Transition Metal Complexes with Bidentate Ligand Having an Imidazole Ring

• US 20100288634A1
• Filed: 07/26/2010
• Published: 11/18/2010
• Est. Priority Date: 11/15/1999
• Status: Active Grant

• Current Assignee: Abbott Diabetes Care Incorporated (Abbott Laboratories Incorporated)
• Original Assignee: Abbott Diabetes Care Incorporated (Abbott Laboratories Incorporated)
• Inventors: Heller, Adam, Mao, Fei
• Granted Patent: US 8,168,052 B2
• Time in Patent Office: Days
• US Class Current: 204/403.14
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/1477 non-invasive
• CPC Class Codes: A61B 5/1486 using enzyme electrodes, e.g. with immobilised oxidase
• CPC Class Codes: C07F 15/0026 without a metal-carbon linkage
• CPC Class Codes: C07F 15/0053 without a metal-carbon linkage
• CPC Class Codes: C07F 15/025 without a metal-carbon linkage
• CPC Class Codes: C07F 15/065 without a metal-carbon linkage
• CPC Class Codes: C07F 9/005 Compounds of elements of Group 5 of the Periodic Table without metal-carbon linkages
• CPC Class Codes: C08F 8/42 Introducing metal atoms or metal-containing groups
• CPC Class Codes: C08F 8/44 Preparation of metal salts or ammonium salts
• CPC Class Codes: C09B 57/10 Metal complexes of organic compounds not being dyes in uncomplexed form
• CPC Class Codes: C12Q 1/004 mediator-assisted

Abstract

Novel transition metal complexes of iron, cobalt, ruthenium, osmium, and vanadium are described. The transition metal complexes can be used as redox mediators in enzyme based electrochemical sensors. In such instances, transition metal complexes accept electrons from, or transfer electrons to, enzymes at a high rate and also exchange electrons rapidly with the sensor. The transition metal complexes include at least one substituted or unsubstituted biimidazole ligand and may further include a second substituted or unsubstituted biimidazole ligand or a substituted or unsubstituted bipyridine or pyridylimidazole ligand. Transition metal complexes attached to polymeric backbones are also described.

Claims

1-18. -18. (canceled)

19. A complex comprising:

a polymer;

at least one spacer covalently bonded to the polymer; and

at least one of an analyte-responsive enzyme and a mediator chemically bonded to the at least one spacer.

20. The complex of claim 19, wherein the at least one spacer comprises at least one non-cyclic functional group selected from the group consisting of —

(CR^rR^s)—

, —

O—

, —

S—

, —

C(O)O—

, —

S(O)₂NR^k—

, —

OC(O)NR^m—

, —

OC(S)NRⁿ, —

C(O)NR^t—

, —

NR^u—

, —

CR^v═

N—

O—

, —

CR^w═

NNR^x—

, and —

(SiR^yR^z) —

, and wherein R^r and R^s are independently hydrogen, chlorine, fluorine, or substituted or unsubstituted alkyl, alkoxy, alkenyl, or alkynyl, and R^k, R^m, Rⁿ, R^t, R^u, R^v, R^w, R^x, R^y, and R^z are independently hydrogen or substituted or unsubstituted alkyl.

21. The complex of claim 19, wherein at least one of the analyte-responsive enzyme and the mediator forms one or more of carbon-carbon, carbon-nitrogen, carbon-silicon, carbon-oxygen, carbon-sulfur, sulfur-nitrogen, silicon-oxygen or metal-carbon covalent bonds with the spacer.

22. The complex of claim 21, wherein the spacer and at least one of the analyte-responsive enzyme and the mediator forms one or more covalent linkages selected from the group consisting of amide, thioether, hydrazone, oxime, alkylamine, ester, imidazolium, pyridinium, ether, aminotriazine, triazinyl ether, urea, urethane, thiourea and sulfonamide.

23. The complex of claim 19, wherein the spacer is covalently bonded to one or more ligands of the mediator.

24. The complex of claim 23, wherein the one or more ligands comprises a substituted or unsubstituted heterocyclic nitrogen-containing moiety.

25. The complex of claim 19, wherein the spacer is coordinatively bonded to a metal of the mediator.

26. The complex of claim 25, wherein the metal of the mediator is cobalt, ruthenium, vanadium or osmium.

27. The complex of claim 19, wherein the spacer is covalently bonded to one or more side chains of the analyte-responsive enzyme.

28. The complex of claim 27, wherein the one or more side chains of the analyte-responsive enzyme is selected from the group consisting of substituted or unsubstituted amines, alcohols, thiols, phenols, imidazoles, indols, and carboxylic acids.

29. The complex of claim 19, wherein the spacer forms a coordination complex with the mediator.

30. The complex of claim 29, wherein one or more nitrogen-containing moieties of the spacer forms a coordination complex with a metal of the mediator.

31. The complex of claim 19, wherein the spacer is ionically bonded to the mediator.

32. The complex of claim 31, wherein the spacer comprises at least one positively charged moiety and the mediator comprises at least one negatively charged moiety.

33. The complex of claim 31, wherein the spacer comprises at least one negatively charged moiety and the mediator comprises at least one positively charged moiety.

