Compounds and methods for delivery of prostacyclin analogs

Patent metadata

Field	Value
Publication number	US-10947177-B2
Application number	US-201916519491-A
Country	US
Kind code	B2
Filing date	Jul 23, 2019
Priority date	May 22, 2003
Publication date	Mar 16, 2021
Grant date	Mar 16, 2021

Abstract

This invention pertains generally to prostacyclin formulations and methods for their use in promoting vasodilation, inhibiting platelet aggregation and thrombus formation, stimulating thrombolysis, inhibiting cell proliferation (including vascular remodeling), providing cytoprotection, preventing atherogenesis and inducing angiogenesis.

First claim

What is claimed is:

1. An ester compound of formula:

wherein R 1 and R 2 are H and R 3 is selected from the group consisting of phosphate and groups in which OR 3 forms an ester of an amino acid or a protein;
an enantiomer of the compound;
or a pharmaceutically acceptable salt of the compound.

2. The compound of claim 1 , wherein OR 3 forms an ester of an amino acid or a protein.

3. The compound of claim 1 , wherein OR 3 forms an ester of an amino acid or a dipeptide.

4. The compound of claim 1 , wherein OR 3 forms an ester of an amino acid.

5. The compound of claim 1 , wherein OR 3 forms an ester of an L-isomer of an amino acid.

6. The compound of claim 1 , wherein OR 3 forms an ester of a D-isomer of an amino acid.

7. The compound of claim 1 , wherein OR 3 forms an ester of an amino acid selected from the group consisting of proline, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, valine, histidine, tryptophan, and tyrosine.

8. The compound of claim 1 , wherein OR 3 forms an ester of an L-isomer of an amino acid selected from the group consisting of proline, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, valine, histidine, tryptophan, and tyrosine.

9. The compound of claim 1 , wherein OR 3 forms an ester of an amino acid selected from the group consisting of alanine, glycine, and valine.

10. The compound of claim 1 , wherein OR 3 forms an ester of an L-isomer of an amino acid selected from the group consisting of alanine, glycine, and valine.

11. The compound of claim 1 , wherein OR 3 forms an ester of valine.

12. The compound of claim 1 , wherein OR 3 forms an ester of L-valine.

13. The compound of claim 1 , wherein OR 3 forms an ester of alanine.

14. The compound of claim 1 , wherein OR 3 forms an ester of L-alanine.

15. The compound of claim 1 , wherein OR 3 forms an ester of glycine.

16. The compound of claim 1 , wherein OR 3 forms an ester of L-glycine.

17. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

18. A method of treating pulmonary hypertension comprising administering to a patient in need thereof a pharmaceutically effective amount of the compound of claim 1 , wherein the compound converts to treprostinil upon said administration.

19. The method of claim 18 , wherein the compound is not therapeutically active before being converted to treprostinil.

20. The method of claim 18 , wherein the compound is administered by oral administration.

21. The method of claim 18 , wherein the compound is administered by ingestion.

22. The method of claim 18 , wherein the compound is administered by transmucosal administration.

23. The method of claim 18 , wherein the compound is administered by parenteral administration.

24. The method of claim 18 , wherein the compound is administered by subcutaneous administration.

25. The method of claim 18 , wherein the compound is administered by injection.

26. The method of claim 25 , wherein the injection is a bolus injection.

27. The method of claim 25 , wherein the injection is continuous infusion.

28. The method of claim 25 , wherein the injection is an intravenous injection.

29. The method of claim 18 , wherein the compound is administered by duodenal administration.

30. The compound of claim 1 , wherein OR 3 forms an ester of proline.

31. The compound of claim 1 , wherein OR 3 forms an ester of L-proline.

32. The method of claim 18 , wherein OR 3 forms an ester of an amino acid or a protein.

33. The method of claim 18 , wherein OR 3 forms an ester of an amino acid or a dipeptide.

34. The method of claim 18 , wherein OR 3 forms an ester of an amino acid.

35. The method of claim 18 , wherein OR 3 forms an ester of an L-isomer of an amino acid.

36. The method of claim 18 , wherein OR 3 forms an ester of a D-isomer of an amino acid.

37. The method of claim 18 , wherein OR 3 forms an ester of an amino acid selected from the group consisting of proline, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, valine, histidine, tryptophan, and tyrosine.

38. The method of claim 18 , wherein OR 3 forms an ester of an L-isomer of an amino acid selected from the group consisting of proline, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, valine, histidine, tryptophan, and tyrosine.

39. The method of claim 18 , wherein OR 3 forms an ester of an amino acid selected from the group consisting of alanine, glycine, and valine.

40. The method of claim 18 , wherein OR 3 forms an ester of an L-isomer of an amino acid selected from the group consisting of alanine, glycine, and valine.

41. The method of claim 18 , wherein OR 3 forms an ester of valine.

42. The method of claim 18 , wherein OR 3 forms an ester of L-valine.

43. The method of claim 18 , wherein OR 3 forms an ester of alanine.

44. The method of claim 18 , wherein OR 3 forms an ester of L-alanine.

45. The method of claim 18 , wherein OR 3 forms an ester of glycine.

46. The method of claim 18 , wherein OR 3 forms an ester of L-glycine.

47. The method of claim 18 , wherein OR 3 forms an ester of proline.

48. The method of claim 18 , wherein OR 3 forms an ester of L-proline.

Assignees

• United Therapeutics Corp

Inventors

• Phares Ken

Classifications

• A61K31/192

  having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid  {(cannabinoids A61K31/658)} · CPC title

• C07C59/70 Primary

  Ethers of hydroxy-acetic acid {, e.g. substitutes on the ring} · CPC title

• C07C405/00 Primary

  Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins {; Analogues or derivatives thereof} · CPC title

• A61K31/19

  Carboxylic acids, e.g. valproic acid (salicylic acid A61K31/60) · CPC title

• A61K31/557

  Eicosanoids, e.g. leukotrienes {or prostaglandins} · CPC title