Prodrugs of treprosiinil
Provided are novel treprostinil based compounds, methods of treatment using the same, and their methods of making.
1. A compound of formula 5a or 5b:
or a pharmaceutically acceptable salt thereof,
wherein R 5 is H or a polymeric carrier.
2. The compound of claim 1 , wherein the compound is the compound of formula 5a.
3. The compound of claim 1 , wherein the compound is the compound of formula 5b.
4. The compound of claim 1 , wherein R 5 is H.
5. The compound of claim 1 , wherein R 5 is a polymeric carrier.
6. A pharmaceutically acceptable batch comprising the compound of claim 1 having a purity of at least 90%.
7. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
8. A method of making an FDKP-treprostinil compound comprising:
i) double-protecting treprostinil (1)
to form a double-protected treprostinil moiety (2)
wherein R 1 is a carboxylic acid protecting group and wherein a) R 2 is H and R 3 is a hydroxyl protecting group or b) R 2 is a hydroxyl protecting group and R 3 is H;
ii) reacting the double-protected treprostinil moiety with a compound of formula (3)
wherein R 4 is H,
to form a double-protected FDKP-treprostinil compound having formula (4a) or (4b); and
and
iii) deprotecting the double-protected FDKP-treprostinil compound to form an FDKP-treprostinil compound having formula (5a) or (5b)
9. The method of claim 8 , wherein R 1 is a silyl carboxylic acid protecting group or a substituted or unsubstituted benzyl carboxylic acid protecting group.
10. The method of claim 9 , wherein R 1 is a silyl carboxylic acid protecting group selected from trimethylsilyl, triethylsilyl, tri-iso-propylsilyloxymethyl, triisopropyl silyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, and phenyldimethylsilyl.
11. The method of claim 9 , wherein R 1 is a substituted or unsubstituted benzyl carboxylic acid protecting group.
12. The method of claim 8 , wherein the R 2 is H and R 3 is a hydroxyl protecting group, the double protected FDKP-treprostinil compound has formula (4b) and the FDKP-treprostinil compound has formula (5b).
13. The method of claim 8 , wherein the R 3 is H and R 2 is a hydroxyl protecting group, the double protected FDKP-treprostinil compound has formula (4a) and the FDKP-treprostinil compound has formula (5a).
14. The method of claim 8 , wherein said reacting the double protected treprostinil moiety with the compound of formula (3) was performed in the presence of a carbodiimide and a nucleophilic catalyst in a polar solvent.
15. The method of claim 14 , wherein said reacting is performed in the presence of an organic base.
16. The method of claim 11 , wherein the said deprotecting comprises deprotecting the double protected FDKP-treprostinil compound to form a single protected FDKP-treprostinil compound of formula (6a) or (6b):
17. The method of claim 16 , wherein deprotecting the double protected FDKP-treprostinil compound to form the single protected FDKP-treprostinil compound is performed in the presence of a chemoselective benzyl cleavage agent.
18. The method of claim 8 , wherein a purity of the FDKP-treprostinil compound is at least 90%.
19. A method of treating a treprostinil-treatable condition comprising administering to a subject in need thereof the compound of claim 1 .
20. The method of claim 19 , wherein the condition is pulmonary hypertension.