Methods of treating cochlear synaptopathy

1. A method for treating cochlear synaptopathy in a patient in need thereof comprising:

administering to said patient a therapeutically effective amount of a compound selected from the group consisting of (2,2,3,3,3-pentafluoropropyl)-carbamic acid (S)-1-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b,d]azepin-7-ylcarbamoyl) ethyl ester, (2R)-2-fluoro-2-methyl-N—[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N′-(2,2,3,3,3-pentafluoropropyl)malonamide,

or a pharmaceutically acceptable salt of any of the foregoing.

2. The method of claim 1 , comprising administering

or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 , comprising administering

or a pharmaceutically acceptable salt thereof.

4. The method of claim 1 , comprising administering

or a pharmaceutically acceptable salt thereof.

5. The method of claim 1 , comprising administering (2,2,3,3,3-pentafluoropropyl)-carbamic acid (S)-1-(S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl) ethyl ester or a pharmaceutically acceptable salt thereof.

6. The method of claim 1 , comprising administering (2R)-2-fluoro-2-methyl-N—[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N′-(2,2,3,3,3-pentafluoropropyl)malonamide, or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 , wherein said compound, or a pharmaceutically acceptable salt thereof, is administered to or near the round window of the cochlea.

8. The method of claim 1 , wherein said compound, or a pharmaceutically acceptable salt thereof, is administered via the oral route.

9. The method of claim 1 , wherein said compound or a pharmaceutically acceptable salt thereof, is administered intratympanically.

10. The method of claim 7 , comprising administering

or a pharmaceutically acceptable salt thereof.

11. The method of claim 7 , comprising administering

or a pharmaceutically acceptable salt thereof.

12. The method of claim 7 , comprising administering (2,2,3,3,3-pentafluoropropyl)-carbamic acid (S)-1-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b,d]azepin-7-ylcarbamoyl) ethyl ester or a pharmaceutically acceptable salt thereof.

13. The method of claim 7 , comprising administering (2R)-2-fluoro-2-methyl-N—[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N′-(2,2,3,3,3-pentafluoropropyl)malonamide, or a pharmaceutically acceptable salt thereof.

14. The method of claim 8 , comprising administering

or a pharmaceutically acceptable salt thereof.

15. The method of claim 8 , comprising administering

or a pharmaceutically acceptable salt thereof.

16. The method of claim 8 , comprising administering (2,2,3,3,3-pentafluoropropyl)-carbamic acid (S)-1-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b,d]azepin-7-ylcarbamoyl) ethyl ester or a pharmaceutically acceptable salt thereof.

17. The method of claim 8 , comprising administering (2R)-2-fluoro-2-methyl-N—[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N′-(2,2,3,3,3-pentafluoropropyl)malonamide, or a pharmaceutically acceptable salt thereof.

18. The method of claim 9 , comprising administering

or a pharmaceutically acceptable salt thereof.

19. The method of claim 9 comprising administering

or a pharmaceutically acceptable salt thereof.

20. The method of claim 9 , comprising administering (2,2,3,3,3-pentafluoropropyl)-carbamic acid (S)-1-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b,d]azepin-7-ylcarbamoyl) ethyl ester, or a pharmaceutically acceptable salt thereof.

21. The method of claim 9 , comprising administering (2R)-2-fluoro-2-methyl-N—[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N′-(2,2,3,3,3-pentafluoropropyl)malonamide, or a pharmaceutically acceptable salt thereof.

22. The method of claim 1 , wherein said compound, or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical composition comprising a pharmaceutically acceptable aqueous solution comprising:

(A) approximately 15% to 25% by weight (w/w) of poloxamer 407; or

(B) (i) approximately 15% to 25% by weight (w/w) of poloxamer 407 and

(ii) approximately 0.5% to 4% by weight (w/w) of hydroxypropyl methylcellulose having a nominal viscosity of 40-60 cP or grade 80-120 cP; or

(C) (i) approximately 10%-20% by weight (w/w) of poloxamer 407, and

(ii) approximately 0.1%-0.3% by weight (w/w) of Carbopol® 974P; or

(D) (i) approximately 0.5% to 8% by weight (w/w) of a hyaluronic acid; or

(E) (i) approximately 0.5% to 4% by weight (w/w) of a hyaluronic acid, and

(ii) approximately 5% to 20% by volume of polyethylene glycol 400;

wherein said compound is present in approximately 0.01% to about 20% w/v of said aqueous solution.

23. The method of claim 22 wherein said compound is selected from the group consisting of crystalline (2,2,3,3,3-pentafluoropropyl)-carbamic acid (S)-1-((S)-6-oxo-6,7-dihydro-5H-dibenzo [b,d]azepin-7-ylcarbamoyl) ethyl ester and crystalline (2R)-2-fluoro-2-methyl-N—[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N′-(2,2,3,3,3-pentafluoropropyl)malonamide, or a pharmaceutically acceptable salt thereof.

24. The method of claim 22 , wherein said pharmaceutically acceptable aqueous solution comprises approximately 15% to 25% by weight (w/w) of poloxamer 407.

25. The method of claim 22 , wherein said pharmaceutically acceptable aqueous solution comprises approximately 15% to 25% by weight (w/w) of poloxamer 407, and wherein said compound is present in approximately 0.1% to 5% w/v, and is selected from the group consisting of crystalline (2,2,3,3,3-pentafluoropropyl)-carbamic acid (S)-1-((S)-6-oxo-6,7-dihydro-5 H-dibenzo [b,d]azepin-7-ylcarbamoyl) ethyl ester and crystalline (2R)-2-fluoro-2-methyl-N—[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N′-(2,2,3,3,3-pentafluoropropyl)malonamide, or a pharmaceutically acceptable salt of any of the foregoing.

26. The method of claim 7 , comprising administering

or a pharmaceutically acceptable salt thereof.

27. The method of claim 8 , comprising administering

or a pharmaceutically acceptable salt thereof.

28. The method of claim 9 , comprising administering

or a pharmaceutically acceptable salt thereof.