methylene)]bis[1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid], digadolinium salt;    (3aα,4α,5β,6α,7β,7aα)-10,10′10″,10″′-[[Hexahydro-2,2-dimethyl-1,3-benzodioxol-4,5,6,7-tetrayl]tetra(oxy)-tetra(2-hydroxy-3,1-propanediyl)]tetrakis[1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid], tetragadolinium salt;    3,4,5,6-Tetra-O-[2-hydroxy-3-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propyl]-myo-inositol, tetragadolinium salt;    (1α,2α,3α,4β,5α,6β)-10,10′-[(2,3,5,6-tetrahydroxy-1,4-cyclohexanediyl)bis(2-hydroxy-3,1-propanediyl)]-bis[1,4,7-10-tetraazacyclododecane-1,4,7-triacetic acid], digadolinium salt;    10-[[1,4-Dihydroxy-2,5-bis[2-hydroxy-3-[4,7,10-tris-(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]-propoxy]-4-[[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]methyl]cyclohexyl]methyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, tetragadolinium salt;    [3aR-(3aα,3″aα,4β,4″β,5α,5″α,6β,6″b,7α,-7″α,7aα,7″aα)]-dodecahydro-4,4″,5,5″,6,6″,7,7″-octakis-[[2-hydroxy-3-[(4,7,10-tricarboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propyl]-oxy]dispiro-[1,3-benzodioxole-2,1′-cyclo-hexane-4′,2″-[1,3]-benzodioxole], octagadolinium salt;    [2S- (2α,5α,8α,11α,)]-2,5,8,11-Tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, gadolinium salt;    [αR-(aR*,α′R*,α″R*,a′″R*,2S*,5S*,8S*,11S*)]-α, -α′,α″,a′″,2,5,8,11-Octamethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, gadolinium salt;    [2S-(2R*,5R*,8R*,11R*)]-2,5,8,11,-Tetramethyl-1,4,7,10-tetraazacylcododecane-1,4,7-triacetic acid, gadolinium salt; and    10-(Phosphonomethyl)-1,4,7,10-tetraaza-cyclododecane-1,4,7-triacetic acid, gadolinium salt.    
     
     
         20 . A chelate other than [1R-(1R*,4R*,7R*,10R*)]-α,α′,α″,α′″-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid or [1R-(1R*,4R*,7R*)]-α,α′,α″-trimethyl-1,4,7 ,10-tetraazacyclododecane-1,4,7-triacetic acid possessing a stability greater than 10 15  M −1  and capable of exhibiting an immobilized relaxivity between about 60 and 200 mM −1 s −1 /metal atom.  
     
     
         21 . A chelate of  claim 20  capable of exhibiting an immobilized relaxivity between about 70 and 150 mM −1 s −1 /metal atom.  
     
     
         22 . A chelate of  claim 20  capable of exhibiting an immobilized relaxivity between about 80 and 100 mM −1 s −1 /metal atom.  
     
     
         23 . A chelate possessing a stability greater than 10 15  M −1  and capable of exhibiting an immobilized relaxivity between about 60 and 200 mM −1 s −1 /metal atom comprising a compound of  claim 1 .  
     
     
         24 . A chelate possessing a stability greater than 10 15  M −1  and capable of exhibiting an immobilized relaxivity between about 70 and 150 mM −1 s −1 /metal atom comprising a compound of  claim 1 .  
     
     
         25 . A chelate possessing a stability greater than 10 15  M −1  and capable of exhibiting an immobilized relaxivity between about 80 and 100 mM −1 s −1 /metal atom comprising a compound of  claim 1 .  
     
     
         26 . A chelate possessing a stability greater than 10 15  M −1  and capable of exhibiting an immobilized relaxivity between about 60 and 200 mM −1 s −1 /metal atom comprising a compound of  claim 8 .  
     
     
         27 . A chelate possessing a stability greater than 10 15  M −1  and capable of exhibiting an immobilized relaxivity between about 70 and 150 mM −1 s −1 /metal atom comprising a compound of  claim 8 .  
     
