PYRIDINIUM BORONIC ACID QUENCHERS FOR USE IN ANALYTE SENSORS

• US 20080305009A1
• Filed: 05/01/2008
• Published: 12/11/2008
• Est. Priority Date: 05/01/2007
• Status: Active Grant

• Current Assignee: Medtronic Minimed Incorporated (Medtronic Plc)
• Original Assignee: GluMetrics, Inc.
• Inventors: Gamsey, Soya, Wessling, Ritchie A.
• Granted Patent: US 7,939,664 B2
• Time in Patent Office: Days
• US Class Current: 422/82.08
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: G01N 2400/00 Assays, e.g. immunoassays or enzyme assays, involving carbohydrates
• CPC Class Codes: G01N 33/523 the element being adapted for a specific analyte
• CPC Class Codes: Y10T 436/104998 Glucose, ketone, nitrate standard or control
• CPC Class Codes: Y10T 436/144444 Glucose
• CPC Class Codes: Y10T 436/145555 Hetero-N

Abstract

Novel pyridinium salts functionalized with boronic acid and methods of making them are disclosed. When combined with a fluorescent dye, the compounds are useful in the detection of polyhydroxyl-substituted organic molecules.

Claims

1. The compound:

2. A method of making the compound of claim 1, comprising the steps of:

29. A glucose sensor comprising any one or more of the compounds of claims 1, 3, 5-10, 12-15, 17, 18, and 20-23, and a fluorescent dye.

30. The glucose sensor of claim 29, wherein said any one or more of the compounds are in the form of a polymer.

31. The glucose sensor of claim 29, further comprising a glucose permeable immobilizing means, e.g., a polymer matrix or a semipermeable membrane.

3. The compound:

4. A method of making the compound of claim 3, comprising the steps of:

5. The reactive compound:

wherein;

X—

is a counterion;

X¹ is —

O—

or —

NH—

;

X² is —

O—

or —

NH—

;

L is a divalent linking group comprising a direct bond or a lower alkylene having 1 to 8 carbon atoms, optionally terminated with or interrupted by one or more divalent connecting groups selected from the group consisting of sulfonamide (—

SO₂NH—

), amide —

(C═

O)N—

, ester —

(C═

O)—

O—

, ether —

O—

, sulfide —

S—

, sulfone (—

SO₂—

), phenylene —

C₆H₄—

, urethane —

NH(C═

O)—

O—

, urea —

NH(C═

O)NH—

, thiourea —

NH(C═

S)—

NH—

, amide —

(C═

O)NH—

, and amine —

NR—

, where R is defined as alkyl having 1 to 6 carbon atoms; and

Z is either a reactive, ethylenically unsaturated group or a reactive functional group, capable of forming a covalent bond with a polymer or matrix.

6. The compound of claim 5, wherein Z is a reactive, ethylenically unsaturated group selected from the group consisting of methacrylamido-, acrylamido-, methacryloyl-, acryloyl- and styryl-.

7. The compound of claim 5, wherein Z is a reactive functional group capable of forming a covalent bond with a polymer or matrix selected from the group consisting of —

Br, —

OH, —

SH, —

CO₂H, and —

NH₂.

8. The compound of claim 5, wherein Z is

wherein R is H or CH₃.

9. The non-reactive compound:

wherein;

X is —

O—

or —

NH—

; and

R′

is an alkyl, optionally including —

O—

units in the carbon chain and terminated with —

OH or —

OCH₃.

10. The compound:

11. A method of making the compound of claim 10, comprising the steps of:

12. The compound:

wherein;

Z is a reactive, ethylenically unsaturated group selected from the group consisting of methacrylamido-, acrylamido-, methacryloyl-, acryloyl- and styryl-, or wherein Z is a reactive functional group capable of forming a covalent bond with a polymer or matrix;

Y is a trivalent connecting group selected from

where R is H or a lower alkyl, and

X¹ and X² are —

O—

or —

NH—

; and

L¹, L², and L³ are selected from a direct bond or, a lower alkylene having 1 to 8 carbon atoms, optionally terminated with or interrupted by one or more divalent connecting groups selected from sulfonamide (—

SO₂NH—

), amide —

(C═

O)N—

, ester —

(C═

O)—

O—

, ether —

O—

, sulfide —

S—

, sulfone (—

SO₂—

), phenylene —

C₆H₄—

, urethane —

NH(C═

O)—

O—

, urea —

NH(C═

O)NH—

, thiourea —

NH(C═

S)—

NH—

, amide —

(C═

O)NH—

, amine —

NR—

(where R is defined as alkyl having 1 to 6 carbon atoms) or combinations thereof.

