Oxidation Resistant Indicator Molecules

• US 20110081727A1
• Filed: 12/13/2010
• Published: 04/07/2011
• Est. Priority Date: 11/30/2006
• Status: Active Grant

• Current Assignee: Senseonics, Incorporated (Senseonics Holdings, Inc.)
• Original Assignee: Sensors For Medicine and Science Incorporated
• Inventors: Colvin, Arthur E. JR., Modzelewska, Aneta, Mortellaro, Mark Alan
• Granted Patent: US 8,143,068 B2
• Time in Patent Office: Days
• US Class Current: 436/95
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: G01N 33/66 involving blood sugars, e.g. galactose
• CPC Class Codes: Y10T 436/14 Heterocyclic carbon compound [i.e. , O, S, N, Se, Te, as only ring hetero atom]
• CPC Class Codes: Y10T 436/142222 Hetero-O [e.g., ascorbic acid, etc.]
• CPC Class Codes: Y10T 436/143333 Saccharide [e.g., DNA, etc.]
• CPC Class Codes: Y10T 436/144444 Glucose

Abstract

Compounds having enhanced oxidation stability are disclosed. The compounds have an aryl boronic acid residue having one or more electron withdrawing groups on the aromatic moiety which contains the boronic acid residue, such that the molecule has enhanced oxidation resistance as compared to a corresponding molecule without the one or more electron withdrawing groups.

Claims

1. A method for using a molecule in oxidative conditions, which comprises:

a) obtaining a molecule having an aryl boronic acid residue having one or more electron withdrawing groups on the aromatic moiety which contains the boronic acid residue, such that the molecule has enhanced oxidation resistance as compared to a corresponding molecule without the one or more electron withdrawing groups; and

b) subjecting the molecule having the one or more electron withdrawing groups to oxidative conditions.

2. The method of claim 1, wherein the electron withdrawing group comprises one or more of the following:

halogen, cyano, nitro, halo substituted alkyl, carboxylic acid, ester, sulfonic acid, ketone, aldehyde, sulfonamide, sulfone, sulfonyl, sulfoxide, halo-substituted sulfone, halo-substituted alkoxy, halo-substituted ketone, amide, or combinations thereof.

3. The method of claim 1, wherein the molecule having one or more electron withdrawing groups on the aromatic moiety further comprises a detectable group.

4. The method of claim 3, wherein the detectable group comprises an anthracene residue.

5. The method of claim 1, wherein the molecule having one or more electron withdrawing groups on the aromatic moiety is associated with a device that is implanted in a mammal.

6. The method of claim 5, wherein the device determines the presence or concentration of glucose in vivo.

7. The method of claim 1, wherein the molecule having one or more electron withdrawing groups on the aromatic moiety comprises:

9-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-3-(trifluoromethyl)benzyl]-N-[3-(methacrylamido)propyl-amino]methyl]-10-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-3-(trifluoromethyl)benzyl]-N-[2-carboxy-ethyl)amino]methyl]anthracene (4c);

9-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-3-(trifluoromethylsulfonyl)benzyl]-N-[3-(methacrylamido)propylamino]methyl]-10-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-3-(trifluoromethylsulfonyl)benzyl]-N-[2-(carboxyethyl)amino]methyl]anthracene (21);

9-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-2,4-bis(trifluoromethyl)benzyl]-N-[3-(methacrylamido)propylamino]methyl]-10-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-2,4-bis(trifluoromethyl)benzyl]-N-[2-(carboxyethyl)amino]-methyl]anthracene (27a);

or a residue or salt thereof.

8. A method for detecting the presence or concentration of an analyte in a sample in an oxidative environment, said method comprising:

a) exposing the sample to an indicator molecule having a detectable quality that changes when the indicator molecule is exposed to the analyte, said molecule comprising an aryl boronic acid residue having one or more electron withdrawing groups on the aromatic moiety which contains the boronic acid residue, such that the indicator molecule has enhanced oxidation resistance as compared to the corresponding molecule without the one or more electron withdrawing groups; and

b) measuring any change in said detectable quality to thereby determine the presence or concentration of said analyte in said sample.

9. The method of claim 8, wherein the electron withdrawing group comprises one or more of the following:

halogen, cyano, nitro, halo substituted alkyl, carboxylic acid, ester, sulfonic acid, ketone, aldehyde, sulfonamide, sulfone, sulfonyl, sulfoxide, halo-substituted sulfone, halo-substituted alkoxy, halo-substituted ketone, amide, or combinations thereof.

