Mitochondrial aldehyde dehydrogenase-2 modulators and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10227304-B2
Application number	US-201715495670-A
Country	US
Kind code	B2
Filing date	Apr 24, 2017
Priority date	Mar 14, 2013
Publication date	Mar 12, 2019
Grant date	Mar 12, 2019

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.

First claim

What is claimed is:

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:

or a pharmaceutically acceptable salt or solvate thereof, wherein
A is C;
X 2 is CR 2 ;
X 3 is CR 3 ;
X 4 is selected from N and NO;
X d is CR d ;
R a , R b , R d , and R e are independently selected from hydrogen, halogen, OH, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy
R c is selected from OH, C 1 -C 6 alkoxy, OCF 3 , OCF 2 H, and OCFH 2 ;
R f , R g , and R h are independently selected from hydrogen and C 1 -C 6 alkyl;
R 1 is halogen;
R 2 and R 3 are independently selected from hydrogen, halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, OR 7 , NH 2 , NO 2 , NHR 7 , NR 7 R 7 , S(O) q R 7 , C(O)R 7 , C(O)OR 7 , CF 3 , CF 2 H, CFH 2 , OCF 3 , OCF 2 H, and OCFH 2 ;
R 5 is selected from halogen, C 1 -C 6 alkyl, OR 7 , and NHR 7 ;
R 6 is selected from hydrogen and C 1 -C 6 alkyl;
R 7 is selected from (a) hydrogen, (b) C 1 -C 6 alkyl, (c) C 2 -C 6 alkenyl, (d) C 2 -C 6 alkynyl, (e) 3-14 membered saturated, partially saturated, or unsaturated carbocycle, and (f) 3-14 membered saturated, partially saturated, or unsaturated heterocycle containing one or more heteroatoms selected from N, O, and S;
wherein (b)-(f) optionally is substituted with one or more R 8 ;
R 8 is selected from (a) halogen, (b) OH, (c) NO 2 , (c) NH 2 , (d) C(O)OH, (e) NH(C 1 -C 6 alkyl), (f) N(C 1 -C 6 alkyl)2, (g) C(O)O—(C 1 -C 6 alkyl), (h) C 1 -C 6 alkyl, (i) C 1 -C 6 alkoxy, (j) 3-14 membered saturated, partially saturated, or unsaturated carbocycle, (k) 3-14 membered saturated, partially saturated, or unsaturated heterocycle containing one or more heteroatoms selected from N, O, and S; and (l) ═O
wherein (e)-(k) optionally is substituted with one or more R 9 ;
R 9 is selected from halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C(O)OH, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , NO 2 , and S(O) q —(C 1 -C 6 alkyl);
n is 1;
p is 1 or 2; and
q is 0, 1, or 2,
wherein the disease or condition associated with ALDH2 modulation is alcohol intolerance, alcohol addiction, an alcohol abuse disorder, alcohol intoxication, alcohol dependence, alcohol poisoning, or symptoms of alcohol consumption in the subject.

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:

or a pharmaceutically acceptable salt or solvate thereof.

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

or a pharmaceutically acceptable salt or solvate thereof.

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

or a pharmaceutically acceptable salt or solvate thereof.

Assignees

• Univ Leland Stanford Junior

Inventors

• Yang Wenjin
• Chen Che-Hong
• Mochly-Rosen Daria

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P27/12

  for cataracts · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61P25/32

  Alcohol-abuse · CPC title

• C07C2601/02

  with a three-membered ring · CPC title