Oxidation resistant indicator molecules

• US 8,143,068 B2
• Filed: 12/13/2010
• Issued: 03/27/2012
• 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: Modzelewska, Aneta, Mortellaro, Mark Alan, Colvin, Jr., Arthur E.
• Primary Examiner(s): Mui, Christine T
• Application Number:
  US12/966,693
• Publication Number:
  US 20110081727A1
• Time in Patent Office: 470 Days
• Field of Search: 562/7, 562/1, 436/164, 436/95, 436/94, 436/93, 436/91, 436/165
• 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 copolymer in oxidative conditions, which comprises:

a) obtaining a copolymer of i) at least one 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 ii) at least one hydrophilic monomer; and

b) subjecting the copolymer having the one or more electron withdrawing groups to oxidative conditions,

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.

2. 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 a copolymer of i) 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, said one or more indicator component monomers 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

ii) one or more hydrophilic monomers;

such that the resulting macromolecule is capable of detecting the presence or concentration of said analyte in an aqueous environment; and

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

wherein the one or more indicator component monomers 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.

3. A copolymer made from i) at least one compound having the following structure:

4. The copolymer of claim 3, 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.

5. The copolymer of claim 3, wherein R₄ comprises an anthracene residue.

6. The copolymer of claim 3, 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.

7. A compound linked to a solid support or to a polymeric matrix, said compound having the following structure:

8. The compound of claim 7, 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.

9. The compound of claim 7, wherein R₄ comprises an anthracene residue.