Species-linked diamine triacetic acids and their chelates

• US 4,352,751 A
• Filed: 09/10/1979
• Issued: 10/05/1982
• Est. Priority Date: 09/10/1979
• Status: Expired due to Term

• Current Assignee: Irwin Wieder
• Original Assignee: Analytical Radiation Corporation
• Inventors: Wollenberg, Robert H., Wieder, Irwin
• Primary Examiner(s): Gron, Teddy S.
• Application Number:
  US06/073,728
• Time in Patent Office: 1,121 Days
• Field of Search: 252/301.16, 252/301.17-301.18, 260/429.2, 260/455 R, 260/112 R, 260/112.5 R, 260/113, 260/112 T, 260/112.7, 260/124 R, 260/397.2, 260/429 J, 260/429.1, 560/169, 562/448, 562/507, 562/565, 562/566, 424/1, 424/1.5, 424/7, 424/8, 424/12, 435/7, 435/4, 23/230 B
• US Class Current: 530/303
• CPC Class Codes: C07D 265/33 Two oxygen atoms, in positions 3 and 5
• CPC Class Codes: C07J 41/0055 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
• CPC Class Codes: C07K 5/022 containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
• CPC Class Codes: G01N 33/533 with fluorescent label
• CPC Class Codes: Y10S 435/968 High energy substrates, e.g. fluorescent, chemiluminescent, radioactive
• CPC Class Codes: Y10S 530/862 involving IgE or IgD
• CPC Class Codes: Y10S 530/868 involving autoimmunity, allergy, immediate hypersensitivity, delayed hypersensitivity, immunosuppression, or immunotolerance

Abstract

Species-linked diamine triacetic acids of the formula ##STR1## wherein T is an organic species containing at least one amine, hydroxyl, or thiol functional group, L is the residue of at least one of those functional groups and R is a two or more atom long covalent bridge, are disclosed. Methods for their preparation, for the preparation of metal chelates from them and for the use of the chelates are also disclosed. In a preferred embodiment, the metal ions employed in the formation of the chelates are rare earth metal ions capable of forming fluorescent chelates which can in turn be employed in fluoroassay techniques.

Claims

1. A reagent for use in the fluorometric quantification of a biologically active organic species comprising a diamine triacetic acid having the structural formula:

##STR11## wherein R is a two to eight atom covalent bridge selected from carbon-oxygen ether bridges, carbon-nitrogen secondary and tertiary amide bridges and carbon-carbon alkylene, cycloalkylene and arylene bridges, T is the biologically active organic species to be fluorometrically quantified, T being other than an aliphatic mono- or polyamine, or aliphatic mono- or polyol, but comprising at least one originally present or added primary amine, secondary amine, thiol or hydroxyl functional group, and L is said at least one functional group in deprotonated form covalently bonding T to the indicated carbonyl carbon of the diamine triacetic acid.

3. A reagent for the fluorometric quantification of an enzyme comprising the reagent of Claim 1 wherein T is the enzyme to be fluorometrically quantified and comprising at least one originally present or added primary amine, secondary amine, thiol or hydroxyl functional group.

5. A reagent for use in the fluorometric quantification of a macromolecular species comprising the reagent of claim 1 wherein T is the macromolecular species to be fluorometrically quantified and comprising at least one originally present or added primary amine, secondary amine, thiol or hydroxyl functional group.

6. A reagent for use in the fluorometric quantification of an antibody comprising the reagent of claim 1 wherein T is the antibody species sought to be fluorometrically quantified and comprising at least one originally present or added primary amine, secondary amine, thiol or hydroxyl functional group.

9. The diamine triacetic acid reagent as defined by claim 1, said biologically active organic species being cholesterol.

17. The diamine triacetic acid reagent as defined by claim 5, said macromolecular species being a protein.

18. The diamine triacetic acid reagent as defined by claim 5, said macromolecular species being a lipid.

19. The diamine triacetic acid reagent as defined by claim 5, said macromolecular species being a hapten.

20. The diamine triacetic acid reagent as defined by claim 5, said macromolecular species being an antigen.

21. The diamine triacetic acid reagent as defined by claim 6, said antibody species being an immunoglobulin.

25. The diamine triacetic acid reagent as defined by claim 1 wherein said biologically active organic species is a peptide.

2. A reagent for use in the fluorometric quantification of a therapeutic drug comprising a diamine triacetic acid having the structural formula:

##STR12## wherein R is a two to eight atom covalent bridge selected from carbon-oxygen ether bridges, carbon-nitrogen secondary and tertiary amide bridges and carbon-carbon alykylene, cycloalkylene and arylene bridges, T is the therapeutic drug species to be fluorometrically quantified, T being other than an aliphatic mono-or polyamine, or aliphatic mono-or polyol, but comprising at least one originally present or added primary amine, secondary amine, thiol or hydroxyl functional group, and L is said at least one functional group in deprotonated form covalently bonding T to the indicated carbonyl carbon of the diamine triacetic acid.

7. The diamine triacetic acid reagent as defined by claim 2, said therapeutic drug species being digoxin.

8. The diamine triacetic acid reagent as defined by claim 2, said therapeutic drug species being morphine.

10. The diamine triacetic acid reagent as defined by claim 2, said therapeutic drug species being procain amide.

22. The diamine triacetic acid reagent as defined by any of claims 2 to 6, wherein R is an alkylene, cycloalkylene, or arylene carbon-carbon bridge.

23. The diamine triacetic acid reagent as defined by any of claims 2 to 6, wherein R is selected from the group consisting of ethylene, n-propylene, isopropylene, n-butylene, 1- and 2-methylpropylene, 1-propylethylene, 1-cyclohexylethylene, 1-phenylethylene, alkylsubstituted 1-phenylethylenes and propylenes, 1-benzylethylene, 2-amidopropylene, cyclohexyl-1,2-ene, phenyl-1,3-ene, --CH₂ --CH₂ --O--CH₂ --CH₂, and --CH₂ --CH₂ --O--CH₂ --CH₂ --O--CH₂ --CH₂ --.

24. The diamine triacetic acid reagent as defined by claim 23, wherein R is ethylene.

4. A reagent for the fluorometric quantification of a hormone comprising a diamine triacetic acid having the structural formula:

##STR13## wherein R is a two to eight atom covalent bridge selected from carbon-oxygen ether bridges, carbon-nitrogen secondary and tertiary amide bridges and carbon-carbon alkylene, cycloalkylene and arylene bridges, T is the hormone species to be fluorometrically quantified comprising at least one originally present or added primary amine, secondary amine, thiol or hydroxyl functional group in deprotonated form covalently bonding T to the indicated carbonyl carbon of the diamine triacetic acid.

11. The diamine triacetic acid reagent as defined by claim 4, said hormone species being thyroxine.

12. The diamine triacetic acid reagent as defined by claim 4, said hormone species being thyronine.

13. The diamine triacetic acid reagent as defined by claim 4, said hormone species being triiodothyronine.

14. The diamine triacetic acid reagent as defined by claim 4, said hormone species being a gonadotropin.

15. The diamine triacetic acid reagent as defined by claim 4, said hormone species being a gastrointestinal hormone.

16. The diamine triacetic acid reagent as defined by claim 4, said hormone species being insulin.