Inhibitors of cellular necrosis

• US 8,143,300 B2
• Filed: 03/18/2008
• Issued: 03/27/2012
• Est. Priority Date: 08/29/2003
• Status: Active Grant

• Current Assignee: Brigham and Women's Hospital Incorporated, President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: Brigham and Women's Hospital Incorporated, President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Degterev, Alexei, Cuny, Gregory D., Jagtap, Prakash, Yuan, Junying
• Primary Examiner(s): SHIAO, REI TSANG
• Application Number:
  US12/077,320
• Publication Number:
  US 20110144169A1
• Time in Patent Office: 1,470 Days
• Field of Search: 514/397, 514/256, 544/333, 548/398
• US Class Current: 514/397
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention relates to compounds and pharmaceutical preparations and their use in therapy for preventing or treating trauma, ischemia, stroke and degenerative diseases associated with cell death. Methods and compositions of the invention are particularly useful for treating neurological disorders associated with cellular necrosis.

Claims

1. A compound of the formula:

2. The compound of claim 1, wherein

R₉ and R₁₀ represent, independently, H, F, Cl, Br, I, lower alkyl, or substituted lower alkyl;

n equals 1; and

n′

equals 0,

or a stereoisomeric form thereof, or a pharmaceutically acceptable acid or base addition salt of the compound or of a stereoisomeric form thereof.

3. The compound of claim 2, wherein

X represents O;

and

Y and G each represents NH,

or a stereoisomeric form thereof, or a pharmaceutically acceptable acid or base addition salt of the compound or of a stereoisomeric form thereof.

4. The compound of claim 3, wherein R₉ and R₁₀ each represents H,

or a stereoisomeric form thereof, or a pharmaceutically acceptable acid or base addition salt of the compound or of a stereoisomeric form thereof.

5. The compound of claim 4, wherein R₄ represents Cl, Br, F, or I,

or a stereoisomeric form thereof, or a pharmaceutically acceptable acid or base addition salt of the compound or of a stereoisomeric form thereof.

6. The compound of claim 5, wherein R₄ represents Cl and R₆ represents methyl,

or a stereoisomeric form thereof, or a pharmaceutically acceptable acid or base addition salt of the compound or of a stereoisomeric form thereof.

7. The compound of claim 6, wherein R₁, R₂, R₃, and R₅ each represents H,

or a stereoisomeric form thereof, or a pharmaceutically acceptable acid or base addition salt of the compound or of a stereoisomeric form thereof.

9. A method of treating a necrotic cell disease comprising administering to a subject having a necrotic cell disease a compound of claim 1,

or a stereoisomeric form thereof, or a pharmaceutically acceptable acid or base addition salt of the compound or of a stereoisomeric form thereof, and

wherein said necrotic cell disease is trauma, ischemia, stroke, cardiac infarction, infection, sepsis, Parkinson'"'"'s disease, Alzheimer'"'"'s disease, amyotrophic lateral sclerosis, Huntington'"'"'s disease, or HIV-associated dementia.

8. A pharmaceutical composition comprising:

(i) a compound of the formula;

10. A method of treating a necrotic cell disease comprising administering to a subject having a necrotic cell disease a compound of the formula:

11. The method of claim 10, wherein said compound has the formula:

12. The method of claim 10, wherein said compound is an enantiomer of the formula:

13. The method of claim 10, wherein said compound is an enantiomer of the formula:

14. The method of claim 10, wherein

R₉, R₁₀, R₉′

, and R₁₀′

represent independently H, F, Cl, Br, I, lower alkyl, or substituted lower alkyl; and

n and n′

are, independently, zero or one,

or a stereoisomeric form thereof, or a pharmaceutically acceptable acid or base addition salt of the compound or of a stereoisomeric form thereof.

15. The method of claim 14, wherein R₉, R₁₀, R₉′

, and R₁₀′

each represents H,

or a stereoisomeric form thereof, or a pharmaceutically acceptable acid or base addition salt of the compound or of a stereoisomeric form thereof.

16. The method of claim 15, wherein R₄ represents Cl, Br, F, or I,

or a stereoisomeric form thereof, or a pharmaceutically acceptable acid or base addition salt of the compound or of a stereoisomeric form thereof.

17. The method of claim 16, wherein R₆ represents methyl,

or a stereoisomeric form thereof, or a pharmaceutically acceptable acid or base addition salt of the compound or of a stereoisomeric form thereof.