Synthetic catalytic free radical scavengers useful as antioxidants for prevention and therapy of disease

• US 5,827,880 A
• Filed: 01/26/1995
• Issued: 10/27/1998
• Est. Priority Date: 12/07/1992
• Status: Expired due to Term

• Current Assignee: Eukarion, Inc.
• Original Assignee: Eukarion, Inc.
• Inventors: Malfroy-Camine, Bernard, Doctrow, Susan Robin
• Primary Examiner(s): NAZARIO GONZALEZ, PORFIRIO
• Application Number:
  US08/380,731
• Time in Patent Office: 1,370 Days
• Field of Search: 514/492, 556/45
• US Class Current: 514/492
• CPC Class Codes: A61K 31/28 Compounds containing heavy metals
• CPC Class Codes: A61K 31/555 containing heavy metals, e.g. hemin, hematin, melarsoprol
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 39/06 Free radical scavengers or antioxidants
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• 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

The invention provides antioxidant salen-metal complexes, compositions of such antioxidant salen-metal complexes having superoxide activity, catalase activity, and/or peroxidase activity, compositions of salen-metal complexes in a form suitable for pharmaceutical administration to treat or prevent a disease associated with cell or tissue damage produced by free radicals such as superoxide, and cosmetic and free radical quenching formulations of salen metal compounds.

Claims

1. A salen-metal compound having the structural formula ##STR15## wherein:

each R₁ is independently hydrogen, fluorine, or methoxy;

each R₂ is independently hydrogen or methoxy;

each R₃ is independently hydrogen or methoxy;

each R₄ is independently hydrogen or methoxy; and

X is chlorine or acetoxy;

provided that;

when R_2-4 are all hydrogen, both R¹ '"'"'s are not methoxy simultaneous with X being acetoxy or chlorine;

when R_1-4 are all hydrogen, X is not chlorine or acetoxy; and

when R₁, R₂ and R₄ are all hydrogen, both R₃ '"'"'s are not methoxy simultaneous with X being chlorine.

2. A salen-metal compound of claim 1 having a structural formula selected from the group of compounds consisting of C33, C34, C35, C36, C37, C38, and C39 as shown below:

space="preserve" listing-type="tabular">______________________________________ ##STR16## R.sub.1 R.sub.2 R.sub.3 R.sub.4 X ______________________________________ C36 F H H H OAc C37 F H H H Cl C38 H H OMe H OAc C35 H OMe H OMe OAc C39 H OMe H OMe Cl C33 H OMe H H OAc C34 H OMe H H Cl. ______________________________________

3. A salen-metal compound of claim 1 having detectable superoxide dismutase activity.

4. A salen-metal compound of claim 1 having detectable catalase activity.

5. A salen-metal compound of claim 1 having detectable peroxidase activity.

6. A salen-metal compound of claim 1 having detectable catalase and peroxidase activity.

7. A salen-metal compound of claim 1 having detectable superoxide dismutase, catalase, and peroxidase activity.

8. An antioxidant composition comprising an excipient or carrier and a therapeutically effective amount of a salen-metal compound of claim 1.

9. An antioxidant composition of claim 8, wherein said salen metal compound of claim 1 is selected from the group consisting of C 31, C33, C34, C35, C36, C37, C38, C39, and C40 as shown in below:

space="preserve" listing-type="tabular">______________________________________ ##STR17## R.sub.1 R.sub.2 R.sub.3 R.sub.4 X ______________________________________ C31 H H H H OAc C36 F H H H OAc C37 F H H H Cl C38 H H OMe H OAc C40 OMe H H H Cl C35 H OMe H OMe OAc C39 H OMe H OMe Cl C33 H OMe H H OAc C34 H OMe H H Cl. ______________________________________

10. A method for inhibiting damage to cells induced by reactive oxygen species, the method comprising contacting cells having oxidative stress with a salen-metal complex having the structural formula ##STR18## wherein:

each R₁ is independently hydrogen, flourine, or methoxy;

each R₂ is independently hydrogen or methoxy;

each R₃ is independently hydrogen or methoxy;

each R₄ is independently hydrogen or methoxy; and

X is chlorine or acetoxy.

11. The method of claim 10, wherein the cells are human cells.

12. A pharmaceutical composition comprising a compound of the formula ##STR19## wherein:

each R₁ is independently hydrogen, fluorine, or methoxy;

each R₂ is independently hydrogen or methoxy;

each R₃ is independently hydrogen or methoxy;

each R₄ is independently hydrogen or methoxy; and

X is chlorine or acetoxy; and

a pharmaceutically acceptable carrier;

provided that;

R_1-4 are not all hydrogen simultaneous with X being chlorine; and

when R₁, R₂ and R₄ are all hydrogen, both R₃ '"'"'s are not methoxy simultaneous with X being chlorine.

13. The pharmaceutical composition of claim 12, wherein:

each R₁ is methoxy;

R_2-4 are hydrogen; and

X is acetoxy.