Sialic acid analogs

• US 9,221,858 B2
• Filed: 08/15/2014
• Issued: 12/29/2015
• 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 J
• Application Number:
  US14/461,295
• Publication Number:
  US 20150038693A1
• Time in Patent Office: 501 Days
• Field of Search: None
• US Class Current: 1/1
• 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 (Ia):

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

3. The compound of claim 1, wherein at least one of R² and R⁴ is hydrogen.

4. The compound of claim 3, wherein R² and R⁴ are hydrogen.

5. The compound of claim 1, wherein R⁶ is hydrogen.

6. The compound of claim 1, wherein

m is 1;

R^8a is hydrogen; and

R^9a is hydrogen or lower alkyl.

7. The compound of claim 1, wherein

R¹ is selected from structural formula (a), (b), (c), and (f);

or a nucleoside phosphate moiety;

R², R⁴, and R⁶ are hydrogen.

8. The compound of claim 1, wherein R¹ is structural formula (a);

and at least one of L¹ and L² is —

O—

or NR^10a.

9. The compound of claim 8, wherein L¹ and L² are —

O—

.

10. The compound of claim 8, wherein R^1a and R^2a are independently hydrogen, optionally substituted lower alkyl, or optionally substituted aryl.

11. The compound of claim 8, wherein R², R⁴, and R⁶ are hydrogen.

12. The compound of claim 1, wherein

R¹ is structural formula (f);

R^3a, together with the carboxyl moiety to which it is attached, form a peptidyl or dipeptidyl group;

the peptidyl is derived from naturally occurring amino acid or non-naturally occurring amino acid; and

the dipeptidyl group is derived from naturally occurring amino acid, non-naturally occurring amino acid, or a combination thereof.

13. The compound of claim 12, wherein the peptidyl 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, and Valine.

14. The compound of claim 12, 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.

15. The compound of claim 12, wherein

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

16. The compound of claim 12, wherein

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

17. The compound of claim 1, wherein

R¹ is a nucleoside phosphate moiety;

and

R², R⁴, and R⁶ are hydrogen.

18. The compound of claim 17, wherein the nucleoside phosphate moiety is an adenosine monophosphate (AMP) moiety or an adenosine triphosphate (ATP) moiety.

19. The compound of claim 1,

wherein

R¹, R², and R⁴ are hydrogen;

and

R⁶ is structural formula (d), (e), or (f).

20. The compound of claim 19, wherein R⁶ is structural formula (f);

and R^3a is optionally substituted C1 to C12 alkyl.

21. The compound of claim 19, wherein R⁶ is structural formula (f);

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

22. The compound of claim 21, wherein the peptidyl or dipeptidyl group is derived from naturally occurring amino acid, non-naturally occurring amino acid, or a combination thereof.

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

24. 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.

25. 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.

26. The sustained release pharmaceutical composition of claim 24, comprising a matrix which comprises

a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof;

and

one or more release rate controlling polymers.

27. The sustained release pharmaceutical composition of claim 26, wherein the matrix is in form of a core or a layer over a core.

28. The sustained release pharmaceutical composition of claim 24, comprising a release rate controlling membrane disposed over:

a pull layer comprising a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, and

an osmotic push layer;

wherein the release rate controlling membrane has an orifice immediately adjacent to the pull layer.

29. The sustained release pharmaceutical composition of claim 28, wherein the pull layer further comprises a release rate controlling polymer.

30. The sustained release pharmaceutical composition of claim 24, comprising one or more particles, and each of the particles comprises

an active core comprising a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof;

and

a release rate controlling polymer disposed over the core.

31. The sustained release pharmaceutical composition of claim 24, comprising one or more particles, and each of the particles comprises

an inert core,

an active layer comprising a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof disposed over the inert core, and

a release rate controlling polymer disposed over the active layer.

32. 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.

33. 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.

34. The method of claim 32, wherein the sialic acid deficiency is a myopathy associated with sialic acid deficiency.

35. The method of claim 34, wherein the myopathy associated with sialic acid deficiency is Hereditary Inclusion Body Myopathy (HIBM), Nonaka myopathy, and/or Distal Myopathy with Rimmed Vacuoles (DMRV).