Mitochondrial aldehyde dehydrogenase-2 modulators and methods of use thereof

• US 10,227,304 B2
• Filed: 04/24/2017
• Issued: 03/12/2019
• Est. Priority Date: 03/14/2013
• 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: Yang, Wenjin, Chen, Che-Hong, Mochly-Rosen, Daria
• Primary Examiner(s): Davis, Zinna Northington
• Application Number:
  US15/495,670
• Publication Number:
  US 20170320828A1
• Time in Patent Office: 687 Days
• Field of Search: None
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/18 Antioxidants, e.g. antiradicals preparations for protection against sunlight A61Q17/00
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/12 for cataracts
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07C 233/66 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
• CPC Class Codes: C07C 233/73 of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 233/78 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
• CPC Class Codes: C07C 233/87 of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 235/48 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 235/60 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 237/32 having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by oxygen atoms
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/04 with a four-membered ring
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 311/16 having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
• CPC Class Codes: C07C 311/17 to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 311/29 having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/40 to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 317/32 : with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07D 213/81 : Amides; Imides
• CPC Class Codes: C07D 213/82 : in position 3
• CPC Class Codes: C07D 213/89 : with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 317/58 : Radicals substituted by nitrogen atoms nitro radicals C07D317/52
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links

Abstract

The present disclosure provides compounds of formula (I) that function as modulators of mitochondrial aldehyde dehydrogenase-2 (ALDH2) activity, and methods of preparing these compounds.

Claims

1. A method of treating a disease or condition associated with ALDH2 modulation, the method comprising:

administering to a subject in need thereof an effective amount of a compound of formula;

2. The method of claim 1, wherein the alcohol poisoning is methanol poisoning.

3. The method of claim 2, wherein the alcohol poisoning is acute alcohol poisoning.

4. The method of claim 3, wherein the alcohol intoxication is acute alcohol intoxication.

5. The method of claim 1, wherein the symptom of alcohol consumption is a hangover symptom.

6. The method of claim 5, wherein the hangover symptom is selected from a group consisting of dehydration, fatigue, headache, body aches, vomiting, diarrhea, flatulence, weakness, elevated body temperature and heart rate, hypersalivation, difficulty concentrating, sweating, anxiety, dysphoria, irritability, sensitivity to light and noise, erratic motor function, trouble sleeping, severe hunger, halitosis, and lack of depth perception.

7. The method of claim 1, further comprising an opioid receptor antagonist.

8. The method of claim 7, wherein the opioid receptor antagonist is naltrexone.

9. The method of claim 1, wherein the administering is effective for sequestering aldehydes in a subject exposed to alcohol or aldehydes.

10. The method of claim 1, wherein the administering is effective for reducing a level of an aldehyde present at a toxic level in the subject to below the toxic level, wherein the aldehyde is a biogenic aldehyde or a xenogenic aldehyde.

11. The method of claim 10, wherein the aldehyde is a biogenic aldehyde selected from the group consisting of acetaldehyde, malondialdehyde (MDA), 3,4-dihydroxyphenylacetaldehyde (DOPAL), 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), hexanal, acrolein, glyoxal, crotonaldehyde, trans-2-nonenal, 4-oxo-2-nonenal, and 4-hydroxy-2-nonenal (HNE).

12. The method of claim 10, wherein the xenogenic aldehyde is an environmental aldehyde that is ingested or inhaled.

13. The method of claim 1, wherein the disease or condition associated with ALDH2 modulation is an acute or a chronic free-radical associated disease in the subject.

14. The method of claim 13, wherein the acute free-radical associated disease is selected from seizures and photo-damage to the skin.

15. The method of claim 1, wherein the disease or condition associated with ALDH2 modulation is an ocular disorder in the subject.

16. The method of claim 15, wherein the ocular disorder is selected from age-related cataracts, secondary cataracts, traumatic cataracts, congenital cataracts, age-related macular degeneration, and radiation cataracts.

17. The method of claim 1, wherein the disease or condition associated with ALDH2 modulation is radiation-induced damage to epithelial cells in the subject.

18. The method of claim 17, wherein the radiation-induced damage results in radiation dermatitis.

19. The method of claim 17, wherein the compound is to be administered before the subject is exposed to ionizing radiation.

20. The method of claim 17, wherein the compound is to be administered after the subject is exposed to ionizing radiation.

21. The method of claim 7, wherein the compound is to be administered both before and after the subject is exposed to ionizing radiation.

22. The method of claim 17, wherein the radiation-induced damage results in mucositis.

23. The method of claim 17, wherein the compound is to be administered to a mucosal surface in the subject.

24. The method of claim 1, wherein the administering is effective for reducing the likelihood that the subject will develop head and neck cancer.

25. The method of claim 24, wherein the subject is a habitual user of betel quid.

26. The method of claim 25, wherein the compound is formulated as a toothpaste, a tooth gel, a tooth powder, a mouth rinse, a chewing gum, or a lozenge.

27. The method of claim 1, wherein the administering is effective for reducing the likelihood that the subject will develop oral cancer or lung cancer.

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

29. The method of claim 1, wherein the administering of the compound to the subject activates ALDH2 activity in the subject.

30. The method of claim 1, wherein the compound is of the formula IIa:

31. The method of claim 1, wherein the compound is of the formula IVa:

32. The method of claim 1, wherein the compound is of the formula IIb:

33. The method of claim 1, wherein the compound is of the formula IVb:

34. The method of claim 1, wherein the compound is of the formula IIc:

35. The method of claim 1, wherein the compound is of the formula IVc:

36. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt or solvate thereof is selected from:

37. The method of claim 1, wherein the compound or a pharmaceutically acceptable salt or solvate thereof is: