Mitochondrial aldehyde dehyrogenase-2 modulators and methods of use thereof

• US 9,670,162 B2
• Filed: 03/13/2014
• Issued: 06/06/2017
• Est. Priority Date: 03/14/2013
• Status: Active Grant

• Current Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford University)
• Original Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford University)
• Inventors: Yang, Wenjin, Chen, Che-Hong, Mochly-Rosen, Daria
• Primary Examiner(s): NORTHINGTON DAVI, ZINNA
• Application Number:
  US14/774,071
• Publication Number:
  US 20160107996A1
• Time in Patent Office: 1,181 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 compound of formula:

2. The compound of claim 1, wherein R^b is halogen, OH, or C₁-C₆ alkoxy.

3. The compound of claim 1, wherein R^b is halogen.

4. The compound of claim 1, wherein R^c is OH, or C₁-C₆ alkoxy.

5. The compound of claim 1, wherein R^c is C₁-C₆ alkoxy.

6. The compound of claim 1, wherein R^c is methoxy or ethoxy.

7. The compound of formula (I) according to claim 1, wherein the compound is formula IIa:

8. The compound of formula (I) according to claim 1, wherein the compound is formula IVa:

9. The compound of formula (I) according to claim 1, wherein the compound is formula IIb:

10. The compound of formula (I) according to claim 1, wherein the compound is formula IVb:

11. The compound of claim 1, wherein R¹ is F, Cl, or Br.

12. The compound of claim 1, wherein R⁷ is C₁-C₆ alkyl or 3-14 membered saturated, partially saturated, or unsaturated carbocycle;

wherein the alkyl and carbocycle are optionally substituted with R⁸.

13. The compound of claim 12, wherein R⁷ is C₁-C₆ alkyl optionally substituted with R⁸.

14. The compound of claim 1, wherein R⁸ is selected from (a) 3-14 membered saturated, partially saturated, or unsaturated carbocycle, and (b) 3-14 membered saturated, partially saturated, or unsaturated heterocycle containing one or more heteroatoms selected from N, O, and S;

wherein the carbocycle and heterocycle are optionally substituted with R⁹.

15. The compound of claim 14, wherein R⁹ is selected from halogen, OH, and C₁-C₆ alkoxy.

16. The compound of formula (I) according to claim 1, wherein the compound is formula IIc:

17. The compound of formula (I) according to claim 1, wherein the compound is IVc:

19. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutical acceptable excipient.

18. A compound or a pharmaceutically acceptable salt or solvate thereof selected from: