Cyclic salen-metal compounds: reactive oxygen species scavengers useful as antioxidants in the treatment and prevention of diseases

• US 6,589,948 B1
• Filed: 11/28/2000
• Issued: 07/08/2003
• Est. Priority Date: 11/28/2000
• Status: Expired due to Fees

• Current Assignee: Eukarion, Inc.
• Original Assignee: Eukarion, Inc.
• Inventors: Doctrow, Susan, Malfroy-Camine, Bernard
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): Habte, Kahsay
• Application Number:
  US09/724,776
• Time in Patent Office: 952 Days
• Field of Search: 540/541, 540/465, 514/450, 514/185, 556/32, 556/45
• US Class Current: 514/185
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 39/00 General protective or antinoxious agents
• CPC Class Codes: A61P 39/06 Free radical scavengers or antioxidants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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: C07F 13/005 Compounds without a metal-carbon linkage

Abstract

This invention provides antioxidant cyclic salen-metal compounds, compositions of such antioxidant cyclic salen-metal compounds having superoxide activity, catalase activity and/or peroxidase activity and methods of using such antioxidant cyclic salen-metal compositions to treat or prevent a disease associated with cell or tissue damage produced by free radicals, such as superoxide. In one embodiment, the present invention provides cyclic salen-metal compounds having the following general formula:

Claims

1. A salen-metal compound having the following structure:

wherein;

M is a metal;

A is an anion;

X¹ and X² are independently selected from the group consisting of hydrogen, halogens, alkyls, substituted alkyls, aryls, substituted aryls, heterocyclics, substituted heterocyclics, heteroaryls, substituted heteroaryls, silyls, aminos, fatty acid ester radicals, alkoxys, aryloxys and acyloxys;

Y¹, Y², Y³, Y⁴, Y⁵, and Y⁶ are independently selected from the group consisting of hydrogen, halogens, alkyls, substituted alkyls, aryls, substituted aryls, heterocyclics, substituted heterocyclics, heteroaryls, substituted heteroaryls, silyls, aminos, fatty acid ester radicals, alkoxys, aryloxys and acyloxys;

R¹, R², R³ and R⁴ are independently selected from the group consisting of hydrogen, halogens, alkyls, substituted alkyls, aryl, substituted aryl, heterocyclics, substituted heterocyclics, heteroaryls, substituted heteroaryls, silyls, aminos, fatty acid ester radicals, alkoxys, aryloxys and acyloxys;

with the proviso that one of R¹ or R² may be covalently linked to one of R³ or R⁴ forming a five- or six-membered ring selected from the group consisting of cycloalkyls, heterocycles, aryls and heteroaryls;

Z is a bridging group selected from the group consisting of

—

(CH₂)_m—

, wherein m is equal to or greater than 1;

—

(CR⁵R⁶)_m—

, wherein each R⁵ and R⁶ is independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, acyl and amino; and

m is equal to or greater than 1; and

—

(CR⁷R⁸)_m—

R⁹—

(CR¹⁰R¹¹)_p—

wherein;

R⁷, R⁸, R¹⁰ and R¹¹ are independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, acyl and amino;

R⁹ is a member selected from the group consisting of alkyls, substituted alkyls, cycloalkyls, substituted cycloalkyls, aryls, substituted aryls, heterocyclics, substituted heterocyclics, heteroaryls, substituted heteroaryls and heteroatoms; and

m and p are independently selected and are equal to 1, 2, 3 or 4; and

Q1 and Q2 are independently selected from the group consisting of hydrogen, halogens, alkyls, substituted alkyls, aryls, substituted aryls, heterocyclics, substituted heterocyclics, heteroaryls, substituted heteroaryls, silyls, aminos, fatty acid ester radicals, alkoxys, aryloxys and acyloxys; and

n is 0, 1, or 2.

2. The salen-metal compound in accordance with claim 1, wherein said metal is a transition metal.

3. The salen-metal compound in accordance with claim 2, wherein said transition metal is a member selected from the group consisting of Mn, Mg, Co, Cu, Zn, V, Cr and Ni.

4. The salen-metal compound in accordance with claim 3, wherein said transition metal is Mn.

5. The salen-metal compound in accordance with claim 1, wherein said anion is a member selected from the group consisting of halogens and organic anions.

6. The salen metal compound in accordance with claim 1, wherein said anion is an organic anion.

7. The salen-metal compound in accordance with claim 6, wherein said organic anion is a member selected from the group consisting of acetate, propionate, butyrate, formate, and triflate.

