Prostacyclin compounds, compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10010518-B2
Application number	US-201615154631-A
Country	US
Kind code	B2
Filing date	May 13, 2016
Priority date	Oct 25, 2013
Publication date	Jul 3, 2018
Grant date	Jul 3, 2018

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 method of treating pulmonary hypertension (PH) in a patient in need thereof comprising administering to the patient via pulmonary administration, a composition comprising an effective amount of a 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 method of claim 1 , wherein the patient is a World Health Organization (WHO) Group I PH patient.

3. The method of claim 1 , wherein the patient is a WHO Group II PH patient.

4. The method of claim 1 , wherein the patient is a WHO Group III PH patient.

5. The method of claim 1 , wherein the patient is a WHO Group IV PH patient.

6. The method of claim 1 , wherein the patient is a WHO Group V PH patient.

7. The method of claim 1 , wherein pulmonary administration comprises administration via a metered dose inhaler, a dry powder inhaler or a nebulizer.

8. The method of claim 1 , wherein the pulmonary hypertension is pulmonary arterial hypertension (PAH).

9. The method of claim 8 , wherein the patient is a class I PAH patient, as categorized by the New York Heart Association (NYHA).

10. The method of claim 8 , wherein the patient is a class II PAH patient, as categorized by the New York Heart Association (NYHA).

11. The method of claim 8 , wherein the patient is a class III PAH patient, as categorized by the New York Heart Association (NYHA).

12. The method of claim 8 , wherein the patient is a class IV PAH patient, as categorized by the New York Heart Association (NYHA).

13. The method of claim 1 , wherein the pulmonary hypertension is chronic thromboembolic pulmonary hypertension.

14. The method of claim 1 , wherein the pulmonary hypertension is portopulmonary hypertension.

15. The method of claim 1 , wherein the pulmonary hypertension is idiopathic pulmonary arterial hypertension.

16. The method of claim 1 , wherein the pulmonary hypertension is familial pulmonary arterial hypertension.

17. The method of claim 1 , wherein the effective amount of the compound of Formula (II), or the pharmaceutically acceptable salt thereof, is administered once daily.

18. The method of claim 1 , wherein the effective amount of the compound of Formula (II), or the pharmaceutically acceptable salt thereof, is administered two or more times daily.

19. The method of claim 1 , wherein n is 1.

20. The method of claim 1 , wherein R 2 is hexadecyl.

21. The method of claim 20 , wherein n is 1.

22. The method of claim 1 , wherein n is 1, R 2 is hexadecyl and pulmonary administration comprises administration via a nebulizer.

23. The method of claim 22 , wherein the nebulizer is a vibrating mesh nebulizer.

24. The method of claim 22 , wherein the pulmonary hypertension is pulmonary arterial hypertension (PAH).

25. The method of claim 23 , wherein the pulmonary hypertension is pulmonary arterial hypertension (PAH).

26. The method of claim 1 , wherein n is 1, R 2 is hexadecyl and pulmonary administration comprises administration via a dry powder inhaler.

27. The method of claim 26 , wherein the pulmonary hypertension is pulmonary arterial hypertension (PAH).

28. The method of claim 1 , wherein the composition further comprises a lipid- polyethylene glycol (PEG) conjugate.

29. The method of claim 28 , wherein the PEG is PEG400, PEG500, PEG 1000, PEG2000, PEG3000, PEG4000 or PEG5000.

30. The method of claim 29 , wherein the PEG is PEG2000.

31. The method of claim 28 , wherein the lipid is cholesterol.

32. The method of claim 28 , wherein the lipid is a phospholipid.

33. The method of claim 28 , wherein the lipid is distearoyl phosphatidylethanolamine (DSPE), dimyristoyl phosphoethanolamine (DMPE) or distearoyl glycerol (DSG).

34. The method of claim 28 , wherein the lipid-PEG conjugate is cholesterol-PEG2000, DSPE-PEG 1000, DSPE-PEG 2000 or DSG-PEG2000.

35. The method of claim 1 , wherein the composition further comprises a hydrophobic additive.

36. The method of claim 35 , wherein the hydrophobic additive is a hydrocarbon, a terpene, a hydrophobic lipid, alkyl ester, cholesteryl ester or an alkyl-alyceride.

37. The method of claim 35 , wherein the hydrophobic additive is a terpene.

38. The method of claim 37 , wherein the terpene is squalane.

39. The method of claim 21 , wherein the composition further comprises a lipid- polyethylene glycol (PEG) conjugate.

40. The method of claim 39 , wherein the PEG is PEG400, PEG500, PEG 1000, PEG2000, PEG3000, PEG4000 or PEG5000.

41. The method of claim 40 , wherein the PEG is PEG2000.

42. The method of claim 40 , wherein the lipid is cholesterol.

43. The method of claim 40 , wherein the lipid is a phospholipid.

44. The method of claim 40 , wherein the lipid is distearoyl phosphatidylethanolamine (DSPE), dimyristoyl phosphoethanolamine (DMPE) or distearoyl glycerol (DSG).

45. The method of claim 39 , wherein the lipid-PEG conjugate is cholesterol-PEG2000, DSPE-PEG 1000, DSPE-PEG 2000 or DSG-PEG2000.

46. The method of claim 45 , wherein the composition further comprises a hydrophobic additive.

47. The method of claim 46 , wherein the hydrophobic additive is a terpene.

48. The method of claim 47 , wherein the terpene is squalane.

49. The method of claim 26 , wherein the composition further comprises lipid-polyethylene glycol(PEG) conjugate.

50. The method of claim 44 , wherein the lipid is distearoyl phosphatidylethanolamine (DSPE).

51. The method of claim 49 , wherein the PEG is PEG400, PEG500, PEG 1000, PEG2000, PEG3000, PEG4000 or PEG5000.

52. The method of claim 49 , wherein the lipid is cholesterol.

53. The method of claim 49 , wherein the lipid is a phospholipid.

54. The method of claim 50 , wherein the PEG is PEG2000.

55. The method of claim 53 , wherein the lipid is distearoyl phosphatidylethanolamine (DSPE), dimyristoyl phosphoethanolamine (DMPE) or distearoyl glycerol (DSG).

56. The method of claim 49 , wherein the lipid-PEG conjugate is cholesterol-PEG2000, DSPE-PEG 1000, DSPE-PEG 2000 or DSG-PEG2000.

57. The method of claim 55 , wherein the lipid-PEG conjugate is DSPE-PEG 2000.

58. The method of claim 49 , wherein the composition further comprises a hydrophobic additive.

59. The method of claim 50 , wherein the composition further comprises a hydrophobic additive.

60. The method of claim 51 , wherein the composition further comprises a hydrophobic additive.

61. The method of claim 52 , wherein the composition further comprises a hydrophobic additive.

62. The method of claim 53 , wherein the composition further com

Assignees

• Insmed Inc

Inventors

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

Classifications

• A61K31/5585

  having five-membered rings containing oxygen as the only ring hetero atom, e.g. prostacyclin · CPC title

• A61K47/14

  Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters · CPC title

• C07C69/753

  of polycyclic acids · CPC title

• A61K31/225 Primary

  Polycarboxylic acids · CPC title

• A61K47/06

  Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite · CPC title