34. The complex of claim 19, wherein the polymer is crosslinked.

35. The complex of claim 34, wherein at least one of the analyte-responsive enzyme and the mediator is crosslinked with the polymer.

36. The complex of claim 35, wherein at least one of the analyte-responsive enzyme and the mediator is crosslinked with the polymer through one or more crosslinking agents.

37. The complex of claim 36, wherein the one or more crosslinking agents comprise at least one bifunctional, trifunctional or tetrafunctional crosslinking agent.

38. The complex of claim 36, wherein the one or more crosslinking agents comprises a pyridine-reactive or imidazole-reactive crosslinking agent.

39. The complex of claim 36, wherein the one or more crosslinking agents is selected from the group consisting of substituted or unsubstituted epoxides, aldehydes, imidoesters, N-hydroxysuccinimide esters, carbodiimides, cyanuric chloride, tetrachlorobenzoquinone, benzoquinone and tetracyanoquinodimethane.

40. The complex of claim 34, wherein one or more ligands of the mediator are crosslinkers of the polymer.

41. The complex of claim 34, wherein one or more side chains of the analyte-responsive enzyme are crosslinkers of the polymer.

42. The complex of claim 19, wherein the analyte-responsive enzyme is a glucose-responsive enzyme.

43. The complex of claim 42, wherein the analyte-responsive enzyme is glucose dehydrogenase (GDH) or glucose oxidase (GOx).

44. The complex of claim 19, wherein the analyte-responsive enzyme further comprises an enzyme cofactor.

45. The complex of claim 44, wherein the enzyme cofactor is flavin adenine dinucleotide.

46. The complex of claim 19, wherein the mediator is a transition metal complex having the formula:

47. The complex of claim 46, wherein at least one ligand of the L¹, L², L³, L⁴, L⁵, and L⁶ ligands is covalently bonded to the at least one spacer.

48. The complex of claim 46, wherein each heterocycle comprises a nitrogen-containing heterocycle that is coordinatively bound to M via a nitrogen atom of the heterocycle.

49. The complex of claim 48, wherein the nitrogen-containing heterocycle comprises a substituted or unsubstituted pyridine, a substituted or unsubstituted imidazole, a substituted or unsubstituted 2,2′

-bipyridine, a substituted or unsubstituted 2-(2-pyridyl)imidazole, or a substituted or unsubstituted 2,2′

-biimidazole.

50. The complex of claim 46, wherein at least two ligands of the L¹, L², L³, L⁴, L⁵, and L⁶ ligands are combined to form at least one multidentate ligand.

51. The complex of claim 46, wherein at least four ligands of the L¹, L², L³, L⁴, L⁵, and L⁶ ligands are combined to form at least two multidentate ligands.

52. The complex of claim 51, wherein the each of the at least two multidentate ligands is independently selected from substituted or unsubstituted 2,2′

-bipyridine, substituted or unsubstituted 2-(2-pyridyl)imidazole, or substituted or unsubstituted 2,2′

-biimidazole.

53. The complex of claim 19, wherein the complex has a molecular weight of at least 5000 daltons.

54. An electrochemical sensor comprising:

a working electrode and a counter electrode, wherein the working electrode comprises;

a polymer;

at least one spacer covalently bonded to the polymer; and

at least one of an analyte-responsive enzyme and a mediator chemically bonded to the at least one spacer.

55. The electrochemical sensor of claim 54, wherein the at least one spacer comprises at least one non-cyclic functional group selected from the group consisting of —

(CR^rR^s)—

, —

O—

, —

S—

, —

C(O)O—

, —

S(O)₂NR^k—

, —

OC(O)NR^m—

, —

OC(S)NRⁿ, —

C(O)NR^t—

, —

NR^u—

, —

CR^v═

N—

O—

, —

CR^w═

NNR^x—

, and —

(SiR^yR^z)—

, and wherein R^r and R^s are independently hydrogen, chlorine, fluorine, or substituted or unsubstituted alkyl, alkoxy, alkenyl, or alkynyl, and R^k, R^m, Rⁿ, R^t, R^u, R^v, R^w, R^x, R^y, and R^z are independently hydrogen or substituted or unsubstituted alkyl.

56. The electrochemical sensor of claim 54, wherein at least one of the analyte-responsive enzyme and the mediator forms one or more of carbon-carbon, carbon-nitrogen, carbon-silicon, carbon-oxygen, carbon-sulfur, sulfur-nitrogen, silicon-oxygen or metal-carbon covalent bonds with the spacer.

57. The electrochemical sensor of claim 56, wherein the spacer and at least one of the analyte-responsive enzyme and the mediator forms one or more covalent linkages selected from the group consisting of amide, thioether, hydrazone, oxime, alkylamine, ester, imidazolium, pyridinium, ether, aminotriazine, triazinyl ether, urea, urethane, thiourea and sulfonamide.

58. The electrochemical sensor of claim 54, wherein the spacer is covalently bonded to one or more ligands of the mediator.

59. The electrochemical sensor of claim 58, wherein the one or more ligands comprises a substituted or unsubstituted heterocyclic nitrogen-containing moiety.

