Hydrophilic metal complexes
First Claim
Patent Images
1. A metal complex having the formula:
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space="preserve" listing-type="equation">[M(L.sub.1 L.sub.2 L.sub.3)].sub.n --X.sub.m AwhereinM is a divalent or trivalent metal cation selected from the group consisting of a rare earth metal cation and a transition metal cation;
L1, L2 and L3 are the same or different, and each is a ligand having at least two nitrogen-containing heterocyclic rings, wherein L1, L2 and L3 are bound to the metal cation via nitrogen atoms;
X is a reactive or activatable functional group selected from the group consisting of an activated carboxylic acid group, a maleimide, a carboxylic acid, a thiol, a halide and a photoactivatable group;
n is 1 to 10;
m is 1 to 6; and
A is at least one negatively charged group,wherein the metal complex contains at least one hydrophilic group selected from the group consisting of a C2 -C3 alkyleneoxy group, a C2 -C3 alkylenethio group, a C2 -C3 alkyleneamino group and a polyhydroxy group, wherein the at least one hydrophilic group is located at at least one of the following locations (a) and (b);
(a) as a substituent or component of a substituent of one of the ligands L1, L2 and L3 ; and
(b) as a linker or component of a linker which links the group X and one of the ligands L1, L2 and L3.
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Abstract
The present invention concerns new hydrophilic metal complexes and their use as luminescent marker groups in immunoassays.
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Citations
18 Claims
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1. A metal complex having the formula:
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space="preserve" listing-type="equation">[M(L.sub.1 L.sub.2 L.sub.3)].sub.n --X.sub.m Awherein M is a divalent or trivalent metal cation selected from the group consisting of a rare earth metal cation and a transition metal cation; L1, L2 and L3 are the same or different, and each is a ligand having at least two nitrogen-containing heterocyclic rings, wherein L1, L2 and L3 are bound to the metal cation via nitrogen atoms; X is a reactive or activatable functional group selected from the group consisting of an activated carboxylic acid group, a maleimide, a carboxylic acid, a thiol, a halide and a photoactivatable group; n is 1 to 10; m is 1 to 6; and A is at least one negatively charged group, wherein the metal complex contains at least one hydrophilic group selected from the group consisting of a C2 -C3 alkyleneoxy group, a C2 -C3 alkylenethio group, a C2 -C3 alkyleneamino group and a polyhydroxy group, wherein the at least one hydrophilic group is located at at least one of the following locations (a) and (b); (a) as a substituent or component of a substituent of one of the ligands L1, L2 and L3 ; and (b) as a linker or component of a linker which links the group X and one of the ligands L1, L2 and L3. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)
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7. The metal complex as claimed in claim 6, wherein the polyhydroxy group has a formula --NR--C(CH2 OH)3, wherein R is as defined in claim 6.
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8. The metal complex as claimed in claim 1, wherein the C2 -C3 alkyleneoxy group is an ethyleneoxy group, the C2 -C3 alkylenethio group is an ethylenethio group, and the C2 -C3 alkyleneamino group is an ethyleneamino group.
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9. The metal complex as claimed in claim 1, wherein the metal complex contains 1-30 hydrophilic groups each independently selected from the group consisting of a C2 -C3 alkyleneoxy group, a C2 -C3 alkylenethio group and a C2 -C3 alkyleneamino group.
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10. The metal complex as claimed in claim 1, wherein the metal complex is of formula (III):
- ##STR8## wherein M, X and A are as defined in claim 1;
one of R1 through R6 is bound to --X; and the remainder of R1 through R6 which are not bound to --X are each independently selected from the group consisting of hydrogen, C1 -C5 alkyl and a substituent containing at least one hydrophilic group which is selected from the group consisting of a C2 -C3 alkyleneoxy group, a C2 -C3 alkylenethio group and a C2 -C3 alkyleneamino group, wherein at least one of the remainder of R1 through R6 is the substituent containing the at least one hydrophilic group.
- ##STR8## wherein M, X and A are as defined in claim 1;
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11. The metal complex as claimed in claim 1, wherein the metal complex is of formula (IIIa):
- ##STR9## wherein M, X and A are as defined in claim 1;
R1 through R5 are each independently selected from the group consisting of hydrogen, C1 -C5 alkyl and a substituent containing at least one hydrophilic group which is selected from the group consisting of a C2 -C3 alkyleneoxy group, a C2 -C3 alkylenethio group and a C2 -C3 alkyleneamino group; s is 0-6; and Y is a linker having 1-10 hydrophilic groups each independently selected from the group consisting of a C2 -C3 alkyleneoxy group, a C2 -C3 alkylenethio group and a C2 -C3 alkyleneamino group.