13. The compound of claim 12, wherein Z is a polymerizable, ethylenically unsaturated group selected from the group consisting of methacrylamido-, acrylamido-, methacryloyl-, acryloyl- and styryl-.

14. The compound of claim 12, wherein Z is a reactive functional group capable of forming a covalent bond with a polymer or matrix selected from the group consisting of —

Br, —

OH, —

SH, —

CO₂H, and —

NH₂.

15. The compound:

wherein n is an integer from 1-10.

16. A method of making the compound of claim 15, comprising the steps of:

19. A method of making the compound of claim 15, comprising the steps of:

17. The compound:

wherein;

X⁻

is a counterion;

X¹ is —

O—

or —

NH—

;

X² is —

O—

or —

NH—

;

L is a divalent linking selected from a direct bond or, a lower alkylene having 1 to 8 carbon atoms, optionally terminated with or interrupted by one or more divalent connecting groups selected from sulfonamide (—

SO₂NH—

), amide —

(C═

O)N—

, ester —

(C═

O)—

O—

, ether —

O—

, sulfide —

S—

, sulfone (—

SO₂—

), phenylene —

C₆H₄—

, urethane —

NH(C═

O)—

O—

, urea —

NH(C═

O)NH—

, thiourea —

NH(C═

S)—

NH—

, amide —

(C═

O)NH—

, amine —

NR—

(where R is defined as alkyl having 1 to 6 carbon atoms) or combinations thereof;

Z is a reactive group selected from a coupling group or an olefinically unsaturated group, or Z is

wherein R is H or CH₃;

the bond from the central benzene ring is to the ortho, meta or para position on the adjacent pyridinium rings; and

—

B(OH)₂ may be in the ortho, meta or para position.

18. The compound:

20. The compound:

wherein;

X⁻

is a counterion;

X¹ is —

O—

or —

NH—

;

X² is —

O—

or —

NH—

;

L is a divalent linker selected from the group consisting of a direct bond and a lower alkylene having 1 to 8 carbon atoms, optionally terminated with or interrupted by one or more divalent connecting groups selected from the group consisting of sulfonamide (—

SO₂NH—

), amide —

(C═

O)N—

, ester —

(C═

O)—

O—

, ether —

O—

, sulfide —

S—

, sulfone (—

SO₂—

), phenylene —

C₆H₄—

, urethane —

NH(C═

O)—

O—

, urea —

NH(C═

O)NH—

, thiourea —

NH(C═

S)—

NH—

, amide —

(C═

O)NH—

, amine —

NR—

(where R is defined as alkyl having 1 to 6 carbon atoms) or combinations thereof;

Z is either a polymerizable ethylenically unsaturated group selected from the group consisting of methacrylamido-, acrylamido-, methacryloyl-, acryloyl-, or styryl- or optionally Z is a reactive functional group capable of forming a covalent bond with a polymer or matrix;

the ambiguously depicted bonds are in the ortho, meta or para position; and

—

B(OH)₂ may be in the ortho, meta or para position.

21. The compound of claim 20, wherein Z is

wherein R is H or CH₃.

22. The compound of claim 20, wherein Z is selected from the group consisting of —

Br, —

OH, —

SH, —

CO₂H, and —

NH₂.

23. The compound:

24. A method of making the compound of claim 23, comprising the steps of:

25. A polymer comprising a quencher monomer selected from the group consisting of HEMA, PEGMA, methacrylic acid, hydroxyethyl acrylate, N-vinyl pyrrolidone, acrylamide, N,N′

-dimethyl acrylamide, and sodium sulfopropyl methacrylate; and

a crosslinker selected from the group consisting of ethylene dimethacrylate, PEGDMA, trimethylolpropane triacrylate, methylene-bis-acrylamide and methylene-bis-methacrylamide.

26. An analyte sensor comprising:

a fluorophore configured to absorb light at a first wavelength and emit light at a second wavelength; and

a quencher configured to modify the light emitted by the fluorophore by an amount related to the analyte concentration, wherein the quencher comprises a boronic acid-substituted pyridinium.

27. The analyte sensor of claim 26, wherein said quencher comprises a monovalent, boronic acid-substituted pyridinium group.

28. The analyte sensor of claim 26, wherein said quencher comprises a boronic acid-substituted polypyridinium, wherein said polypyridinium comprises three or more pyridinium groups.