Compounds and methods for delivery of prostacyclin analogs
This invention pertains generally to prostacyclin analogs 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. Generally, the compounds and methods of the present invention increase the oral bioavailability and circulating concentrations of treprostinil when administered orally. Compounds of the present invention have the following formula:
1. A method of treating pulmonary hypertension comprising orally administering a pharmaceutically effective amount of a compound of structure II to a subject in need thereof:
wherein,
R 1 is independently selected from the group consisting of H, substituted and unsubstituted alkyl groups, arylalkyl groups and groups wherein OR 1 form a substituted or unsubstituted glycolamide ester;
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 or proteins, with the proviso that all of R 1 , R 2 and R 3 are not H;
enantiomers thereof; and
a pharmaceutically acceptable salt of the compound.
2. The method of claim 1 , wherein when OR 1 forms a substituted or unsubstituted glycolamide ester, R 1 is —CH 2 CONR 4 R 5 , wherein R 4 and R 5 may be the same or different and are independently selected from the group consisting of H, OH, substituted and unsubstituted alkyl groups,—(CH 2 ) m CH 3 , —CH 2 OH, and —CH 2 (CH 2 ) n OH, with the proviso that m is 0, 1, 2, 3 or 4, and n is 0,1,2,3 or 4.
3. The method of claim 2 , wherein R 1 is a C 1 -C 4 alkyl group.
4. The method of claim 3 , wherein R1 is selected from the group consisting of methyl, ethyl, propyl or butyl.
5. The method of claim 1 , wherein R 1 is a substituted or unsubstituted benzyl group.
6. The method of claim 5 , wherein R 1 is —CH 3 or —CH 2 C 6 H 5 .
7. The method of claim 2 , wherein R 4 and R 5 are the same or different and are independently selected from the group consisting of H, OH, —CH 3 , and —CH 2 CH 2 OH.
8. The method of claim 1 , wherein one or both of R 2 and R 3 are H.
9. The method of claim 1 , wherein one or both of R 2 and R 3 are not H and R 2 and R 3 are independently selected from phosphate and groups wherein OR 2 and OR 3 are esters of amino acids, dipeptides, esters of tripeptides and esters of tetrapeptides.
10. The method of claim 1 , wherein only one of R 2 or R 3 is a phosphate group.
11. The method of claim 9 , wherein R 2 and R 3 are independently selected from groups wherein OR 2 and OR 3 are esters of amino acids.
12. The method of claim 11 , wherein one or both of R 2 and R 3 are esters of glycine or alanine.
13. The method of claim 9 , wherein one of R 1 is H.
14. The method of claim 9 , wherein one of R 1 and R 2 is H.
15. The method of claim 14 , wherein R 2 is H.
16. The method of claim 1 , wherein the oral bioavailability of the compound is greater than the oral bioavailability of treprostinil.
17. The method of claim 16 , wherein the oral bioavailability of the compound is at least 50% greater than the oral bioavailability of treprostinil.
18. The method of claim 17 , wherein the oral bioavailability of the compound is at least 100% greater than the oral bioavailability of treprostinil.
19. The method of claim 1 , further comprising administering pharmaceutically effective amount of a p-glycoprotein inhibitor.
20. The method of claim 19 , wherein the p-glycoprotein inhibitor is administered simultaneously with the compound of structure II.
21. The method of claim 19 , wherein the p-glycoprotein inhibitor is administered prior to administration of the compound of structure II.
22. The method of claim 19 , wherein the p-glycoprotein inhibitor is administered orally or intravenously.
23. A method of treating pulmonary hypertension comprising orally administering to a subject in need thereof an effective amount of a compound of the following structure:
24. The method of claim 23 , wherein the compound melts at about 107° C.
25. The method of claim 24 , wherein the compound has an x-ray powder diffraction pattern having a pattern peak at about 17.2 degrees 2 theta.
26. A method of treating peripheral vascular disease, promoting vasodilation, inhibiting platelet aggregation and thrombus formation, stimulating thrombolysis, inhibiting cell proliferation, providing cytoprotection, preventing atherogenesis, or inducing angiogenesis comprising orally administering a pharmaceutically effective amount of a compound of structure II to a subject in need thereof:
wherein,
R 1 is independently selected from the group consisting of H, substituted and unsubstituted alkyl groups, arylalkyl groups and groups wherein OR 1 form a substituted or unsubstituted glycolamide ester;
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 or proteins, with the proviso that all of R 1 , R 2 and R 3 are not H;
enantiomers thereof; and
a pharmaceutically acceptable salt of the compound.