- ##STR9## wherein M, X and A are as defined in claim 1;
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12. The metal complex as claimed in claim 1, wherein the metal complex is of formula (IIIb):
- ##STR10## wherein M, X and A are as defined in claim 1;
R1 through R5 are each independently selected from the group consisting of hydrogen, C1 -C5 alkyl and a substituent containing 1-10 hydrophilic groups each of which is selected from the group consisting of a C2 -C3 alkyleneoxy group, a C2 -C3 alkylenethio group and a C2 -C3 alkyleneamino group, wherein at least one of R1 through R5 is the substituent containing the 1-10 hydrophilic groups; and s is 0-6.
- ##STR10## wherein M, X and A are as defined in claim 1;
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13. The metal complex as claimed in claim 1, wherein the metal complex is of formula (IV):
- ##STR11## wherein M, Y, X and n are as defined in claim 1;
R1 through R3 are each independently selected from the group consisting of hydrogen, C1 -C5 alkyl and a substituent containing at least one hydrophilic group which is selected from the group consisting of a C2 -C3 alkyleneoxy group, a C2 -C3 alkylenethio group and a C2 -C3 alkyleneamino group; and Y is a linker having 1-10 hydrophilic groups each independently selected from the group consisting of a C2 -C3 alkyleneoxy group, a C2 -C3 alkylenethio group and a C2 -C3 alkyleneamino group.
- ##STR11## wherein M, Y, X and n are as defined in claim 1;
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14. The metal complex as claimed in claim 1, wherein the metal complex is of formula (V):
- ##STR12## wherein M, X and A are as defined in claim 1;
Z is a linker; R1 '"'"' through R4 '"'"' are each independently selected from the group consisting of hydrogen, C1 -C5 alkyl and a substituent containing at least one polyhydroxy group, wherein at least one of R1 '"'"' through R4 '"'"' is the substituent containing the at least one polyhydroxy group; and R5 '"'"' is hydrogen or C1 -C5 alkyl.
- ##STR12## wherein M, X and A are as defined in claim 1;
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15. The metal complex as claimed in claim 14, wherein the --OH group of the at least one polyhydroxy group is substituted by a hydrophilic group.
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16. The metal complex as claimed in claim 15, wherein the hydrophilic group comprises an element of formula (VIa) or (VIb):
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space="preserve" listing-type="equation">--A.sub.1 --NR--W.sub.1 (A.sub.2 --NR--W.sub.2).sub.n '"'"' (VIa)
space="preserve" listing-type="equation">--A.sub.1 --O--W.sub.1 (A.sub.2 --O--W.sub.2).sub.n '"'"' (VIb)wherein A1 and A2 are each a same or different linker; W1 and W2 are each a same or different organic residue having at least two hydroxy groups; R is hydrogen or C1 -C5 alkyl; and n'"'"' is 0 or the same number as the number of hydroxy groups on W1.
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17. A conjugate, comprising a metal complex coupled with a biological substance, wherein the metal complex has the formula:
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space="preserve" listing-type="equation">[M(L.sub.1 L.sub.2 L.sub.3)].sub.n --X.sub.m Awherein M is a divalent or trivalent metal cation selected from the group consisting of a rare earth metal cation and a transition metal cation; L1, L2 and L3 are the same or different, and each is a ligand having at least two nitrogen-containing heterocyclic rings, wherein L1, L2 and L3 are bound to the metal cation via nitrogen atoms; X is a reactive or activatable functional group; n is 1 to 10; m is 1 to 6; and A is at least one negatively charged group, wherein the metal complex contains at least one hydrophilic group selected from the group consisting of a C2 -C3 alkyleneoxy group, a C2 -C3 alkylenethio group, a C2 -C3 alkyleneamino group and a polyhydroxy group, wherein the at least one hydrophilic group is located at at least one of the following locations (a) and (b); (a) as a substituent or component of a substituent of one of the ligands L1, L2 and L3 ; and (b) as a linker or component of a linker which links the group X and one of the ligands L1, L2 and L3. - View Dependent Claims (18)
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Specification