Modulators of aldehyde dehydrogenase activity and methods of use thereof

• US 9,345,693 B2
• Filed: 11/10/2014
• Issued: 05/24/2016
• Est. Priority Date: 09/08/2008
• Status: Active Grant

• Current Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Original Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Inventors: Chen, Che-Hong, Mochly-Rosen, Daria, Yang, Wenjin
• Primary Examiner(s): NORTHINGTON DAVI, ZINNA
• Application Number:
  US14/537,245
• Publication Number:
  US 20150182511A1
• Time in Patent Office: 561 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/443 containing a five-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61P 39/02 Antidotes
• CPC Class Codes: A61P 39/06 Free radical scavengers or antioxidants
• 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 9/10 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 405/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention provides compounds that function as modulators of aldehyde dehydrogenase activity; and pharmaceutical compositions comprising the compounds. The present invention provides therapeutic methods involving administering a subject compound, or a subject pharmaceutical composition.

Claims

1. A method of treating an ALDH-mediated disorder selected from alcohol intolerance, alcohol addiction, alcohol abuse disorder, methanol poisoning, and ethylene glycol monomethyl ether poisoning, the method comprising administering to individual in need thereof a compound Formula I:

2. The method of claim 1, wherein Ar₁ is:

3. The method of claim 1, wherein Ar₁ is a substituted or unsubstituted heterocyclic group.

4. The method claim 1, wherein the substituted pyridine oxide is selected from:

5. The method of claim 1, wherein the compound is of Formula Ia:

6. The method of claim 1, wherein the compound is of Formula II:

7. The method of claim 6, wherein the substituted pyridine oxide is of a formula selected from:

8. The method of claim 1, wherein the compound is of Formula a:

9. The method of claim 8, wherein the compound has a structure selected from:

10. The method of claim 1, wherein the compound is of Formula b:

11. The method of claim 10, wherein the compound has a structure selected from:

12. The method of claim 1, wherein the compound is of Formula c:

13. The method of claim 12, wherein the compound has a structure selected from:

14. The method of claim 1, wherein the compound is present in a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient.

15. The method of claim 1, wherein the compound is administered by a route selected from intramuscular, intravenous, subcutaneous, and oral.

16. The method of claim 1, wherein the individual has an ALDH2*2 allele.

17. The method of claim 14, wherein the pharmaceutical composition administered by a route selected from intramuscular, intravenous, subcutaneous, and oral.

18. The method of claim 14, wherein the individual has an ALDH2*2 allele.

19. The method of claim 3, wherein Ar₁ is selected from a substituted or unsubstituted pyridine, a thiazole, an imidazole, a thiophene, a quinoline, an isoquinoline, and a furan group.