Oxidant scavengers

• US 6,127,356 A
• Filed: 06/07/1996
• Issued: 10/03/2000
• Est. Priority Date: 10/15/1993
• Status: Expired due to Term

• Current Assignee: Aeolus Sciences Incorporated, Duke University, Goodnow Capital, L.L.C., The University Of Alabama At Birmingham Research Foundation
• Original Assignee: Duke University
• Inventors: Day, Brian J., Fridovich, Irwin, Trova, Michael P., Batinic-Haberle, Ines, Crapo, James D., Freeman, Bruce A., Folz, Rodney J., Oury, Tim
• Primary Examiner(s): Wax, Robert A.
• Assistant Examiner(s): Saidha, Tekchand
• Application Number:
  US08/663,028
• Time in Patent Office: 1,579 Days
• Field of Search: 514/185, 435/189, 435/252.3, 435/254, 435/320.1, 536/27, 540/145, 252/399, 252/400.23
• US Class Current: 514/185
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/555 containing heavy metals, e.g. hemin, hematin, melarsoprol

Abstract

The present invention relates, in general, to a method of modulating physiological and pathological processes and, in particular, to a method of modulating intra- and extracellular levels of oxidants and thereby processes in which such oxidants are a participant. The invention also relates to compounds and compositions suitable for use in such methods.

Claims

1. An oxidant scavenger of the formula:

##STR83## or a pharmaceutically acceptable salt thereof, wherein;

R₁ is a bond, ##STR84## wherein and Y is an alkyl group and wherein ##STR85## indicates bonding to R₂ at any position and ##STR86## indicates bonding to R₂ and the substituent at any position; and

R₂ is a bond, --(CY'"'"'₂)_n^-, --(CY'"'"'₂ --CY'"'"'═

CY'"'"')_n^-, --(CY'"'"'₂ --CY'"'"'₂ CH═

CH)_n^-, --(CY'"'"'═

CY'"'"')_n^-, ##STR87## wherein Y'"'"' is hydrogen or an alkyl group and wherein n is 1 to 8; and

R₃ is --Y", --N⁺ (Y")₃, --COOH, --COO^-, --CH₂ --PO₃ H₂ or --CH₂ --PO₃ H^-, wherein Y" is an alkyl group,

wherein, when R₁ is ##STR88## and R₂ is a bond, R₃ is not Y", and wherein, --R₁ --R₂ --R₃ is not ##STR89##

9. A pharmaceutical composition comprising the scavenger according to claim 1 or 2 and a pharmaceutically acceptable carrier.

10. A kit comprising the scavenger according to claim 1 or 2 disposed within a container means.

21. The scavenger according to claim 1 wherein at least one of said R₁ '"'"'s, R₂ '"'"'s, or R₃ '"'"'s is different than the other of said R₁ '"'"'s, R₂ '"'"'s, or R₃ '"'"'s, respectively.

22. The scavenger according to claim 21 wherein at least one of said R₁ '"'"'s, R₂ '"'"'s, or R₃ '"'"'s is different than the other of said R₁ '"'"'s, R₂ '"'"'s, or R₃ '"'"'s, respectively.

26. The scavenger according to claim 1 or claim 2 wherein said scavenger is complexed with a metal selected from the group consisting of manganese, copper and iron.

38. The scavenger according to claim 1 wherein

R₁ is a bond, ##STR139##

40. The scavenger according to claim 21 wherein R₁ is a bond, ##STR141##

41. The scavenger according to claim 40 wherein R₁ is ##STR142##

42. The scavenger according to claim 1 or 2 wherein R₂ is a bond or --(CY'"'"'₂)_n --.

43. The scavenger according to claim 1 wherein

R₃ is --Y", --N⁺ (Y")₃, --COOH, or --COO^-.

44. The scavenger according to claim 43 wherein

R₃ is --N⁺ (Y")₃, --COOH, or --COO^-.

48. The scavenger according to claim 26 wherein R₁ '"'"' is a bond,

50. The scavenger according to claim 26 wherein R₃ '"'"' is COY".

2. An oxidant scavenger of the formula:

or a pharmaceutically acceptable salt thereof, wherein;

R₁ is a bond, ##STR90## wherein and Y is an alkyl group and wherein ##STR91## indicates bonding to R₂ at any position and ##STR92## indicates bonding to R₂ and the substituent at any position; and

R₂ is a bond, --(CY'"'"'₂)_n^-, --(CY'"'"'₂ --CY'"'"'═

CY'"'"')_n^-, --(CY'"'"'₂ --CY'"'"'₂ --CH═

CH)_n^-, --(CY'"'"'═

CY'"'"')_n^-, or ##STR93## wherein Y'"'"' is hydrogen or an alkyl group and wherein n is 1 to 8; and

R₃ is --Y", --OH, --NH₂, --N⁺ (Y")₃, --COOH, --COO^-, --CH₂ --PO₃ H₂ or --CH₂ --PO₃ H^-, wherein Y" is an alkyl group,

wherein, when R₁ is ##STR94## and R₂ is a bond, R₃ is not Y", and wherein R₁ --R₂ --R₃ is not ##STR95##

45. The scavenger according to claim 2 wherein

R₃ is --Y", --OH, --NH₂, --N⁺ (Y")₃, --COOH, or --COO^-.

46. The scavenger according to claim 45 wherein

R₃ is --N⁺ (Y")₃, --COOH, or --COO^-.

3. An oxidant scavenger of the formula:

or a pharmaceutically acceptable salt thereof, or metal complex thereof wherein said metal is selected from the group consisting of manganese, copper and iron,

each R₁ '"'"' is independetly a bond, ##STR96## wherein Y" is an alkyl group, and wherein ##STR97## indicates bonding to R₂ '"'"' at any position and ##STR98## indicates bonding to R₂ '"'"' and the R₁ '"'"' phenyl substituent at any position;

each R₂ '"'"' is independently a bond, or --(CH₂)_n -- wherein n is 1-4,

each R₃ '"'"' is independently --Y'"'"'", --COY", or a heterocyclic group, wherein Y" is as defined above and Y'"'"'" is a primary, secondary, tertiary or quaternary amine,

wherein when R₁ '"'"' is ##STR99## R₃ '"'"' is not COY", wherein when R₁ '"'"' is ##STR100## R₃ '"'"' is not --NO₂, and wherein --R₁ '"'"'--R₂ '"'"'--R₃ '"'"', collectively, are not ##STR101##

23. The scavenger according to claim 3 wherein said scavenger is complexed with manganese.

4. A method of protecting cells from oxidant-induced toxicity comprising contacting said cells with an amount of a scavenger of the formula, or a pharmaceutically acceptable salt thereof, sufficient to effect said protection, wherein:

R₁ is a bond, ##STR102## wherein X is a halogen and Y is an alkyl group and wherein ##STR103## indicates bonding to R₂ at any position and ##STR104## indicates bonding to R₂ and the substituent at any position; and

R₂ is a bond, --(CY'"'"'₂)_n^-, --(CY'"'"'₂ --CY'"'"'═

CY'"'"')_n^-, --(CY'"'"'₂ --CY'"'"'₂ --CH═

CH)_n^-, --(CY'"'"'═

CY'"'"')_n^-, or ##STR105## wherein Y'"'"' is hydrogen or an alkyl group and wherein n is 1 to 8; and

R₃ is --Y", --OH, --NH₂, --N⁺ (Y")₃, --COOH, --COO^-, --SO₃ H, --SO₃^-, --CH₂ --PO₃ H₂ or --CH₂ --PO₃ H^-, wherein Y" is an alkyl group,

optionally complexed with a metal selected from the group consisting of manganese, copper and iron, sufficient to effect said protection.

5. The method according to claim 4 wherein said scavenger is complexed with a metal selected from the group consisting of manganese, copper or iron.

6. The method according to claim 4 wherein said cells are mammalian cells or plant cells.

24. The method according to claim 5 wherein said scavenger is complexed with manganese.

51. The method according to claim 4 or 7 wherein R₁ is ##STR144##

52. The method according to claim 4 or 7 wherein R₂ is a bond or --(CY'"'"'₂)_n.

53. The method according to claim 4 or 7 wherein

R₃ is --N⁺ (Y")₃, --COOH, --COO^-, --SO₃ H or --SO₂^-.

7. A method of inhibiting damage due to oxidation of a substance comprising contacting said substance with an amount of a scavenger of the formula, ##STR106## or a pharmaceutically acceptable salt thereof, sufficient to effect said inhibition, wherein:

R₁ is a bond, ##STR107## wherein X is a halogen and Y is an alkyl group and wherein ##STR108## indicates bonding to R₂ at any position and ##STR109## indicates bonding to R₂ and the substituent at any position; and

R₂ is a bond, --(CY'"'"'₂)_n^-, --(CY'"'"'₂ --CY'"'"'═

CY'"'"')_n^-, --(CY'"'"'₂ --CY'"'"'₂ --CH═

CH)_n^-, --(CY'"'"'═

CY'"'"')_n^-, or ##STR110## wherein Y'"'"' is hydrogen or an alkyl group and wherein n is 1 to 8; and

R₃ is --Y", --OH, --NH₂, --N⁺ (Y")₃, --COOH, --COO^-, --SO₃ H, --SO₃^-, --CH₂ --PO₃ H₂ or --CH₂ --PO₃ H^-, wherein Y" is an alkyl group,

optionally complexed with a metal selected from the group consisting of manganese, copper and iron, sufficient to effect said inhibition.

8. The method according to claim 7 wherein said mimetic is completed with a metal selected from the group consisting of manganese, copper or iron.

25. The method according to claim 8 wherein said mimetic is complexed with manganese.

11. An oxidant scavenger of the formula:

##STR111## or a pharmaceutically acceptable salt thereof, or metal complex thereof wherein said metal is selected from the group consisting of manganese, copper and iron, wherein;

each R₁ '"'"' is independently ##STR112## wherein Y" is an alkyl group, and wherein ##STR113## indicates bonding to R₂ '"'"' at any position and ##STR114## indicates bonding to R₂ '"'"' and the R₁ '"'"' phenyl substituent at any position;

each R₂ '"'"' is independently a bond, or --(CH₂)_n -- wherein n is 1-4,

each R₃ '"'"' is independently --Y", --Y'"'"'", --H, --OH, --OY", --NO₂, --CN, --NH₂, --COOH, --COY", --COO^-, or a heterocyclic group, wherein Y- is as defined above and Y'"'"'" is a primary, secondary, tertiary or quaternary amine,

wherein when R₁ '"'"' is ##STR115## R₃ '"'"' is not COOH, COY" or COO^-, wherein when R₁ '"'"' is ##STR116## R₃ '"'"' is not --NO₂, and wherein --R₁ '"'"'--R₂ '"'"'--R₃ '"'"', collectively, are not ##STR117##

12. The scavenger according to claim 3 or 11 wherein Y'"'"'" is a secondary, tertiary or quaternary amine and each hydrogen replacement group on the amine nitrogen is a C₁ -C₄ alkyl group.

27. The scavenger according to claim 3 or 11 wherein said scavenger is a manganese complex.

28. A pharmaceutical composition comprising the scavenger according to claim 3 or 11 and a pharmaceutically acceptable carrier.

29. A kit comprising the scavenger according to claim 3 or 11 disposed within a container means.

47. The scavenger according to claim 11 wherein R₁ '"'"' is ##STR143##

49. The scavenger according to claim 28 wherein R₃ '"'"' is --NO₂, --NH₂, --COOH, --COY" or --COO^-.

13. A compound having the structure

14. A compound having the structure

15. A compound having the structure

16. A compound having the structure

17. An oxidant scavenger of the formula:

or a pharmaceutically acceptable salt thereof, wherein;

R₁ is a bond, ##STR118## wherein and Y is an alkyl group and wherein ##STR119## indicates bonding to R₂ at any position and ##STR120## indicates bonding to R₂ and the substituent at any position; and

R₂ is a bond, --(CY'"'"'₂)_n^-, --(CY'"'"'₂ --CY'"'"'═

CY'"'"')_n^-, --(CY'"'"'₂ --CY'"'"'₂ --CH═

CH)_n^-, --(CY'"'"'═

CY'"'"')_n^-, or ##STR121## wherein Y'"'"' is hydrogen or an alkyl group and wherein n is 1 to 8; and

R₃ is --Y", --N⁺ (Y")₃, --COOH, --COO^-, --CH₂ --PO₃ H₂ or --CH₂ --PO₃ H^-, wherein Y" is an alkyl group,

wherein, when R₁ is ##STR122## and R₂ is a bond, R₃ is not --CH₃, and wherein, R₁ --R₂ --R₃ is not ##STR123##

18. An oxidant scavenger of the formula:

or a pharmaceutically acceptable salt thereof, wherein;

each R₁ is independently, a bond, ##STR124## wherein X is a halogen and Y is an alkyl group and wherein ##STR125## indicates bonding to R₂ at any position and ##STR126## indicates bonding to R₂ and the substituent at any position; and

each R₂ is independently, a bond, --(CY'"'"'₂)_n^-, --(CY'"'"'₂ --CY'"'"'═

CY'"'"')_n³¹ , --(CY'"'"'₂ --CY'"'"'₂ --CH═

CH)_n^-, --(CY'"'"'═

CY'"'"')_n^-, or ##STR127## wherein Y'"'"' is hydrogen or an alkyl group and wherein n is 1 to 8; and

each R₃ is, independently --Y", --OH, --NH₂, --N⁺ (Y")₃, --C--PO₃ H₂ or --C--PO₃ H^-, wherein Y" is an alkyl group,

each P is, independently, an electron withdrawing group or hydrogen wherein at least one P is not hydrogen

wherein said oxidant scavenger is a metal complex wherein said metal is selected from the group consisting of manganese, copper or iron,

wherein when said metal is copper and all P'"'"'s are Br, and when R₁ is ##STR128## and R₂ is a bond, R₃ is not --CH₃.

20. A method of protecting a biological substance from oxidative stress or a method of maintaining biological function of NO·

, or active forms thereof, in an intracellular or extracellular space of a tissue or organ comprising contacting said substance or said tissue or organ with an amount of said scavenger according to claim 18 sufficient to effect said protection or said maintenance.

31. A pharmaceutical composition comprising the scavenger according to claim 18 and a pharmaceutically acceptable carrier.

32. A kit comprising the scavenger according to claim 18 disposed within a container means.

19. A manganese, copper or iron complex of

octobromo--TBAP (tetrakis (4-benzoic acid)porphyrin)

octochloro--TBAP

octofluro--TBAP

octonitro--TBAP

octobromo--TMPyP (tetrakis (1-methyl-4-pyridyl)porphyrin)

octochloro--TMPyP

octofluro--TMPyP

octonitro --TMPyP

octobromo--tetrakis 4-phenyl sulfonate porphyrin

octochloro--tetrakis 4-phenyl sulfonate porphyrin

octofluro--tetrakis 4-phenyl sulfonate porphyrin or

octonitro--tetrakis 4-phenyl sulfonate porphyrin.

36. The complex according to claim 19 wherein said complex is a manganese complex.

30. An oxidant scavenger of the formula:

##STR129## or a pharmaceutically acceptable salt thereof, wherein;

R₁ is a bond, ##STR130## wherein and Y is an alkyl group and wherein ##STR131## indicates bonding to R₂ at any position and ##STR132## indicates bonding to R₂ and the substituent at any position; and

R₂ is a bond, --(CY'"'"'₂)_n^-, --(CY'"'"'₂ --CY'"'"'═

CY'"'"')_n^-, --(CY'"'"'₂ --CY'"'"'₂ --CH═

CH)_n^-, --(CY'"'"'═

CY'"'"')_n^-, or ##STR133## wherein Y'"'"' is hydrogen or an alkyl group and wherein n is 1 to 8; and

R₃ is --Y", --OH, --NH₂, --N⁺ (Y")₃, --COOH, --COO^-, --CH₂ --PO₃ H₂ or --CH₂ --PO₃ H^-, wherein Y" is an alkyl group,

wherein, when R₁ is ##STR134## and R₂ is a bond, R₃ is not --CH₃, and wherein, when R₁ --R₂ --R₃ is not ##STR135##

33. An oxidant scavenger of the formula:

or a pharmaceutically acceptable salt thereof, wherein

each R₁ '"'"' is independently a bond, ##STR136## wherein Y" is an alkyl group, and wherein ##STR137## indicates bonding to R₂ '"'"' at any position and ##STR138## indicates bonding to R₂ '"'"' and the R₁ '"'"' phenyl substituent at any position;

each R₂ '"'"' is independently a bond, or --(CH₂)_n -- wherein n is 1-4,

each R₃ '"'"' is independently --Y", --Y'"'"'", --OY", --NO₂, --CN, --NH₂, --COY", or a heterocyclic group, wherein Y" is as defined above and Y'"'"'" is a primary, secondary, tertiary or quaternary amine,

each P is, independently, an electron withdrawing group or hydrogen wherein at least one P is not hydrogen;

wherein said oxidant scavenger is a metal complex wherein said metal is selected from the group consisting of manganese, copper or iron.

34. A pharmaceutical composition comprising the scavenger according to claim 33 and a pharmaceutically acceptable carrier.

35. A kit comprising the scavenger according to claim 33 disposed within a container means.

37. A method of protecting a biological substance from oxidative stress or a method of maintaining biological function of NO·

, or active forms thereof, in an intracellular or extracellular space of a tissue or organ comprising contacting said substance or said tissue or organ with an amount of said scavenger according to claim 33 sufficient to effect said protection or said maintenance.

39. The scavenger according to claim 33 wherein R₁ is ##STR140##40.