8. The salen-metal compound in accordance with claim 7, wherein said organic anion is acetate.

9. The salen-metal compound in accordance with claim 1, wherein said anion is a halogen.

10. The salen-metal compound in accordance with claim 9, wherein said halogen is —

Cl.

11. The salen-metal compound in accordance with claim 1, wherein X¹ and X² are independently selected from the group consisting of hydrogen, alkyls, halogens, alkoxys and aminos.

12. The salen-metal compound in accordance with claim 11, wherein X¹ and X² are both hydrogen.

13. The salen-metal compound in accordance with claim 11, wherein X¹ and X² are both alkoxy.

14. The salen-metal compound in accordance with claim 1, wherein Y¹, Y², Y³ and Y⁴ are independently selected from the group consisting of hydrogen, alkyls, halogens, alkoxys and aminos.

15. The salen-metal compound in accordance with claim 14, wherein Y¹, Y², Y³, Y⁴, Y⁵ and Y⁶ are all hydrogen.

16. The salen-metal compound in accordance with claim 14, wherein Y¹ and Y⁴ are both halogen, and Y², Y³, Y⁵ and Y⁶ are all hydrogen.

17. The salen-metal compound in accordance with claim 14, wherein Y¹ and Y⁴ are both amino, and Y², Y³, Y⁵ and Y⁶ are all hydrogen.

18. The salen-metal compound in accordance with claim 14, wherein Y¹ and Y⁴ are both alkoxy, and Y², Y³, Y⁵ and Y⁶ are all hydrogen.

19. The salen-metal compound in accordance with claim 1, wherein n is 0;

and R¹, R², R³ and R⁴ are all hydrogen.

20. The salen-metal compound in accordance with claim 1, wherein n is 0;

R¹ and R³ are both aryl; and

R² and R⁴ are both hydrogen.

21. The salen-metal compound in accordance with claim 1, wherein n is 0;

R¹ and R³ are both aryloxy; and

R² and R⁴ are both hydrogen.

22. The salen-metal compound in accordance with claim 1, wherein n is 0;

R¹ and R³ are both acyloxy; and

R² and R⁴ are both hydrogen.

23. The salen-metal compound in accordance with claim 1, wherein n is 0;

and one of R¹ or R² is covalently linked to one of R³ and R⁴, and together with the atoms to which they are attached, form a six-membered ring.

24. The salen-metal compound in accordance with claim 23, wherein said six-membered ring is a member selected from the group consisting of a cyclohexyl ring, a benzene ring and a pyridine ring.

25. The salen-metal compound in accordance with claim 23, wherein said six-membered ring is a benzene ring.

26. The salen-metal compound in accordance with claim 1, wherein n is 1 and Q¹ and Q² are both hydrogen.

27. The salen-metal compound in accordance with claim 1, wherein said bridging group Z is —

(CH₂)_m—

, wherein m is equal to or greater than 1.

28. The salen-metal compound in accordance with claim 27, wherein m is 2 to 6.

29. The salen-metal compound in accordance with claim 1, wherein said bridging group Z is —

(CR⁵R⁶)_m—

, wherein each R⁵ and R⁶ is independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, acyl and amino; and

m is equal to or greater than 1.

30. The salen-metal compound in accordance with claim 29, wherein m is from 2 to 6.

31. The salen-metal compound in accordance with claim 29, wherein m is equal to or greater then 1 and wherein at least one of the (CR⁵R⁶) groups is replaced by a heteroatom.

32. The salen-metal compound in accordance with claim 31, wherein said heteroatom is oxygen.

33. The salen-metal compound in accordance with claim 31, wherein said bridging group Z is selected from the group consisting of:

—

CH₂—

CH₂—

O—

CH₂—

CH₂—

; and

—

CH₂—

CH₂—

O—

CH₂—

CH₂—

O—

CH₂—

CH₂—

.

34. The salen-metal compound in accordance with claim 1, wherein said bridging group has the general formula:

35. The salen-metal compound in accordance with claim 34, wherein R⁹ is an aryl.

36. The salen-metal compound in accordance with claim 35, wherein said aryl is benzene.

37. The salen-metal compound in accordance with claim 34, wherein R⁹ is a cycloalkyl.

38. The salen-metal compound in accordance with claim 37, wherein said cycloalkyl is cyclohexyl.

39. The salen-metal compound in accordance with claim 34, wherein R⁹ is an alkyl.

40. The salen-metal compound in accordance with claim 39, wherein said alkyl is an alkenyl.

41. The salen-metal compound in accordance with claim 34, wherein R⁹ is a heteroatom selected from the group consisting of oxygen, sulfur and nitrogen.

