Treprostinil derivatives and compositions and uses thereof
The present disclosure provides treprostinil derivatives that can act as prodrugs of treprostinil. The treprostinil derivatives can be used to treat any conditions responsive to treatment with treprostinil, including pulmonary hypertension, such as pulmonary arterial hypertension.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomer thereof, wherein R 1 and R 2 independently are selected from the group consisting of:
hydrogen,
wherein each moiety that has a stereocenter adjacent to the carbonyl group can have the (R)-stereochemistry or the (S)-stereochemistry or can be racemic at that stereocenter;
with the proviso that both R 1 and R 2 are not hydrogen.
2. The compound of claim 1 , wherein R 1 and R 2 independently are selected from the group consisting of:
hydrogen,
with the proviso that both R 1 and R 2 are not hydrogen.
3. The compound of claim 1 , wherein R 2 is hydrogen and —OR 1 is derivatized.
4. The compound of claim 1 , wherein R 1 is hydrogen and —OR 2 is derivatized.
5. The compound of claim 1 , wherein both —OR 1 and —OR 2 are derivatized, optionally with the same moiety.
6. The compound of claim 5 , wherein both —OR 1 and —OR 2 are derivatized with the same moiety.
7. A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients or carriers and a compound of Formula (I):
or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomer thereof, wherein R 1 and R 2 independently are selected from the group consisting of:
hydrogen,
wherein each moiety that has a stereocenter adjacent to the carbonyl group can have the (R)-stereochemistry or the (S)-stereochemistry or can be racemic at that stereocenter;
with the proviso that both R 1 and R 2 are not hydrogen.
8. The pharmaceutical composition of claim 7 , wherein R 2 is hydrogen and —OR 1 is derivatized.
9. The pharmaceutical composition of claim 7 , wherein R 1 is hydrogen and —OR 2 is derivatized.
10. The pharmaceutical composition of claim 7 , wherein both —OR 1 and —OR 2 are derivatized, optionally with the same moiety.
11. The pharmaceutical composition of claim 10 , wherein both —OR 1 and —OR 2 are derivatized with the same moiety.
12. The pharmaceutical composition of claim 7 , which is formulated for transdermal delivery of the compound.
13. The pharmaceutical composition of claim 12 , which is configured as a transdermal patch.
14. A method of treating a medical condition responsive to treatment with treprostinil, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of Formula (I):
or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomer thereof, wherein R 1 and R 2 independently are selected from the group consisting of:
hydrogen,
wherein each moiety that has a stereocenter adjacent to the carbonyl group can have the (R)-stereochemistry or the (S)-stereochemistry or can be racemic at that stereocenter;
with the proviso that both R 1 and R 2 are not hydrogen.
15. The method of claim 14 , wherein R 2 is hydrogen and —OR 1 is derivatized.
16. The method of claim 14 , wherein R 1 is hydrogen and —OR 2 is derivatized.
17. The method of claim 14 , wherein both —OR 1 and —OR 2 are derivatized, optionally with the same moiety.
18. The method of claim 17 , wherein both —OR 1 and —OR 2 are derivatized with the same moiety.
19. The method of claim 14 , wherein the medical condition is selected from the group consisting of pulmonary hypertension, pulmonary fibrosis, ischemic diseases, peripheral vascular disease, peripheral ischemic lesions on the skin, critical limb ischemia, heart failure, atherogenesis, inflammatory diseases, diabetic neuropathic foot ulcer, kidney malfunction and failure, tumors, cancers, and pain associated with each of the preceding conditions.
20. The method of claim 19 , wherein the medical condition is pulmonary hypertension.
21. The method of claim 20 , wherein the medical condition is pulmonary arterial hypertension.
22. The method of claim 14 , wherein the compound is administered topically.
23. The method of claim 22 , wherein the compound is administered transdermally or pulmonarily by oral inhalation.
24. The method of claim 14 , wherein the compound is administered orally.
25. The method of claim 14 , wherein the compound is administered parenterally.
26. The method of claim 25 , wherein the compound is administered subcutaneously or intravenously.
27. The method of claim 14 , further comprising administering an additional therapeutic agent.
28. The method of claim 27 , wherein the additional therapeutic agent comprises a vasoactive agent, a diuretic, an anticoagulant or a cardiac glycoside, or any combination thereof.
29. The method of claim 14 , wherein R 1 and R 2 independently are selected from the group consisting of:
hydrogen,
with the proviso that both R 1 and R 2 are not hydrogen.
30. The pharmaceutical composition of claim 7 , wherein R 1 and R 2 independently are selected from the group consisting of:
hydrogen,
with the proviso that both R 1 and R 2 are not hydrogen.