Luminescent metal complexes for monitoring renal function

Abstract

Some embodiments of the present invention may be said to be directed to metal complexes of Formula I wherein at least one of X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4 or R 5 is what may be characterized as an antenna capable of providing (e.g., absorbing and/or emitting) an appropriate electromagnetic signal. Some embodiments of the present invention are directed to ligands corresponding to metal complexes of Formula I. Some embodiments of the invention are directed to methods of determining renal function using at least one metal complex of Formula I.

1 . A metal complex of Formula I, 
     
       
         
         
             
             
         
       
     
     wherein
 M is a metal ion that exhibits spectral absorption and emission in the visible and/or NIR regions; 
 each of X 1 , X 2 , and X 3  is independently selected from Ar 1 —Z 1 —, —O − , —NH(CH 2 ) a OH, —NH(CH 2 ) a CO 2 H, —NH(CH 2 ) a SO 3   − , —NH(CH 2 ) a OSO 3   − ,—NH(CH 2 ) a NHSO 3   − , —O(CH 2 ) a SO 3   − , —O(CH 2 ) a OSO 3   − , —O(CH 2 ) a NHSO 3   − , —NH(CH 2 ) a PO 3 H − , —NH(CH 2 ) a PO 3   = , —NH(CH 2 ) a OPO 3 H − , —NH(CH 2 ) a OPO 3   = , —NH(CH 2 ) a NHPO 3 H − , —NH(CH 2 ) a NHPO 2 H − , —NH(CH 2 ) a NHPO 3   = , —O(CH 2 ) a PO 3 H − , —O(CH 2 ) a PO 3   = , —O(CH 2 ) a OPO 3 H − , —O(CH 2 ) a OPO 3   = , —O(CH 2 ) a NHPO 3 H − , and —O(CH 2 ) a NHPO 3   = ; 
 each of Y 1  and Y 2  is independently selected from a single bond, —(CH 2 ) m —, —(CH 2 ) m O—, —(CH 2 ) m OCO—, —(CH 2 ) m CO 2 —, —(CH 2 ) m OCNH—, —(CH 2 ) m OCO 2 —, —(CH 2 ) m NHCO—, —(CH 2 ) m NHCSNH—, —(CH 2 ) m OSO 2 —, —(CH 2 ) m OSO 3 —, —(CH 2 ) m SO 2 , —, —(CH 2 ) m NHSO 2 —, and —(CH 2 ) m SO 2 NH—; 
 Z 1  is —NH—, —O—, —NH(CH 2 ) m —, or —O(CH 2 ) m —; 
 Ar 1  is a bicyclic heteroaromatic radical having a base ring structure containing 5 to 10 carbon atoms; 
 each of R1 to R5 is independently selected from Ar 2 —Z 2 —, hydrogen, C1-C10 alkyl, C1-C10 hydroxyalkyl, C1-C10 polyhydroxyalkyl, carboxyl, C1-C10 carboxyalkyl, C1-C10 alkoxyalkyl, —(CH 2 ) b SO 3   − , —(CH 2 ) b OSO 3   − , —(CH 2 ) b NHSO 3   − , —(CH 2 ) b CO 2 (CH 2 ) c SO 3   − , —(CH 2 ) b OCO(CH 2 ) c SO 3   − , —(CH 2 ) b CONH(CH 2 ) c SO 3   − , —(CH 2 ) b NHCO(CH 2 ) c SO 3   − , —(CH 2 ) b NHCONH(CH 2 ) c SO 3   − , —(CH 2 ) b NHCSNH(CH 2 ) c SO 3   − , —(CH 2 ) b OCONH(CH 2 ) c SO 3   − , —(CH 2 ) b PO 3 H − , —(CH 2 ) b PO 3   = , —(CH 2 ) b OPO 2 H − , —(CH 2 ) b OPO 3   = , —(CH 2 ) b NHPO 3 H − , —(CH 2 ) b NHPO 3   = , —(CH 2 ) b CO 2 (CH 2 ) c PO 3 H − , —(CH 2 ) b CO 2 (CH 2 ) c PO 3   = , —(CH 2 ) b OCO(CH 2 ) c PO 3 H − , —(CH 2 ) b OCO(CH 2 ) c PO 3   = , —(CH 2 ) b CONH(CH 2 ) c PO 3 H − , —(CH 2 ) b CONH(CH 2 ) c PO 3   = , —(CH 2 ) b NHCO(CH 2 ) c PO 3 H − m —(CH 2 ) b NHCO(CH 2 ) c PO 3   = , —(CH 2 ) b NHCONH(CH 2 ) c PO 3 H − , —(CH 2 ) b NHCONH(CH 2 ) c PO 3   = , —(CH 2 ) b NHCSNH(CH 2 ) c PO 3 H − , —(CH 2 ) b NHCSNH(CH 2 ) c PO 3   = , —(CH 2 ) b OCONH(CH 2 ) c PO 3 H − , or —(CH 2 ) b OCONH(CH 2 ) c PO 3   = ; 
 Z 2  is a single bond; 
 Ar 2  is a bicyclic heteroaromatic radical having a base ring structure containing 5 to 10 carbon atoms; 
 a, b, and c are independently 1 to 6; 
 m is 1 to 10; and 
 n is 1 to 5; 
 
     with the proviso that at least one of X 1  to X 3  is Ar 1 —Z 1 — or at least one of R 1  to R 5  is Ar 2 —Z 2 —. 
   
   
       2 . The complex of  claim 1 , wherein Ar 1 —Z 1 — is an aromatic or heteroaromatic chromophore derived from an unsubstituted or substituted aromatic or heteroaromatic compound. 
   
   
       3 . The complex of  claim 2 , wherein the aromatic or heteroaromatic compound is represented by the formula Ar 1 —Z 1 — where Ar 1  is a monocyclic or bicyclic ring structure of 5 to 10 carbon atoms, and Z 1  is selected from amino, hydroxyl, carboxyl, carboxylate, acid halide, alkyl halides, alkyl sulfonates, sulfonyl halide, phosphoryl chloride, N-succinimido ester, chloroformate, isocyanate, acyl azide, and isothiocyanate. 
   
   
       4 . The complex of  claim 3 , wherein the at least one of Ar' or Are is further substituted with at least one hydrophilic group, and the aromatic or heteroaromatic compound is represented by the formula W—Ar—Z, wherein W is —COOH, —NH 2 , —OH, —SO 3 H, or —PO 3 H 2 . 
   
   
       5 . The complex of  claim 3 , wherein Ar' is selected from pyrazine, quinoline, quinoxaline, and coumarin groups. 
   
   
       6 . The complex of  claim 3 , wherein Ar 1 —Z 1 — is selected from 7-amino-4-methylcoumarin, 4-aminosalicylic acid, 1-aminonaphthalene, aminopyrazines, diaminopyrazines, pyrazine carboxylic acid, pyrazine carboxamide, 2,5-diamino-3,6-dicyanopyrazine, 3,6-diamino-2,5-pyrazinedicarboyxlic acid, 3,6-diamino-2,5-pyrazinedicarboyxlic esters, and 3,6-diamino-2,5-pyrazinedicarboxamides. 
   
   
       7 . The complex of  claim 1 , wherein at least one absorption band of the Ar 1 —Z 1 — substantially matches with at least one excitation band of M. 
   
   
       8 . The complex of  claim 1 , wherein M is a metal ion selected from Eu, Tb, Dy, Sm, Rh, Re, Ru, Cr, and In. 
   
   
       9 . The complex of  claim 8 , wherein
 X 1  is Ar 1 —Z 1 —;   X 2  and X 3  are independently selected from —O − , —NH(CH 2 ) a OH, —NH(CH 2 ) a CO 2 H, —NH(CH 2 ) a SO 3   − , and —O(CH 2 ) a SO 3   − ,   R 1  to R 5  are independently selected from hydrogen, C1-C10 hydroxyalkyl, carboxyl, C1-C10 carboxyalkyl, —(CH 2 ) b SO 3   − —(CH 2 ) b NHSO 3   − , —(CH 2 ) b OCO(CH 2 ) b SO 3   − , —(CH 2 ) b CONH(CH 2 ) c SO 3   − , and —(CH 2 ) b NHCO(CH 2 ) c SO 3   − .   
   
   
       10 . The complex of  claim 8 , wherein
 R 1  is an Ar 2 —Z 2 —;   X 1  to X 3  are independently selected from —O − , —NH(CH 2 ) a OH, —NH(CH 2 ) a CO 2 H, —NH(CH 2 ) a SO 3   − , and —O(CH 2 ) a SO 3   − ; and   R 2  to R 5  are independently selected from hydrogen, C1-C10 hydroxyalkyl, carboxyl, C1-C10 carboxyalkyl, —(CH 2 ) b SO 3   − —(CH 2 ) b NHSO 3   − , —(CH 2 ) b OCO(CH 2 ) b SO 3   − , —(CH 2 ) b CONH(CH 2 ) c SO 3   − , and —(CH 2 ) b NHCO(CH 2 ) c SO 3   − .   
   
   
       11 . The complex of  claim 8 , wherein
 R 2  is Ar 2 —Z 2 —;   X 1  to X 3  are independently selected from —O − , —NH(CH 2 ) a OH, —NH(CH 2 ) a CO 2 H, —NH(CH 2 ) a SO 3   − , and —O(CH 2 ) a SO 3   − ; and   R 1 , R 3 , R 4 , and R 5  are independently selected from hydrogen, C1-C10 hydroxyalkyl, carboxyl, C1-C10 carboxyalkyl, —(CH 2 ) b SO 3   − —(CH 2 ) b NHSO 3   − , —(CH 2 ) b OCO(CH 2 ) b SO 3   − , —(CH 2 ) b CONH(CH 2 ) c SO 3   − , and —(CH 2 ) b NHCO(CH 2 ) c SO 3   − .   
   
   
       12 . The complex of  claim 8 , wherein
 R 3  is Ar 2 —Z 2 —;   X 1  to X 3  are independently selected from —O − , —NH(CH 2 ) a OH, —(CH 2 ) a CO 2 H, —NH(CH 2 ) a SO 3   − , and —O(CH 2 ) a SO 3   − ; and   R 1 , R 2 , R 4 , and R 5  are independently selected from hydrogen, C1-C10 hydroxyalkyl, carboxyl, C1-C10 carboxyalkyl, —(CH 2 ) b SO 3   − , —(CH 2 ) b NHSO 3   − , —(CH 2 ) b OCO(CH 2 ) b SO 3   − , —(CH 2 ) b CONH(CH 2 ) c SO 3   − , and —(CH 2 ) b NHCO(CH 2 ) c SO 3   − .   
   
   
       13 . The complex of  claim 9 , wherein
 X 2  and X 3  are —O − ;   Y 1  and r are independently selected from —(CH 2 ) m O—, —(CH 2 ) m OCNH—, —(CH 2 ) m OCO 2 —, —(CH 2 ) m NHCO—, —(CH 2 ) m NHCONH—, —(CH 2 ) m OSO 2 —, and —(CH 2 ) m NHSO 2 —; and   R 1  to R 5  are hydrogens.   
   
   
       14 . The complex of  claim 10 , wherein
 X 1  to X 3  are —O − ;   R 2  to R 5  are hydrogens; and   Y 1  and Y 2  are independently selected from —(CH 2 ) m O—, —(CH 2 ) m OCNH—, —(CH 2 ) m OCO 2 —, —(CH 2 ) m NHCO—, —(C 2 ) m NHCONH—, —(CH 2 ) m OSO 2 —, and —(CH 2 ) m NHSO 2 —.   
   
   
       15 . The complex of  claim 11 , wherein
 X 1  to X 3  are —O − ;   R 1 , R 3 , R 4 , and R 5  are hydrogens; and   Y 1  and Y 2  are independently selected from —(CH 2 ) m O—, —(CH 2 ) m OCNH—, —(CH 2 ) m OCO 2 —, —(C 2 ) m NHCO, —(CH 2 ) m NHCONH—, —(CH 2 ) m OSO 2 —, and —(CH 2 ) m NHSO 2 —.   
   
   
       16 . The complex of  claim 12 , wherein
 X 1  to X 3  are —O − ;   R 1 , R 2 , R 4 , and R 5  are hydrogens; and   Y 1  and Y 2  are independently selected from —(CH 2 ) m O—, —(CH 2 ) m OCNH—, —(CH 2 ) m OCO 2 —, —(CH 2 ) m NHCO, —(CH 2 ) m NHCONH—, —(CH 2 ) m OSO 2 —, and —(CH 2 ) m NHSO 2 —.   
   
   
       17 . The complex of  claim 1 , wherein X 1  is Ar 1 —Z 1 — and X 2  is —O − . 
   
   
       18 . The complex of  claim 1 , wherein each of X 1  and X 2  is Ar 1 —Z 1 —. 
   
   
       19 . The complex of  claim 1  wherein Ar 1  is quinoxaline, quinoxaline carboxylate, or cyanoquinoxaline. 
   
   
       20 . The complex of  claim 1  wherein Z 1 — is —NH— or —NH(CH 2 ) m —. 
   
   
       21 . The complex of  claim 1 , wherein each of Y 1  and Y 2  is a single bond, X 3  is —O − , and each of R 1 -R 5  is hydrogen. 
   
   
       22 . The complex of  claim 1 , wherein Ar 1  is quinoxaline, quinoxaline carboxylate, or cyanoquinoxaline; and Z 1 — is —NH— or —NH(CH 2 ) m —. 
   
   
       23 . The complex of  claim 1 , wherein Ar 1  is quinoxaline, quinoxaline carboxylate or cyanoquinoxaline; each of Y 1  and Y 2  is a single bond; X 3  is —O − ; and each of R 1 -R 5  is hydrogen. 
   
   
       24 . The complex of  claim 1 , wherein Z 1 — is —NH— or —NH(CH 2 ) m —; each of Y 1  and Y 2  is a single bond; X 3  is —O − ; and each of R 1 -R 5  is hydrogen. 
   
   
       25 . The complex of  claim 1 , wherein Ar 1  is quinoxaline, quinoxaline carboxylate, or cyanoquinoxaline; Z 1 — is —NH— or —NH(CH 2 ) m —; each of Y 1  and Y 2  is a single bond; X 3  is —O − ; and each of R 1 -R 5  is hydrogen.