Prostacyclin compounds, compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9469600-B2
Application number	US-201414523538-A
Country	US
Kind code	B2
Filing date	Oct 24, 2014
Priority date	Oct 25, 2013
Publication date	Oct 18, 2016
Grant date	Oct 18, 2016

Abstract

Prostacyclin compounds and compositions comprising the same are provided herein. Specifically, prostacyclin compounds comprising treprostinil covalently linked to a linear C 5 -C 18 alkyl, branched C 5 -C 18 alkyl, linear C 2 -C 18 alkenyl, branched C 3 -C 18 alkenyl, aryl, aryl-C 1 -C 18 alkyl or an amino acid or a peptide (e.g., dipeptide, tripeptide, tetrapeptide) are described. The linkage, in one embodiment, is via a carbamate, amide or ester bond. Prostacyclin compounds provided herein can also include at least one hydrogen atom substituted with at least one deuterium atom. Methods for treating pulmonary hypertension (e.g., pulmonary arterial hypertension) and portopulmonary hypertension are also provided.

First claim

The invention claimed is:

1. A composition comprising a PEGylated lipid and a prostacyclin compound of Formula (II), or a pharmaceutically acceptable salt thereof:

wherein R 1 is O;
R 2 is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl; and
n is an integer from 0 to 5.

2. The composition of claim 1 , wherein n is 0 or 1.

3. The composition of claim 1 , wherein n is 0.

4. The composition of claim 1 , wherein n is 1.

5. The composition of claim 1 , wherein R 2 is hexadecyl and n is 1.

6. The composition of claim 1 , wherein the PEGylated lipid comprises PEG400, PEG500, PEG1000, PEG2000, PEG3000, PEG4000 or PEG5000.

7. The composition of claim 1 , wherein the PEGylated lipid comprises PEG2000.

8. The composition of claim 1 , wherein the PEGylated lipid comprises cholesterol.

9. The composition of claim 1 , wherein the PEGylated lipid comprises a phospholipid.

10. The composition of claim 1 , wherein the PEGylated lipid comprises phosphatidylethanolamine (DSPE), dirnyristoyl phosphoethanolamine (DMPE) or distearoyl glycerol (DSG).

11. The composition of claim 1 , wherein the PEGylated lipid is cholesterol-PEG2000, DSPE-PEG1000 or DSG-PEG2000.

12. The composition of claim 1 , further comprising a hydrophobic additive.

13. The composition of claim 12 , wherein the hydrophobic additive is a hydrocarbon, a terpene or a hydrophobic lipid, alkyl ester, cholesteryl ester or an alkyl-glyceride.

14. The composition of claim 13 , wherein the hydrophobic additive is a terpene.

15. The composition of claim 14 , wherein the terpene is squalane.

16. The composition of claim 4 , wherein the PEGylated lipid comprises PEG400, PEG500, PEG1000, PEG2000, PEG3000, PEG4000 or PEG5000.

17. The composition of claim 4 , wherein the PEGylated lipid comprises PEG2000.

18. The composition of claim 4 , wherein the PEGylated lipid comprises cholesterol.

19. The composition of claim 4 , wherein the PEGylated lipid comprises a phospholipid.

20. The composition of claim 4 , wherein the PEGylated lipid comprises phosphatidylethanolamine (DSPE), dimyristoyl phosphoethanolamine (DMPE) or distearoyl glycerol (DSG).

21. The composition of claim 4 , PEGylated lipid is cholesterol-PEG2000, DSPE-PEG1000 or DSG-PEG2000.

22. The composition of claim 4 , further comprising a hydrophobic additive.

23. The composition of claim 22 , wherein the hydrophobic additive is a hydrocarbon, a terpene or a hydrophobic lipid, alkyl ester, cholesteryl ester or an alkyl-glyceride.

24. The composition of claim 23 , wherein the hydrophobic additive is a terpene.

25. The composition of claim 24 , wherein terpene is squalane.

26. The composition of claim 25 , wherein the PEGylated lipid is cholesterol-PEG2000.

27. The composition of claim 25 , wherein the PEGylated lipid is DSPE-PEG1000.

28. The composition of claim 25 , wherein the PEGylated lipid is DSG-PEG2000.

29. The composition of claim 10 , wherein R 2 is hexadecyl.

30. The composition of claim 11 , wherein R 2 is hexadecyl.

31. The composition of claim 12 , wherein R 2 is hexadecyl.

32. The composition of claim 13 , wherein R 2 is hexadecyl.

33. The composition of claim 14 , wherein R 2 is hexadecyl.

34. The composition of claim 15 , wherein R 2 is hexadecyl.

35. The composition of claim 16 , wherein R 2 is hexadecyl.

36. The composition of claim 17 , wherein R 2 is hexadecyl.

37. The composition of claim 18 , wherein R 2 is hexadecyl.

38. The composition of claim 19 , wherein R 2 is hexadecyl.

39. The composition of claim 20 , wherein R 2 is hexadecyl.

40. The composition of claim 21 , wherein R 2 is hexadecyl.

41. The composition of claim 22 , wherein R 2 is hexadecyl.

42. The composition of claim 23 , wherein R 2 is hexadecyl.

43. The composition of claim 24 , wherein R 2 is hexadecyl.

44. The composition of claim 25 , wherein R 2 is hexadecyl.

45. The composition of claim 26 , wherein R 2 is hexadecyl.

46. The composition of claim 27 , wherein R 2 is hexadecyl.

47. The composition of claim 28 , wherein R 2 is hexadecyl.

Assignees

• Insmed Inc

Inventors

• Malinin Vladimir
• Perkins Walter
• Leifer Franziska
• Konicek Donna
• Li Zhili
• Plaunt Adam

Classifications

• C07C69/736

  the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring · CPC title

• C07C2601/18

  with a ring being at least seven-membered · CPC title

• C07C69/712

  the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07C2603/14

  Benz[f]indenes; Hydrogenated benz[f]indenes · CPC title