10. The method of claim 8, wherein the change in the detectable quality is an optical change.

11. The method of claim 8, wherein the analyte is glucose.

12. The method of claim 8, wherein the molecule having one or more electron withdrawing groups on the aromatic moiety comprises:

9-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-3-(trifluoromethyl)benzyl]-N-[3-(methacrylamido)propyl-amino]methyl]-10-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-3-(trifluoromethyl)benzyl]-N-[2-carboxy-ethyl)amino]methyl]anthracene (4c);

9-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-3-(trifluoromethylsulfonyl)benzyl]-N-[3-(methacrylamido)propylamino]methyl]-10-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-3-(trifluoromethylsulfonyl)benzyl]-N-[2-(carboxyethyl)amino]methyl]anthracene (21);

9-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-2,4-bis(trifluoromethyl)benzyl]-N-[3-(methacrylamido)propylamino]methyl]-10-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-2,4-bis(trifluoromethyl)benzyl]-N-[2-(carboxyethyl)amino]-methyl]anthracene (27a);

or a residue or salt thereof.

13. A compound having the following structure:

14. The compound of claim 13, wherein R₁ and R₂ each comprises one or more of the following:

halogen, cyano, nitro, halo substituted alkyl, carboxylic acid, ester, sulfonic acid, ketone, aldehyde, sulfonamide, sulfone, sulfonyl, sulfoxide, halo-substituted sulfone, halo-substituted alkoxy, halo-substituted ketone, amide, or combinations thereof.

15. The compound of claim 13, wherein R₄ comprises an anthracene residue.

16. The compound of claim 13, wherein the compound comprises:

9-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-3-(trifluoromethyl)benzyl]-N-[3-(methacrylamido)propyl-amino]methyl]-10-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-3-(trifluoromethyl)benzyl]-N-[2-carboxy-ethyl)amino]methyl]anthracene (4c);

9-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-3-(trifluoromethylsulfonyl)benzyl]-N-[3-(methacrylamido)propylamino]methyl]-10-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-3-(trifluoromethylsulfonyl)benzyl]-N-[2-(carboxyethyl)amino]methyl]anthracene (21);

9-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-2,4-bis(trifluoromethyl)benzyl]-N-[3-(methacrylamido)propylamino]methyl]-10-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-2,4-bis(trifluoromethyl)benzyl]-N-[2-(carboxyethyl)amino]-methyl]anthracene (27a);

or a residue or salt thereof.

17. A compound having the following structure:

18. The compound of claim 17, wherein R₁ and R₂ each comprises one or more of the following:

halogen, cyano, nitro, halo substituted alkyl, carboxylic acid, ester, sulfonic acid, ketone, aldehyde, sulfonamide, sulfone, sulfonyl, sulfoxide, halo-substituted sulfone, halo-substituted alkoxy, halo-substituted ketone, amide, or combinations thereof.

19. The compound of claim 17, wherein R₄ comprises an anthracene residue.

20. A method for the production of an indicator macromolecule for detecting the presence or concentration of an analyte in an oxidative environment, said method comprising copolymerizing:

a) one or more indicator component monomers which individually are not sufficiently water soluble to permit their use in an aqueous environment for detecting the presence or concentration of said analyte, wherein the indicator component monomer comprises compound having the following structure;

21. The method of claim 20, wherein R₁ and R₂ each comprises one or more of the following:

halogen, cyano, nitro, halo substituted alkyl, carboxylic acid, ester, sulfonic acid, ketone, aldehyde, sulfonamide, sulfone, sulfonyl, sulfoxide, halo-substituted sulfone, halo-substituted alkoxy, halo-substituted ketone, amide, or combinations thereof.

22. The method of claim 20, wherein R₄ comprises an anthracene residue.

23. The method of claim 20, wherein the compound comprises:

9-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-3-(trifluoromethyl)benzyl]-N-[3-(methacrylamido)propyl-amino]methyl]-10-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-3-(trifluoromethyl)benzyl]-N-[2-carboxy-ethyl)amino]methyl]anthracene (4c);

9-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-3-(trifluoromethylsulfonyl)benzyl]-N-[3-(methacrylamido)propylamino]methyl]-10-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-3-(trifluoromethylsulfonyl)benzyl]-N-[2-(carboxyethyl)amino]methyl]anthracene (21);

9-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-2,4-bis(trifluoromethyl)benzyl]-N-[3-(methacrylamido)propylamino]methyl]-10-[N-[6-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolano)-2,4-bis(trifluoromethyl)benzyl]-N-[2-(carboxyethyl)amino]-methyl]anthracene (27a);

or a residue or salt thereof.

24. A compound having the following structure:

25. The compound of claim 24, wherein R₁ comprises one or more of the following:

halogen, cyano, nitro, halo substituted alkyl, carboxylic acid, ester, sulfonic acid, ketone, aldehyde, sulfonamide, sulfone, sulfonyl, sulfoxide, halo-substituted sulfone, halo-substituted alkoxy, halo-substituted ketone, amide, or combinations thereof.

26. The compound of claim 24, wherein the detectable moiety comprises an anthracene residue.

27. A compound having the following structure:

28. The compound of claim 27, wherein R₁ comprises one or more of the following:

halogen, cyano, nitro, halo substituted alkyl, carboxylic acid, ester, sulfonic acid, ketone, aldehyde, sulfonamide, sulfone, sulfonyl, sulfoxide, halo-substituted sulfone, halo-substituted alkoxy, halo-substituted ketone, amide, or combinations thereof.