Functionalized 1,2,4,5-tetrazine compounds for use in bioorthogonal coupling reactions

• US 9,902,705 B2
• Filed: 03/14/2013
• Issued: 02/27/2018
• Est. Priority Date: 10/24/2012
• Status: Active Grant

• Current Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Inventors: Hilderbrand, Scott A., Devaraj, Neal K., Weissleder, Ralph, Karver, Mark R.
• Primary Examiner(s): Balasubramanian, Venkataraman
• Application Number:
  US14/437,905
• Publication Number:
  US 20150246893A1
• Time in Patent Office: 1,811 Days
• Field of Search: 544179
• CPC Class Codes: C07D 257/08 Six-membered rings
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links

Abstract

The present application relates to functionalized 1,2,4,5-tetrazine compounds. The compounds are useful in compositions and methods using bioorthogonal inverse electron demand Diels-Alder cycloaddition reactions for the rapid and specific covalent delivery of a “payload” to a ligand bound to a biological target.

Claims

1. A compound according to the Formula (I):

2. A compound or salt thereof according to claim 1, wherein R^N is hydrogen, a tert-butyloxycarbonyl group, or a 9-fluorenylmethoxycarbonyl group.

3. A compound or salt thereof according to claim 1, wherein R^C is hydrogen or (C₁-C₆)alkyl.

4. A compound or salt thereof according to claim 1, wherein R¹ is hydrogen, (C₁-C₆)alkyl, or (C₁-C₆)haloalkyl.

5. A compound or salt thereof according to claim 1, wherein the compound is according to the formula (IA):

6. A compound or salt thereof according to claim 5, wherein n1 is 1.

7. A compound or salt thereof according to claim 1, wherein A is according to formula (A2):

8. A compound or salt thereof according to claim 7, wherein the compound is according to the formula (IC):

9. A compound or salt thereof according to claim 8, wherein n2 is 0, 1, or 2.

10. A compound or salt thereof according to claim 1, wherein the compound is according to the formula (ID):

11. A compound or salt thereof according claim 1, wherein A is according to formula (A4):

12. A compound or salt thereof according to claim 11, wherein n1 is 1 or 2.

13. A compound or salt thereof according to claim 11, wherein n2 is 5.

14. A compound or salt thereof according to claim 1, wherein A is according to formula (A5):

15. A compound or salt thereof according to claim 14, wherein n1 is 3, 4 or 5.

16. A compound or salt thereof according to claim 14, wherein n2 is 0.

17. A compound or salt thereof according to claim 1, wherein the compound is selected from compounds of the following formulae:

20. A compound or salt thereof according to claim 1, wherein R^N is an amine protecting group.

21. A compound or salt thereof according to claim 20, wherein R^N is a tert-butyloxycarbonyl group or a 9-fluorenylmethoxycarbonyl group.

22. A compound or salt thereof according to claim 1, wherein R^C is a carboxyl protecting group.

23. A compound or salt thereof according to claim 1, wherein R^C is (C₁-C₆)alkyl.

24. A compound or salt thereof according to claim 1, wherein A is according to formula (A3):

18. A compound according to the Formula (II):

19. A compound or salt thereof according to claim 18, wherein the compound is selected from compounds of the following formulae: