Super-oxide dismutase mimetics

• US 10,350,193 B2
• Filed: 05/20/2016
• Issued: 07/16/2019
• Est. Priority Date: 11/14/2007
• Status: Active Grant

• Current Assignee: Galera Labs, LLC
• Original Assignee: Galera Labs, LLC
• Inventors: Riley, Dennis P.
• Primary Examiner(s): Jarrell, Noble E
• Application Number:
  US15/160,055
• Publication Number:
  US 20160263085A1
• Time in Patent Office: 1,152 Days
• CPC Class Codes: A61K 31/395 having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• CPC Class Codes: A61K 31/4353 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/555 containing heavy metals, e.g. hemin, hematin, melarsoprol
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 259/00 Heterocyclic compounds containing rings having more than four nitrogen atoms as the only ring hetero atoms
• CPC Class Codes: C07D 471/08 Bridged systems

Abstract

The present invention relates to compounds which are effective as catalysts for dismutating superoxide and, more particularly, the manganese or iron complexes of substituted, unsaturated heterocyclic 16-membered macrocyclic complexes that catalytically dismutate superoxide. It also relates to methods of using these complexes to reduce the concentration or the effects of superoxide, pharmaceutical compositions comprising these compounds or their metal complexes, and methods of treating conditions associated with excessive superoxide activity.

Claims

1. A method to treat a condition associated with excessive superoxide activity wherein the condition comprises radiation-induced injury, the method comprising administering to a patient in need of such treatment the compound of formula (1):

2. The method of claim 1, wherein M is a metal cation.

3. The method of claim 2, wherein the metal cation is Mn (III) or Mn(II).

4. The method of claim 1, wherein each p is 0.

5. The method of claim 1, wherein n is 1 for position 6 and position 7, or wherein n is 1 for position 15 and position 16.

6. The method of claim 5, wherein n is 1 for positions 6 and 7, and wherein R¹ groups at positions 6 and 7 cyclize to form a 5-8 membered optionally substituted ring.

7. The method of claim 6, wherein n is 1 for positions 15 and 16, and wherein R¹ groups at positions 15 and 16 cyclize to form a 5-8 membered optionally substituted ring.

8. The method of claim 7, wherein M represents Mn(III).

9. The method of claim 1, wherein two R¹ groups on adjacent carbon atoms are in a trans orientation relative to each other on the 16-membered ring of formula (1).

10. The method of claim 9, wherein two R¹ groups at positions 6 and 7 are in a trans orientation relative to each other on the 16-membered ring of formula (1), and wherein two R¹ groups at positions 15 and 16 are also in a trans orientation relative to each other on the 16-membered ring of formula (1).

11. The method of claim 10, wherein two R¹ groups at positions 6 and 7 cyclize to form a cyclohexane or cyclopentane ring.

12. The method of claim 11, wherein two R¹ groups at positions 15 and 16 cyclize to form a cyclohexane or cyclopentane ring.

13. The method of claim 2, wherein each n is 1, and each p is 0.

14. The method of claim 1, wherein the compound of formula (1) has the structure of formulae (2a) or (2b):

15. The method of claim 14, wherein each p is 0.

16. The method of claim 15, wherein two R¹ groups are in a trans orientation relative to each other on the 16-membered ring of formula (1), and wherein said two R¹ groups cyclize to form a five or six membered ring.

17. The method of claim 16, wherein M is Mn(III).

18. The method of claim 1, wherein the compound of formula (1) has the structure of formula (3):

19. The method of claim 18, wherein M is H.

20. The method of claim 19, wherein each R³ is H.

21. The method of claim 1, wherein the compound of formula (1) has a structure selected from the group consisting of: