Treprostinil derivatives and compositions and uses thereof

1. A pharmaceutical composition comprising a compound of Formula (II):

wherein:

—O—Z—CO 2 H is

—O-heteroalkyl-CO 2 H, —O-cyclyl-CO 2 H, —O—CH 2 -cyclyl-CO 2 H, —O-cyclyl-CH 2 —CO 2 H, or —O—CH 2 -cyclyl-CH 2 —CO 2 H, each of which may optionally be substituted,

wherein:

cyclyl- is -cycloalkyl-, -heterocyclyl-, -aryl- or -heteroaryl-;

R 7 and R 8 in each occurrence independently are hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, or R 7 and R 8 and the carbon atom to which they are connected form a C 3 -C 6 cycloalkyl ring; and

n is an integer from 1 to 10;

with the proviso that —O—Z—CO 2 H is not

 and does not contain a sugar moiety;

or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomer thereof, and one or more pharmaceutically acceptable excipients or carriers, wherein the pharmaceutical composition is formulated for administration of the compound of Formula (II) to a subject for therapeutic use.

2. The pharmaceutical composition of claim 1 , wherein n is an integer from 1 to 6.

3. The pharmaceutical composition of claim 1 , wherein —O—Z—CO 2 H is

and wherein:

R 7 and R 8 are as defined as in claim 1 ;

p is an integer from 1 to 9; and

q is an integer from 0 to 8.

4. The pharmaceutical composition of claim 3 , wherein both R 7 and R 8 are hydrogen, and p is an integer from 1 to 9 or from 1 to 5 (or each occurrence of R 7 and R 8 is hydrogen, and q is an integer from 0 to 8 or from 0 to 4).

5. The pharmaceutical composition of claim 3 , wherein —O—Z—CO 2 H is

and p is an integer from 2 to 9 or from 2 to 5.

6. The pharmaceutical composition of claim 1 , wherein —O—Z—CO 2 H is —O-heteroalkyl-CO 2 H, and —O-heteroalkyl-CO 2 H is selected from the group consisting of:

wherein r is each of 1, 2 and 3.

7. The pharmaceutical composition of claim 1 , wherein —O—Z—CO 2 H is —O-cycloalkyl-CO 2 H, —O—CH 2 -cycloalkyl-CO 2 H, —O-cycloalkyl-CH 2 —CO 2 H, or —O—CH 2 -cycloalkyl-CH 2 —CO 2 H, and for each of the preceding moieties -cycloalkyl- is:

1,2-cyclopropyl (cis or trans); or

1,3-cyclobutyl (cis or trans) or 1,2-cyclobutyl (cis or trans); or

1,3-cyclopentyl (cis or trans) or 1,2-cyclopentyl (cis or trans); or

1,4-cyclohexyl (cis or trans), 1,3-cyclohexyl (cis or trans), or 1,2-cyclohexyl (cis or trans).

8. The pharmaceutical composition of claim 1 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts, solvates, hydrates, clathrates, polymorphs and stereoisomers thereof.

9. The pharmaceutical composition of claim 1 , which is formulated for transdermal delivery of the compound of Formula (II).

10. The pharmaceutical composition of claim 9 , which is configured as a transdermal patch.

11. A compound of Formula (II):

wherein:

—O—Z—CO 2 H is

wherein:

R 7 and R 8 in each occurrence independently are hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, or R 7 and R 8 and the carbon atom to which they are connected form a C 3 -C 6 cycloalkyl ring; and

n is 3, 4, 5, 6, 7, 8, 9 or 10;

with the proviso that —O—Z—CO 2 H does not contain a sugar moiety;

or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomer thereof.

12. The compound of claim 11 , wherein n is 3, 4, 5 or 6.

13. The compound of claim 11 , wherein —O—Z—CO 2 H is

R 7 and R 8 are as defined in claim 11 , and p is 2, 3, 4, 5, 6, 7, 8 or 9.

14. The compound of claim 13 , wherein p is 2, 3, 4 or 5.

15. A pharmaceutical composition comprising a compound of claim 11 or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomer thereof, and one or more pharmaceutically acceptable excipients or carriers.

16. The pharmaceutical composition of claim 15 , which is formulated for transdermal delivery of the compound.

17. 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 claim 11 or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomer thereof.

18. The method of claim 17 , 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.

19. The method of claim 18 , wherein the medical condition is pulmonary hypertension.

20. The method of claim 19 , wherein the medical condition is pulmonary arterial hypertension.

21. The method of claim 17 , wherein the compound is administered transdermally.