Indirubin-Type Compounds, Compositions, and Methods for Their Use

• US 20070276025A1
• Filed: 10/28/2004
• Published: 11/29/2007
• Est. Priority Date: 10/28/2003
• Status: Abandoned Application

• Current Assignee: Alexios-Leandros Skaltounis, Laurent Meijer, Marie Knockaert, Paul Greengard
• Original Assignee: Alexios-Leandros Skaltounis, Laurent Meijer, Marie Knockaert, Paul Greengard
• Inventors: Greengard, Paul, Meijer, Laurent, Skaltounis, Alexios-Leandros, Knockaert, Marie
• Application Number:
  US10/577,686
• Publication Number:
  US 20070276025A1
• Time in Patent Office: Days
• US Class Current: 514/414
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07D 209/34 in position 2
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Compounds and compositions including 6-bromo-indirubin, 5-amino-indirubin and N-methyl-indirubins and related indirubin derivatives are provided that are useful as selective modulators of glycogen synthase kinase-3, cyclin-dependent protein kinases or aryl hydrocarbon receptors. Methods of inhibiting or modulating cell growth or cell cycling are provided using the compounds of the invention. In other aspects, compounds and methods for the treatment of protozoan-mediated diseases, Alzheimer'"'"'s disease and diabetes are provided.

Claims

1. An isolated compound comprising an indirubin molecule substituted with a halogen at position C6 of the indirubin molecule.

2. The isolated compound of claim 1, wherein the compound inhibits GSK-3 activity with an IC₅₀ value of less than 0.1 μ

M using GS-1 peptide as a substrate.

3. A pharmaceutically acceptable salt or solvate of the isolated compound of claim 1.

4. The isolated compound of claim 1, wherein the compound is selected from the group consisting of 6-bromoindirubin (5a), 6,6′

-dibromoindimibin (12b), 6-bromoindirubin-3′

-oxime (“

BIO”

) (7a), 6,6′

-dibromnoindirubin-3′

-oxime (13b), 6-bromoindirubin-3′

-methoxime (9a), 6-bromo-5-methylindirubin (51) and 6-bromoindirubin-3′

-acetoxime (8a), and pharmaceutically acceptable salts thereof

5. The isolated compound of claim 1, wherein the compound is selected from the group consisting of 6-bromo-5-aminoindirubin (27) and 6-bromo-5-amino-3′

-oxime-indirubin (28) and pharmaceutically acceptable salts thereof.

6. A compound selected from the group of 6-bromoindirubin (5a), 6,6′

-dibromoindirubin (12b), 6-bromoindirubin-3′

-oxime (“

BIO”

) (7a), 6,6′

-dibromoindirubin-3′

-oxime (13b), 6-bromoindirubin-3′

-methoxime (9a), 6-bromo-5-methylindirubin (51), 6-bromo-5-aminoindirubin (27), 6-bromo-5-amino-3′

-oxime-indirubin (28), 6-bromoindirubin-3′

-acetoxime (8a), 5-amino-indirubin (23), 5-amino-3′

-oxime-indirubin (24) and pharmaceutically acceptable salts thereof.

7. An inhibitor of GSK-3 activity, wherein the inhibitor comprises an indirubin molecule with a halogen atom covalently attached to carbon number 6, and the inhibitor inhibits GSK-3 activity with an IC₅₀ below 5 μ

M in an activity assay using GS-1 peptide as a substrate.

8. The inhibitor of claim 7, wherein the halogen atom is bromine.

10. A method of inhibiting GSK-3 activity comprising contacting GSK-3 with the inhibitor of claim 7.

11. The method of claim 10, wherein the GSK-3 activity is inhibited in vitro.

12. The method of claim 10, wherein the GSK-3 activity is inhibited in a cell.

13. The method of claim 10, wherein the inhibitor is selected from group of compounds consisting of 6-bromoindirubin (5a), 6,6′

-dibromoindirubin (12b), 6-bromoindirubin-3′

-oxime (7a), 6,6′

-dibromoindirubin-3′

-oxime (13b), 6-bromoindirubin-3′

-methoxime (9a), 6-bromoindirubin-3′

-acetoxime (8a), 6-iodoindirubin (5c), 6-iodoindirubin-3′

-oxime (7c) and 6-iodoindirubin-3′

-acetoxime (8c), and pharmaceutically acceptable salts thereof

14. The method of claim 10, wherein the inhibitor is selected from group of compounds consisting of 6-bromo-5-aminoindirubin (27), 6-bromo-5-amino-3′

-oxime-indirubin (28), and pharmaceutically acceptable salts thereof.

9. A pharmaceutical composition comprising 6-bromoindirubin, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle.

15. A method for the isolation of 6-bromoindirubin from a natural source comprising the steps described in Example 6.1.2.

16. A method for preventing, treating or ameliorating type 2 diabetes or Alzheimer'"'"'s disease in a mammal, comprising administering to the mammal an effective disease-treating or condition-treating amount of a pharmaceutical composition of indirubin-type compound consisting of 6-bromoindirubin (5a) or a 6-bromoindirubin derivative or analogue.