42. The salen-metal compound in accordance with claim 41, wherein R⁹ is oxygen.

43. The salen-metal compound in accordance with claim 34, wherein said bridging group Z is a member selected from the group consisting of:

87. A pharmaceutical composition comprising a salen-metal compound of claim 1 or claim 44 and a pharmaceutically acceptable carrier, excipient or adjuvant.

88. The pharmaceutical composition in accordance with claim 87, wherein said pharmaceutical composition comprises an antioxidant amount of said salen-metal compound.

89. The pharmaceutical composition of claim 87, wherein said salen-metal compound is present in an amount such that said pharmaceutical composition has a predetermined level of superoxide dismutase activity and/or detectable catalase activity per mmol dissolved in an aqueous solution.

91. A salen-metal compound in accordance with claim 1 or claim 44 having detectable catalase activity.

92. A salen-metal compound in accordance with claim 1 or claim 44 having detectable peroxidase activity.

93. A salen-metal compound in accordance with claim 1 or claim 44 having detectable catalase and peroxidase activity.

94. A salen-metal compound in accordance with claim 1 or claim 44 having detectable superoxide dismutase, catalase and peroxidase activity.

95. A method for inhibiting damage to cells induced by reactive oxygen species, said method comprising contacting said cells with an antioxidant salen-metal compound of claim 1 or claim 44.

96. The method in accordance with claim 95, wherein said cells are blood cells.

97. The method in accordance with claim 95, wherein said cells are present in an excised organ.

98. The method in accordance with claim 97, wherein said excised organ is a member selected from the group consisting of heart, kidney, pancreas, liver, lung, skin, cornea and vasculature.

99. A method for arresting or treating a free-radical associated disease state in a mammal, said method comprising administering to said mammal a therapeutically effective amount of an antioxidant salen-metal compound of claim 1 or claim 44.

100. The method in accordance with claim 99, wherein said salen-metal compound is formulated in a pharmaceutically acceptable form with a carrier, excipient or adjuvant.

101. The method in accordance with claim 99, wherein said free-radical associated disease state is a member selected from the group consisting of neurological damage resulting from Parkinson'"'"'s disease, Alzheimer'"'"'s disease or transient cerebral anoxia injury;

cardiac tissue necrosis resulting from cardiac ischemia;

autoimmune neurodegeneration;

acute lung injury from sepsis and/or endotoxemia;

neuronal damage resulting from anoxia or trauma; and

iatrogenic free-radical toxicity.

102. The method in accordance with claim 99, wherein said mammal is a human.

103. A method for treating cardiac tissue necrosis resulting from cardiac ischemia, acute injury from sepsis and/or endotoxemia, neuronal damage resulting from anoxia or trauma, or iatrogenic free-radical toxicity resulting from MPTP intoxication, said method comprising administering to a mammal a therapeutically-effective amount of an antioxidant salen-metal compound of claim 1 or claim 44.

104. A method for treating ischemia or reoxygenation injury, said method comprising administering to a mammal a therapeutically-effective amount of an antioxidant salen-metal compound of claim 1 or claim 44.

105. A method for treating free-radical associated inflammation in a mammal, said method comprising administering to said mammal a therapeutically effective amount of a salen-metal compound of claim 1 or claim 44.

106. The method in accordance with claim 105, wherein said salen-metal compound is formulated in a pharmaceutically acceptable form with a carrier, excipient or adjuvant.

107. The method in accordance with claim 105, wherein said salen-metal compound is formulated in a pharmaceutically acceptable topical carrier.

108. A method for preventing or retarding the aging of skin, said method comprising applying to said skin an effective amount of a salen-metal complex of claim 1 or claim 44.

109. A method for preventing the deleterious effects of ultraviolet light exposure to skin, said method comprising topically applying to said skin an effective amount of a salen-metal complex of claim 1 or claim 44.

110. The method in accordance with claim 109, wherein said salen-metal complex is topically applied to said skin prior to ultraviolet light exposure.

111. The method according to claim 109, wherein said salen-metal complex is topically applied to said skin in conjunction with ultraviolet light exposure.

112. The method in accordance with claim 109, wherein said salen-metal complex is topically applied to said skin after ultraviolet light exposure.

113. A method for enhancing the recovery of skin of a mammal to a wound, said method comprising applying to said skin an effective amount of a salen-metal compound of claim 1 or claim 44.

114. The method in accordance with claim 113, wherein said wound is a member selected from the group consisting of surgical incisions, burns, inflammation, ulcers and irritations due to oxidative damage.