60. The electrochemical sensor of claim 54, wherein the spacer is coordinatively bonded to a metal of the mediator.

61. The electrochemical sensor of claim 60, wherein the metal of the mediator is cobalt, ruthenium, vanadium or osmium.

62. The electrochemical sensor of claim 54, wherein the spacer is covalently bonded to one or more side chains of the analyte-responsive enzyme.

63. The electrochemical sensor of claim 62, wherein the one or more side chains of the analyte-responsive enzyme is selected from the group consisting of substituted or unsubstituted amines, alcohols, thiols, phenols, imidazoles, indols, and carboxylic acids.

64. The electrochemical sensor of claim 54, wherein the spacer forms a coordination complex with the mediator.

65. The electrochemical sensor of claim 64, wherein one or more nitrogen-containing moieties of the spacer forms a coordination complex with a metal of the mediator.

66. The electrochemical sensor of claim 54, wherein the spacer is ionically bonded to the mediator.

67. The electrochemical sensor of claim 66, wherein the spacer comprises at least one positively charged moiety and the mediator comprises at least one negatively charged moiety.

68. The electrochemical sensor of claim 66, wherein the spacer comprises at least one negatively charged moiety and the mediator comprises at least one positively charged moiety.

69. The electrochemical sensor of claim 64, wherein the polymer is crosslinked.

70. The electrochemical sensor of claim 69, wherein at least one of the analyte-responsive enzyme and the mediator is crosslinked with the polymer.

71. The electrochemical sensor of claim 70, wherein at least one of the analyte-responsive enzyme and the mediator is crosslinked with the polymer through one or more crosslinking agents.

72. The electrochemical sensor of claim 71, wherein the one or more crosslinking agents comprise at least one bifunctional, trifunctional or tetrafunctional crosslinking agent.

73. The electrochemical sensor of claim 71, wherein the one or more crosslinking agents comprises a pyridine-reactive or imidazole-reactive crosslinking agent.

74. The electrochemical sensor of claim 71, wherein the one or more crosslinking agents is selected from the group consisting of substituted or unsubstituted epoxides, aldehydes, imidoesters, N-hydroxysuccinimide esters, carbodiimides, cyanuric chloride, tetrachlorobenzoquinone, benzoquinone and tetracyanoquinodimethane.

75. The electrochemical sensor of claim 69, wherein one or more ligands of the mediator are crosslinkers of the polymer.

76. The electrochemical sensor of claim 69, wherein one or more side chains of the analyte-responsive enzyme are crosslinkers of the polymer.

77. The electrochemical sensor of claim 54, wherein the analyte-responsive enzyme is a glucose-responsive enzyme.

78. The electrochemical sensor of claim 77, wherein the analyte-responsive enzyme is glucose dehydrogenase (GDH) or glucose oxidase (GOx).

79. The electrochemical sensor of claim 54, wherein the analyte-responsive enzyme further comprises an enzyme cofactor.

80. The electrochemical sensor of claim 79, wherein the enzyme cofactor is flavin adenine dinucleotide.

81. The electrochemical sensor of claim 54, wherein the mediator is a transition metal complex having the formula:

82. The electrochemical sensor of claim 81, wherein at least one ligand of the L¹, L², L³, L⁴, L⁵, and L⁶ ligands is covalently bonded to the at least one spacer.

83. The electrochemical sensor of claim 81, wherein each heterocycle comprises a nitrogen-containing heterocycle that is coordinatively bound to M via a nitrogen atom of the heterocycle.

84. The electrochemical sensor of claim 83, wherein the nitrogen-containing heterocycle comprises a substituted or unsubstituted pyridine, a substituted or unsubstituted imidazole, a substituted or unsubstituted 2,2′

-bipyridine, a substituted or unsubstituted 2-(2-pyridyl)imidazole, or a substituted or unsubstituted 2,2′

-biimidazole.

85. The electrochemical sensor of claim 81, wherein at least two ligands of the L¹, L², L³, L⁴, L⁵, and L⁶ ligands are combined to form at least one multidentate ligand.

86. The electrochemical sensor of claim 81, wherein at least four ligands of the L¹, L², L³, L⁴, L⁵, and L₆ ligands are combined to form at least two multidentate ligands.

87. The electrochemical sensor of claim 86, wherein the each of the at least two multidentate ligands is independently selected from substituted or unsubstituted 2,2′

-bipyridine, substituted or unsubstituted 2-(2-pyridyl)imidazole, or substituted or unsubstituted 2,2′

-biimidazole.

88. The electrochemical sensor of claim 54, wherein the polymer is chemically bonded to the surface of the working electrode.

89. The electrochemical sensor of claim 54, wherein the polymer forms a sensing layer membrane on the surface of the working electrode.

90. The electrochemical sensor of claim 89, wherein the sensing layer membrane is formed in situ on the working electrode.

91. The electrochemical sensor of claim 90, wherein the sensing layer membrane is formed in situ on the working electrode by crosslinking the polymer on the working electrode.

92. The electrochemical sensor of claim 89, wherein the working electrode further comprises a mass transport limiting membrane disposed over the sensing layer membrane.