Sialic acid analogs

• US 10,065,981 B2
• Filed: 11/18/2015
• Issued: 09/04/2018
• Est. Priority Date: 10/24/2011
• Status: Active Grant

• Current Assignee: Ultragenyx Pharmaceutical Inc.
• Original Assignee: Ultragenyx Pharmaceutical Inc.
• Inventors: Kakkis, Emil, Jungles, Steven, Zhao, He
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): Al-Awadi, Danah
• Application Number:
  US14/944,779
• Publication Number:
  US 20160297846A1
• Time in Patent Office: 1,021 Days
• Field of Search: None
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: C07D 493/08 Bridged systems
• CPC Class Codes: C07H 13/04 having the esterifying carboxyl radicals attached to acyclic carbon atoms
• CPC Class Codes: C07H 13/10 having the esterifying carboxyl radicals directly attached to heterocyclic rings
• CPC Class Codes: C07H 7/02 Acyclic radicals
• CPC Class Codes: C07H 7/027 Keto-aldonic acids

Abstract

The present invention provides sialic acid analogs and their compositions useful for the treatment of sialic acid deficiencies.

Claims

1. A compound having structural Formula (I):

2. The compound of claim 1, wherein structural Formula (I) is represented by structural Formula (II), and structural Formula (II) is represented by structural Formula (IIa):

3. The compound of claim 1, wherein the monopeptidyl group is derived from amino acids selected from the group consisting of Alanine, Arginine, Asparagine, Aspartic acid, Cysteine, Glutamic acid, Glutamine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Proline, Serine, Threonine, Tryptophan, Tyrosine, and Valine.

4. The compound of claim 1, wherein the dipeptidyl group is derived from amino acids selected from the group consisting of Alanine, Arginine, Asparagine, Aspartic acid, Cysteine, Glutamic acid, Glutamine, Glycine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Proline, Serine, Threonine, Tryptophan, Tyrosine, Valine, and a combination thereof.

5. The compound of claim 1, wherein

R¹ is structural formula (f), wherein the monopeptidyl group is represented by structural formula (d) or (e);

6. The compound of claim 1, wherein

R¹ is structural formula (f), wherein the dipeptidyl group is represented by structural Formula (h) or (i):

7. A compound having structural Formula (III):

8. The compound of claim 7, wherein structural Formula (III) is represented by structural Formula (IV):

9. A compound having a structural Formula (Ia):

10. The compound of claim 9, wherein R¹, R², and R⁴ are hydrogen and R⁶ is structural formula (f);

and R^3a, together with the carboxyl moiety to which it is attached, form a monopeptidyl or dipeptidyl group.

11. The compound of claim 10, wherein the monopeptidyl or dipeptidyl group is derived from naturally occurring amino acid, non-naturally occurring amino acid, or a combination thereof.

12. The compound of claim 1, which is represented by structural Formula (V):

13. A compound selected from the group consisting of

14. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

15. A sustained release pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the release of the compound is over a period of about four hours or more.

16. A sustained release pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the pharmacological effect from the compound lasts about four hours or more upon administration of the composition.

17. A sustained release pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof;

wherein the composition, upon administration, provides a therapeutically effective amount of the compound for about 4 hours or more.

18. A method for treating a sialic acid deficiency in a patient in need thereof comprising administering an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof.

19. A method for treating a sialic acid deficiency in a patient in need thereof comprising administering a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof;

wherein upon administration, the compound, or a pharmaceutically acceptable salt or solvate thereof, continuously provides a therapeutically effective amount of sialic acid for about 4 hours to about 24 hours.

20. The compound of claim 9, wherein at least one of R² and R⁴ are hydrogen.

21. The compound of claim 9, wherein R⁶ is hydrogen.

22. The compound of claim 9, wherein

m is 1;

R^8a is hydrogen; and

R^9a is hydrogen or lower alkyl.

23. The compound of claim 9, wherein:

R¹ is hydrogen or structural formula (f);

R² and R⁴ are hydrogen;

R⁶ is structural formula (f); and

R^3a is optionally substituted C₅-C₂₀ alkyl.

24. The compound of claim 23, wherein R¹, R² and R⁴ are hydrogen.

25. The compound of claim 9, wherein structural Formula (II) is represented by structural Formula (IIa):

26. A pharmaceutical composition comprising a compound of claim 9, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

27. A sustained release pharmaceutical composition comprising a compound of claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein the release of the compound is over a period of about four hours or more.

28. A sustained release pharmaceutical composition comprising a compound of claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein the pharmacological effect from the compound lasts about four hours or more upon administration of the composition.

29. A sustained release pharmaceutical composition comprising a compound of claim 9, or a pharmaceutically acceptable salt or solvate thereof;

wherein the composition, upon administration, provides a therapeutically effective amount of the compound for about 4 hours or more.

30. A method for treating a sialic acid deficiency in a patient in need thereof comprising administering an effective amount of a compound of claim 9, or a pharmaceutically acceptable salt or solvate thereof.

31. A method for treating a sialic acid deficiency in a patient in need thereof comprising administering a compound of claim 9, or a pharmaceutically acceptable salt or solvate thereof wherein upon administration, the compound, or a pharmaceutically acceptable salt or solvate thereof, continuously provides a therapeutically effective amount of sialic acid for about 4 hours to about 24 hours.

32. The method of claim 31, wherein sialic acid deficiency is myopathy associated with sialic acid deficiency.

33. The method of claim 32, wherein the myopathy associated with sialic acid deficiency is Hereditary Inclusion Body Myopathy (HIBM), Nonaka myopathy, and/or Distal Myopathy with Rimmed Vacuoles (DMRV).