115. The method for protecting cells from the deleterious effects of ionizing radiation, said method comprising:

contacting said cells with an effective amount of a salen-metal compound of claim 1 or claim 44.

116. The method in accordance with claim 115, wherein said ionizing radiation is ultraviolet radiation.

117. The method in accordance with claim 115, wherein said ionizing radiation is gamma (γ

)-radiation.

118. The method in accordance with claim 115, wherein said cells are human cells.

119. The method in accordance with claim 115, wherein said contacting is carried out by administering to a human said salen-metal compound.

120. A method for protecting cells from the deleterious effects of a chemotherapeutic agent, said method comprising:

contacting said cells with an effective amount of a salen-metal compound of claim 1 or claim 44.

121. The method in accordance with claim 2, wherein said cells are human cells.

122. A composition useful for topical application, said composition comprising a topical carrier and a salen-metal compound of claim 1 or claim 44.

44. A salen-metal compound having the following structure:

wherein;

M is a metal;

A is an anion;

X¹ and X² are independently selected from the group consisting of hydrogen, halogens, alkyls, substituted alkyls, aryls, substituted aryls, heterocyclics, substituted heterocyclics, heteroaryls, substituted heteroaryls, silyls, aminos, fatty acid ester radicals, alkoxys, aryloxys and acyloxys;

y¹, Y², Y³, Y⁴, Y⁵, and Y⁶ are independently selected from the group consisting of hydrogen, halogens, alkyls, substituted alkyls, aryls, substituted aryls, heterocyclics, substituted heterocyclics, heteroaryls, substituted heteroaryls, silyls, aminos, fatty acid ester radicals, alkoxys, aryloxys and acyloxys;

R¹, R², R³ and R⁴ are independently selected from the group consisting of hydrogen, halogens, alkyls, substituted alkyls, aryl, substituted aryl, heterocyclics, substituted heterocyclics, heteroaryls, substituted heteroaryls, silyls, aminos, fatty acid ester radicals, alkoxys, aryloxys and acyloxys;

with the proviso that one of R¹ or R² may be covalently linked to one of R³ or R⁴ forming a five- or six-membered ring selected from the group consisting of cycloalkyls, heterocycles, aryls and heteroaryls;

Z is a bridging group selected from the group consisting of

—

(CH₂)_m—

, wherein m is equal to or greater than 1;

—

(CR⁵R⁶)_m—

, wherein each R⁵ and R⁶ is independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, acyl and amino; and

m is equal to or greater than 1; and

—

(CR⁷R⁸)_m—

R⁹—

(CR¹⁰R¹¹)_p—

wherein;

R⁷, R⁸, R¹⁰ and R¹¹ are independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, acyl and amino;

R⁹ is a member selected from the group consisting of alkyls, substituted alkyls, cycloalkyls, substituted cycloalkyls, aryls, substituted aryls, heterocyclics, substituted heterocyclics, heteroaryls, substituted heteroaryls and heteroatoms; and

m and p are independently selected and are equal to 1, 2, 3 or 4; and

Q1 and Q2 are independently selected from the group consisting of hydrogen, halogens, alkyls, substituted alkyls, aryls, substituted aryls, heterocyclics, substituted heterocyclics, heteroaryls, substituted heteroaryls, silyls, aminos, fatty acid ester radicals, alkoxys, aryloxys and acyloxys; and

n is 0, 1, or 2.

45. The salen-metal compound in accordance with claim 44, wherein said metal is a transition metal.

46. The salen-metal compound in accordance with claim 45, wherein said transition metal is a member selected from the group consisting of Mn, Mg, Co, Fe, Cu, Zn, V, Cr and Ni.

47. The salen-metal compound in accordance with claim 46, wherein said transition metal is Mn.

48. The salen-metal compound in accordance with claim 44, wherein said anion is a member selected from the group consisting of halogens and organic anions.

49. The salen metal compound in accordance with claim 44, wherein said anion is an organic anion.

50. The salen-metal compound in accordance with claim 49, wherein said organic anion is a member selected from the group consisting of acetate, propionate, butyrate, formate, and triflate.

51. The salen-metal compound in accordance with claim 50, wherein said organic anion is acetate.

52. The salen metal compound in accordance with claim 44, wherein said anion is a halogen.

53. The salen-metal compound in accordance with claim 52, wherein said halogen is —

Cl.

54. The salen-metal compound in accordance with claim 44, wherein X¹ and X² are independently selected from the group consisting of hydrogen alkyls, halogens, alkoxys and aminos.

