Compounds and methods for delivery of prostacyclin analogs

Patent metadata

Field	Value
Publication number	US-9878972-B2
Application number	US-201615239014-A
Country	US
Kind code	B2
Filing date	Aug 17, 2016
Priority date	May 22, 2003
Publication date	Jan 30, 2018
Grant date	Jan 30, 2018

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. A compound having structure I:

wherein R 1 is independently selected from the group consisting of H, and groups wherein OR 1 are substituted or unsubstituted glycolamide esters, and
wherein R 2 and R 3 may be the same or different and are independently selected from the group consisting of H, phosphate and groups wherein OR 2 and OR 3 form esters of amino acids, with the proviso that all of R 1 , R 2 , and R 3 are not H;
an enantiomer of the compound; or
a pharmaceutically acceptable salt of the compound.

2. The compound of claim 1 , wherein R 1 is H.

3. The compound of claim 2 , wherein at least one of R 2 and R 3 is phosphate.

4. The compound of claim 3 , wherein each of R 2 and R 3 is phosphate.

5. The compound of claim 2 , wherein R 2 is H and R 3 is phosphate.

6. The compound of claim 2 , wherein R 2 is phosphate and R 3 is H.

7. The compound of claim 2 , wherein at least one of OR 2 and OR 3 forms an ester of an amino acid.

8. The compound of claim 7 , wherein OR 2 forms an ester of an amino acid and R 3 is H.

9. The compound of claim 7 , wherein R 2 is H and OR 3 forms an ester of an amino acid.

10. A pharmaceutical composition comprising:
(A) a compound having structure I:

wherein R 1 is independently selected from the group consisting of H, substituted and unsubstituted benzyl groups, and groups wherein OR 1 are substituted or unsubstituted glycolamide esters, and
wherein R 2 and R 3 may be the same or different and are independently selected from the group consisting of H, phosphate and groups wherein OR 2 and OR 3 form esters of amino acids, with the proviso that all of R 1 , R 2 , and R 3 are not H;
an enantiomer of the compound; or
a pharmaceutically acceptable salt of the compound; and
(B) a pharmaceutically acceptable excipient.

11. The composition of claim 10 , wherein R 1 is H.

12. The composition of claim 11 , wherein at least one of R 2 and R 3 is phosphate.

13. The composition of claim 12 , wherein each of R 2 and R 3 is phosphate.

14. The composition of claim 11 , wherein R 2 is H and R 3 is phosphate.

15. The composition of claim 11 , wherein R 2 is phosphate and R 3 is H.

16. The composition of claim 11 , wherein at least one of OR 2 and OR 3 forms an ester of an amino acid.

17. The compound of claim 16 , wherein OR 2 forms an ester of an amino acid and R 3 is H.

18. The compound of claim 16 , wherein R 2 is H and OR 3 forms an ester of an amino acid.

19. A method of treating pulmonary hypertension in a human subject comprising administering to a subject in need thereof an effective amount of a compound having structure I:

wherein R 1 is independently selected from the group consisting of H, substituted or unsubstituted alkyl groups, substituted and unsubstituted benzyl groups, and groups wherein OR 1 are substituted or unsubstituted glycolamide esters, and
wherein R 2 and R 3 may be the same or different and are independently selected from the group consisting of H, phosphate and groups wherein OR 2 and OR 3 form esters of amino acids, with the proviso that all of R 1 , R 2 and R 3 are not H;
an enantiomer of the compound; or
a pharmaceutically acceptable salt of the compound.

20. The method of claim 19 , wherein R 1 is H.

21. The method of claim 20 , wherein at least one of R 2 and R 3 is phosphate.

22. The method of claim 21 , wherein each of R 2 and R 3 is phosphate.

23. The method of claim 20 , wherein R 2 is H and R 3 is phosphate.

24. The method of claim 20 , wherein R 2 is phosphate and R 3 is H.

25. The method of claim 20 , wherein at least one of OR 2 and OR 3 forms an ester of an amino acid.

26. The method of claim 25 , wherein OR 2 forms an ester of an amino acid and R 3 is H.

27. The method of claim 25 , wherein R 2 is H and OR 3 forms an ester of an amino acid.

28. The method of claim 19 , wherein said administering is performed orally.

29. The method of claim 19 , wherein said administering is performed subcutaneously.

30. The method of claim 19 , wherein both R 2 and R 3 are H.

31. The method of claim 30 , wherein R 1 is a substituted or unsubstituted alkyl group.

32. The method of claim 31 , wherein R 1 is a substituted alkyl group.

33. The method of claim 32 , wherein R 1 is an alkyl group in which one or more bonds to one or more carbon or one or more hydrogen atoms is replaced by a bond to an oxygen atom in a carbonyl, carboxyl or ester group.

34. The method of claim 33 , wherein R 1 is an alkyl group in which one or more bonds to one or more carbon or one or more hydrogen atoms is replaced by a bond to an oxygen atom in a carboxyl group.

Assignees

• United Therapeutics Corp

Inventors

• Phares Ken
• Mottola David

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P9/08

  Vasodilators for multiple indications · CPC title