Toxic aldehyde related diseases and treatment

Patent metadata

Field	Value
Publication number	US-11701331-B2
Application number	US-202117227568-A
Country	US
Kind code	B2
Filing date	Apr 12, 2021
Priority date	Jan 23, 2013
Publication date	Jul 18, 2023
Grant date	Jul 18, 2023

Abstract

The present invention provides for the treatment, prevention, and/or reduction of a risk of a disease, disorder, or condition in which aldehyde toxicity is implicated in the pathogenesis, including ocular disorders, skin disorders, conditions associated with injurious effects from blister agents, and autoimmune, inflammatory, neurological and cardiovascular diseases by the use of a primary amine to scavenge toxic aldehydes, such as MDA and HNE.

First claim

We claim:

1. A method of treating scleritis, comprising:
administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein,
X is CH; Z is N; and Y is C with the —NH 2 attached;
p is 0, 1, 2, or 3;
each R B is independently a halogen, hydroxyl, carbamoyl, amino, or aryl;
R A is

 and
each Q a is independently a C 1 -C 6 straight chain alkyl.

2. The method of claim 1 , wherein p is 1.

3. The method of claim 1 , wherein each Q a is methyl.

4. The method of claim 1 , wherein R B is a halogen.

5. The method of claim 4 , wherein the halogen is chlorine or fluorine.

6. The method of claim 5 , wherein the halogen is chlorine.

7. The method of claim 1 , wherein the compound is present at a concentration of about 0.05-10% w/v.

8. The method of claim 1 , wherein the compound is present at a concentration of about 0.1-5% w/v.

9. The method of claim 1 , wherein the compound is present at a concentration of about 0.1-2% w/v.

10. The method of claim 1 , wherein the compound is present at a concentration of about 0.1-1.0% w/v.

11. The method of claim 1 , wherein the compound is present at a concentration of about 0.09-0.5% w/v.

12. The method of claim 1 , wherein the compound is present in an admixture with a cyclodextrin.

13. The method of claim 12 , wherein the cyclodextrin comprises a β-cyclodextrin or a pharmaceutically acceptable salt thereof.

14. The method of claim 13 , wherein the β-cyclodextrin is selected from the group consisting of sulfobutylether-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, and 3-hydroxypropyl-β-cyclodextrin.

15. The method of claim 14 , wherein the β-cyclodextrin is sulfobutylether-β-cyclodextrin or a pharmaceutically acceptable salt thereof.

16. The method of claim 15 , wherein the salt of sulfobutylether-β-cyclodextrin is sulfobutylether-β-cyclodextrin sodium salt.

17. The method of claim 16 , wherein the sulfobutylether-β-cyclodextrin sodium salt is present at a concentration of about 0.01-30% w/v.

18. The method of claim 1 , wherein the sulfobutylether-β-cyclodextrin is present at a concentration of about 2-25% w/v.

19. The method of claim 10 , wherein the sulfobutylether-β-cyclodextrin is present at a concentration of about 6-20% w/v.

20. The method of claim 1 , wherein for the compound of formula (I):
each Q a is methyl;
R B is halogen; and
p is 1.

21. The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

22. The method of claim 21 , wherein the subject is a human and the compound is administered topically to one or both eyes of the subject.

23. The method of claim 19 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

24. The method of claim 20 , wherein the compound is administered topically to one or both eyes of the subject as an aqueous composition comprising the compound, and a cyclodextrin or a pharmaceutically acceptable salt thereof.

25. The method of claim 24 , wherein the cyclodextrin is a β-cyclodextrin or a pharmaceutically acceptable salt thereof.

26. The method of claim 25 , wherein the β-cyclodextrin is sulfobutylether-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, or a pharmaceutically acceptable salt thereof.

27. The method of claim 26 , wherein the β-cyclodextrin is hydroxypropyl-β-cyclodextrin, or a pharmaceutically acceptable salt thereof.

28. The method of claim 27 , wherein the hydroxypropyl-β-cyclodextrin is 2-hydroxypropyl-β-cyclodextrin, 3-hydroxypropyl-β-cyclodextrin, or a pharmaceutically acceptable salt thereof.

29. The method of claim 26 , wherein the β-cyclodextrin is sulfobutylether-β-cyclodextrin, or a pharmaceutically acceptable salt thereof.

30. The method of claim 29 , wherein the sulfobutylether-β-cyclodextrin is present at a concentration of about 0.01%-30% w/v.

31. The method of claim 30 , wherein the sulfobutylether-β-cyclodextrin is present at a concentration of about 5%-25% w/v.

32. The method of claim 31 , wherein the compound is present at a concentration of about 0.09-0.5% w/v.

33. The method of claim 31 , wherein the compound is present at a concentration of about 0.08-1% w/v.

34. The method of claim 31 , wherein the compound is present at a concentration of about 0.06-5% w/v.

35. The method of claim 31 , wherein the compound is present at a concentration of about 0.1-5% w/v.

36. The method of claim 31 , wherein the compound is present at a concentration of about 0.2-2.0% w/v.

37. The method of claim 31 , wherein the compound is present at a concentration of about 0.1-1.0% w/v.

38. The method of claim 22 , wherein the compound is present at a concentration of 0.08%-1.0% w/v; and the cyclodextrin is sulfobutylether-β-cyclodextrin, wherein the sulfobutylether-β-cyclodextrin is present at 6%-12% w/v.

39. The method of claim 38 , wherein the compound is present at a concentration of about 0.09%-0.5% w/v.

40. The method of claim 38 , wherein the compound is present at a concentration of about 0.1% w/v.

41. The method of claim 39 , wherein the sulfobutylether-β-cyclodextrin is present at a concentration of about 9.5% w/v.

Assignees

• Aldeyra Therapeutics Inc

Inventors

• Brady Todd
• Young Scott
• Kinney William A
• Mandell Kenneth J

Classifications

• A61K31/47

  Quinolines; Isoquinolines · CPC title

• A61K31/435

  having six-membered rings with one nitrogen as the only ring hetero atom · CPC title

• A61K31/41

  having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole · CPC title

• A61P27/00

  Drugs for disorders of the senses · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title