3-3-DI-SUBSTITUTED-OXINDOLES AS INHIBITORS OF TRANSLATION INITIATION

• US 20070099976A1
• Filed: 08/09/2006
• Published: 05/03/2007
• Est. Priority Date: 02/13/2004
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Natarajan, Amarnath, Aktas, Huseyin, Fan, Yun-Hua, Halperin, Jose, Chen, Han
• Granted Patent: US 7,737,172 B2
• Time in Patent Office: Days
• US Class Current: 514/397
• 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 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: C07D 209/34 in position 2
• CPC Class Codes: C07D 209/36 in position 3, e.g. adrenochrome
• CPC Class Codes: C07D 403/02 containing two hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/10 linked by a carbon chain containing aromatic rings

Abstract

Compositions and methods for inhibiting translation using 3-(5-tert-Butyl-2-Hydroxy-phenyl)-3-phenyl-1,3-dihydro-indol-2-one and/or its derivatives are provided. Compositions, methods and kits for treating (1) cellular proliferative disorders, (2) non-proliferative, degenerative disorders, (3) viral infections, and/or (4) disorders associated with viral infections, using 3-(5-tert-butyl-2-hydroxy-phenyl)-3-phenyl-1,3-dihydro-indol-2-one and/or its derivatives are described.

Claims

1. A compound of formula I:

2. A compound of formula II:

3. A compound of formula III:

4. A compound of formula IV:

5. A compound of formula V:

6. A compound of formula VI:

9. A compound of formula IX:

10. A compound of formula X:

11. A compound of formula XI:

12. A compound of formula XII:

13. A compound of formula XIII:

14. A compound of formula XIV:

15. A compound for inhibiting translation, wherein said compound is selected from formulae I-XIV above.

16. A method of treating a cellular proliferative disorder in a human or non-human mammal in need thereof, the method comprising administering to the human or non-human mammal the compound of claim 15.

17. The method of claim 16, wherein the compound is administered by inhalation, transdermally, orally, rectally, transmucosally, intestinally, parenterally, intramuscularly, subcutaneously or intravenously.

24. A method of treating a non-proliferative, degenerative disorder in a human or non-human mammal in need thereof, the method comprising administering to the human or non-human mammal the compound of claim 15.

25. The method of claim 24, wherein the compound is administered by inhalation, transdermally, orally, rectally, transmucosally, intestinally, parenterally, intramuscularly, subcutaneously or intravenously.

18. A method of treating a cellular proliferative disorder in a human or non-human mammal in need thereof, the method comprising administering to the human or non-human mammal a compound selected from formulae I-XIV above in an amount effective to deplete intracellular calcium stores of an aberrantly proliferating cell.

19. The method of claim 18, wherein said cellular proliferative disorder is cancer.

20. A method of treating a viral infection in a human or non-human mammal in need thereof, the method comprising administering to a human or non-human mammal a compound selected from formulae I-XIV above.

21. The method of claim 20, wherein the compound is administered by inhalation, transdermally, orally, rectally, transmucosally, intestinally, parenterally, intramuscularly, subcutaneously or intravenously.

22. A method of treating a viral infection in a human or non-human mammal in need thereof, the method comprising administering to the human or non-human mammal a compound selected from formulae I-XIV above in an amount effective to deplete intracellular calcium stores of an infected cell.

23. The method of claim 22, wherein viral translation is inhibited.

26. A method of treating a non-proliferative, degenerative disorder in a human or non-human mammal in need thereof, the method comprising administering to the human or non-human mammal a compound selected from formulae I-XIV above in an amount effective to deplete intracellular calcium stores of a cell associated with a non-proliferative, degenerative disorder.

27. The method of claim 26, wherein said non-proliferative, degenerative disorder is Alzheimer'"'"'s disease or insulin resistance.

28. A method of treating a disorder associated with a viral infection in a human or non-human mammal in need thereof, the method comprising administering to a human or non-human mammal a compound selected from formulae I-XIV above.

29. The method of claim 28, wherein the compound is administered by inhalation, transdermally, orally, rectally, transmucosally, intestinally, parenterally, intramuscularly, subcutaneously or intravenously.

30. A method of treating a disorder associated with a viral infection in a human or non-human mammal in need thereof, the method comprising administering to the human or non-human mammal a compound selected from formulae I-XIV above in an amount effective to deplete intracellular calcium stores of an infected cell.

31. The method of claim 30, wherein viral translation is inhibited.

32. A kit containing a pharmaceutical composition comprising:

a compound selected from formulae I-XIV above and a pharmaceutically acceptable carrier for treatment of one or more of a cellular proliferative disorder or a viral infection.

33. The kit of claim 32, further comprising instructions for use.

34. The kit of claim 32, wherein said pharmaceutical composition is administered to a human subject.