     
         28 . A chelate possessing a stability greater than 10 15  M −1  and capable of exhibiting an immobilized relaxivity between about 80 and 100 mM −1 s −1 /metal atom comprising a compound of  claim 8 .  
     
     
         29 . A chelate other than [1R-(1R*,4R*,7R*,10R*)]-α,α′,α″,α′″-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid or [1R*,4R*,7R *)]-α,α′,α″-trimethyl-1,4,7,10-tetraazcyclododecane-1,4,7-triacetic acid, including an immobilized functional group, capable of exhibiting an immobilized relaxivity between about 60 and 200 mM −1 s −1 /metal atom.  
     
     
         30 . A chelate of  claim 29 , capable of exhibiting an immobilized relaxivity between about 70 and 150 mM −1 s −1 /metal atom.  
     
     
         31 . A chelate of  claim 29 , capable of exhibiting an immobilized relaxivity between about 80 and 100 mM −1 s −1 /metal atom.  
     
     
         32 . A chelate including a functional group, capable of exhibiting an immobilized relaxivity between about 60 and 200 mM −1 s −1 /metal atom comprising a compound of  claim 1 .  
     
     
         33 . A chelate including a functional group, capable of exhibiting an immobilized relaxivity between about 70 and 150 mM −1 s −1 /metal atom comprising a compound of  claim 1 .  
     
     
         34 . A chelate including a functional group, capable of exhibiting an immobilized relaxivity between about 80 and 100 mM −1 s −1 /metal atom comprising a compound of  claim 1 .  
     
     
         35 . A chelate including a functional group, capable of exhibiting an immobilized relaxivity between about 60 and 200 mM −1 s −1 /metal atom comprising a compound of  claim 8 .  
     
     
         36 . A chelate including a functional group, capable of exhibiting an immobilized relaxivity between about 70 and 150 mM −1 s −1 /metal atom comprising a compound of  claim 8 .  
     
     
         37 . A chelate including a functional group, capable of exhibiting an immobilized relaxivity between about 80 and 100 mM 1 s −1 /metal atom comprising a compound of  claim 8 .  
     
     
         38 . A chelate other than [1R-(1R*,4R*,7R*,10R*)]-α,α′,α″,α′″-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, conjugated to a biomolecule, capable of exhibiting an immobilized relaxivity between about 60 and 200 mM −1 s −1 /metal atom.  
     
     
         39 . A chelate of  claim 38 , capable of exhibiting an immobilized relaxivity between about 70 and 150 mM −1 s −1 /metal atom.  
     
     
         40 . A chelate of  claim 38 , capable of exhibiting an immobilized relaxivity between about 80 and 100 mM −1 s −1 /metal atom.  
     
     
         41 . A chelate conjugated to a biomolecule, capable of exhibiting an immobilized relaxivity between about 60 and 200 mM −1 s −1 /metal atom comprising a compound of  claim 1 .  
     
     
         42 . A chelate conjugated to a biomolecule, capable of exhibiting an immobilized relaxivity between about 70 and 150 mM −1 s −1 /metal atom comprising a compound of  claim 1 .  
     
     
         43 . A chelate conjugated to a biomolecule, capable of exhibiting an immobilized relaxivity between about 80 and 100 mM −1 s −1 /metal atom comprising a compound of  claim 1 .  
     
     
         44 . A chelate conjugated to a biomolecule, capable of exhibiting an immobilized relaxivity between about 60 and 200 mM −1 s −1 /metal atom comprising a compound of  claim 8 .  
     
     
         45 . A chelate conjugated to a biomolecule, capable of exhibiting an immobilized relativity between about 70 and 150 mM −1 s −1 /metal atom comprising a compound of  claim 8 .  
     
     
         46 . A chelate conjugated to a biomolecule, capable of exhibiting an immobilized relaxivity between about 80 and 100 mM −1 s −1 /metal atom comprising a compound of  claim 8.