55. The salen-metal compound in accordance with claim 54, wherein X¹ and X² are both hydrogen.

56. The salen-metal compound in accordance with claim 54, wherein X¹ and X² are both alkoxy.

57. The salen-metal compound in accordance with claim 44, wherein Y¹, Y², Y³ and Y⁴ are independently selected from the group consisting of hydrogen, alkyls, halogens, alkoxys and aminos.

58. The salen-metal compound in accordance with claim 57, wherein Y¹, Y², Y³, Y⁴, Y⁵ and Y⁶ are all hydrogen.

59. The salen-metal compound in accordance with claim 57, wherein Y¹ and Y⁴ are both alkoxy, and Y², Y³, Y⁵ and Y⁶ are all hydrogen.

60. The salen-metal compound in accordance with claim 57, wherein Y¹ and Y⁴ are both halogen, and Y², Y³, Y⁵ and Y⁶ are all hydrogen.

61. The salen-metal compound in accordance with claim 57, wherein Y¹ and Y⁴ are both amino, and Y², Y³, Y⁵ and Y⁶ are all hydrogen.

62. The salen-metal compound in accordance with claim 57, wherein Y¹ and Y⁴ are both alkoxy, and Y², Y³, Y⁵ and Y⁶ are all hydrogen.

63. The salen-metal compound in accordance with claim 44, wherein n is 0;

and R¹, R², R³ and R⁴ are all hydrogen.

64. The salen-metal compound in accordance with claim 44, wherein n is 0;

R¹ and R³ are both aryl; and

R² and R⁴ are both hydrogen.

65. The salen-metal compound in accordance with claim 44, wherein n is 0;

R¹ and R³ are both aryloxy; and

R² and R⁴ are both hydrogen.

66. The salen-metal compound in accordance with claim 44, wherein n is 0;

R¹ and R³ are both acyloxy; and

R² and R⁴ are both hydrogen.

67. The salen-metal compound in accordance with claim 44, wherein n is 0;

and one of R¹ or R² is covalently linked to one of R³ or R⁴, and together with the atoms to which they are attached, form a six-membered ring.

68. The salen-metal compound in accordance with claim 67, wherein said six-membered ring is a member selected from the group consisting of a cyclohexyl ring, a benzene ring and a pyridine ring.

69. The salen-metal compound in accordance with claim 67, wherein said six-membered ring is a benzene ring.

70. The salen-metal compound in accordance with claim 44, wherein n is 1;

and Q¹ and Q² are both hydrogen.

71. The salen-metal compound in accordance with claim 44, wherein said bridging group Z is —

(CH₂)_m—

, wherein m is equal to or greater than 1.

72. The salen-metal compound in accordance with claim 71, wherein m is 2 to 6.

73. The salen-metal compound in accordance with claim 44, wherein said bridging group Z is —

(CR⁵R⁶)_m—

, wherein each R⁵ and R⁶ is independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, acyl and amino; and

m is equal to or greater than 1.

74. The salen-metal compound in accordance with claim 73, wherein m is from 2to 6.

75. The salen-metal compound in accordance with claim 73, wherein m is equal to or greater than 1 and wherein at least one of the (CR⁵R⁶) groups is replaced by a heteroatom.

76. The salen-metal compound in accordance with claim 75, wherein said heteroatom is oxygen.

77. The salen-metal compound in accordance with claim 73, wherein said bridging group Z is selected from the group consisting of

— CH₂—

CH₂—

O—

CH₂—

CH₂—

; and

—

CH₂—

CH₂—

O—

CH₂—

CH₂—

O—

CH₂—

CH₂—

.

78. The salen-metal compound in accordance with claim 44, wherein said bridging group has the general formula:

79. The compound in accordance with claim 78, wherein R⁹ is an aryl.

80. The compound in accordance with claim 79, wherein said aryl is benzene.

81. The compound in accordance with claim 78, wherein R⁹ is a cycloalkyl.

82. The compound in accordance with claim 81, wherein said cycloalkyl is cyclohexyl.

83. The compound in accordance with claim 78, wherein R⁹ is an alkyl.

84. The salen-metal compound in accordance with claim 83, wherein said alkyl is an alkenyl.

85. The compound in accordance with claim 78, wherein R⁹ is a heteroatom selected from the group consisting of oxygen, nitrogen and sulfur.

86. The compound in accordance with claim 78, wherein said bridging group Z is a member selected from the group consisting of:

90. A salen-metal compound in accordance with claim, or claim 44 having detectable superoxide dismutase activity.