Small molecule inhibitors of necrosis

• US 6,756,394 B1
• Filed: 10/13/2000
• Issued: 06/29/2004
• Est. Priority Date: 10/15/1999
• Status: Expired due to Term

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Mitchison, Timothy J., Yuan, Junying, Degterev, Alexei
• Primary Examiner(s): Ramsuer, Robert W.
• Assistant Examiner(s): SMALL, ANDREA D SOUZA
• Application Number:
  US09/688,015
• Time in Patent Office: 1,355 Days
• Field of Search: 548/312.1, 514/402
• US Class Current: 514/389
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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: C07C 43/2055 containing more than one ether bond
• CPC Class Codes: C07C 43/23 containing hydroxy or O-metal groups
• CPC Class Codes: C07C 49/255 containing ether groups, groups, groups, or groups
• CPC Class Codes: C07D 231/54 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 309/32 having two double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 309/38 one oxygen atom in position 2 or 4, e.g. pyrones
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The invention features methods for decreasing necrosis. The invention also features methods for treating a subject with a condition in which necrosis occurs. The invention further features chemical compounds used to decrease necrosis.

Claims

1. A method for decreasing necrosis in a subject in a with a disease or condition selected from the group consisting of:

Alzheimer'"'"'s disease, Huntington'"'"'s disease, cerebral ischemia, stroke, amyotropic lateral sclerosis, multiple sclerosis, Lewy body disease, Menke'"'"'s disease, Wilson disease, Creutzfeldt-Jakob disease, and Fahr disease, said method comprising treating a cell with a chemical compound of the formula;

wherein

each R₁ is independently selected from the group consisting of hydrogen methyl, carboxy, hydroxyl, methyl, amino, and nitro;

R₂ is selected from the group consisting of hydrogen, alkyl, and acyl;

R₃ is selected from the group consisting of alkyl, acyl, halogen, hydrogen, and hydroxyl;

R₄ is selected from the group consisting of methyl, hydroxyl, carboxyl, and linear and branching alkyl groups; and

each of the bonds (a), (b), and (c) independently is either a double or single bond, provided, however, that bond (a) and bond (b) are not both double bonds.

2. The method of claim 1, wherein said compound is selected from the group consisting of:

3. The method of claim 1, wherein said cell is capable of undergoing necrosis in the presence of zVAD-fmk and TNF.

4. The method of claim 1, wherein said cell is capable of undergoing necrosis in the presence of zVAD-fmk and DMSO.

5. The method of claim 1, wherein said cell is mammalian.

6. The method of claim 1, wherein said cell is human.

7. The method of claim 1, wherein said cell is a neuron.

8. The method of claim 1, wherein said cell is a rodent cell.

9. The method of claim 1, wherein said compound is in a pharmaceutically acceptable carrier.

10. A method for treating a subject with a condition selected from the group consisting of:

Alzheimer'"'"'s disease, Huntington'"'"'s disease, cerebral ischemia, stroke, amyotropic lateral sclerosis, multiple sclerosis, Lewy body disease, Menke'"'"'s disease, Wilson disease, Creutzfeldt-Jakob disease, and Fahr disease, wherein decreasing necrosis is of benefit, said method comprising administering to said subject a chemical having the formula;

wherein

each R₁ is independently selected from the group consisting of hydrogen, methyl, carboxy, hydroxyl, methoxyl, amino, and nitro;

R₂ is selected from the group consisting of hydrogen, alkyl, and acyl;

R₃ is selected from the group consisting of alkyl, acyl, halogen, hydrogen, and hydroxyl;

R₄ is selected from the group consisting of methyl, hydroxyl, carboxyl, and linear and branching alkyl groups; and

each of the bonds (a), (b), and (c) independently is either a double or single bond, provided, however, that bond (a) and bond (b) are not both double bonds.

11. The method of claim 10, wherein said subject is selected from the group consisting of:

12. The method of claim 10, wherein said subject is a mammal.

13. The method of claim 12, wherein said subject is a human.

14. The method of claim 12, wherein said subject is a rodent.

15. A method for treating a subject with a disease or condition selected from the group consisting of:

a liver disease, a pancreatic disease, an ischemic brain injury, an ischemic heart injury, an ischemic injury to non-cardiac and non-neural tissue, a head trauma, a necrotic ulceration, septic shock, coronary heart disease, a gastrointestinal disease, tuberculosis, a viral infection, and conditions associated with HIV infection or AIDS, said method comprising treating a cell with a chemical compound of the formula;

wherein

each R₁ is independently selected from the group consisting of hydrogen, methyl, carboxy, hydroxyl, methoxyl, and nitro;

R₂ is selected from the group consisting of hydrogen, alkly, and acyl;

R₃ is selected from the group consisting of alkyl, acyl, hydrogen, and hydroxyl;

R₄ is selected from the group consisting of methyl, hydoxyl, carboxyl, and linear and branching alkyl groups; and

each of the bonds (a), (b), and (c) independently is either a double or single bond, provided, however, that bond (a) and bond (b) are not both double bonds.

16. A method for decreasing necrosis in a subject with a disease or condition selected from the group consisting of:

a liver disease, a pancreatic disease, an ischemic brain injury, an ischemic heart injury, an ischemic injury to non-cardiac and non-neural tissue, a head trauma, a necrotic ulceration, septic shock, coronary heart disease, a gastrointestinal disease, tuberculosis, a viral infection, and conditions associated with HIV infection or AIDS, wherein decreasing necrosis is of benefit, said method comprising administering to said subject a chemical compound having the formula;

wherein

each R₁ is independently selected from the group consisting of hydrogen, methyl, carboxy, hydroxyl, methoxyl, amino, and nitro;

R₂ is selected from the group consisting of hydrogen, alyl, and acyl;

R₃ is selected from the group consisting of alkyl, acyl, halogen, hydrogen, and hydroxyl;

R₄ is selected from the group consisting of methyl, hydroxyl, carboxyl, and linear and branching alkyl groups; and

each of the bonds (a), (b), and (c) independently is either a double or single bond, provided, however, that bond (a) and bond (b) are not both double bonds.