Treprostinil derivatives and compositions and uses thereof

1. A transdermal patch comprising a compound of Formula (I):

wherein R 1 and R 2 independently are hydrogen,

wherein:

R 3 in each occurrence independently is alkyl, -alkylaryl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which may optionally be substituted with one to six substituents independently selected from the group consisting of halide, cyano, nitro, hydroxyl, —SH, —NH 2 , —OR 11 , —SR 11 , —NR 12 R 13 , —C(═O)R 11 , —C(═O)OR 11 , —OC(═O)R 11 , —C(═O)NR 12 R 13 , —NR 11 C(═O)R 11 , cycloalkyl, heterocyclyl, aryl, heteroaryl and unsubstituted alkyl, wherein:

R 11 in each occurrence independently is hydrogen, cycloalkyl, heterocyclyl, aryl, heteroaryl or unsubstituted alkyl; and

R 12 and R 13 in each occurrence independently are hydrogen, cycloalkyl, heterocyclyl, aryl, heteroaryl or unsubstituted alkyl, or R 12 and R 13 and the nitrogen atom to which they are connected form a heterocyclic or heteroaryl ring;

R 4 and R 5 in each occurrence independently are hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, or R 4 and R 5 and the carbon atom to which they are connected form a C 3 -C 6 cycloalkyl ring;

R 6 in each occurrence independently is hydrogen, R 3 , —C(═O)R 3 , —C(═O)OR 3 or —C(═O)NR 9 R 10 ; or

R 6 and R 4 or R 5 , together with the atoms to which they are connected, form a heterocyclic ring;

R 9 and R 10 in each occurrence independently are hydrogen, alkyl, -alkylaryl, cycloalkyl, heterocyclyl, aryl or heteroaryl; or

R 9 and R 10 and the nitrogen atom to which they are connected form a heterocyclic or heteroaryl ring;

j in each occurrence independently is an integer from 0 to 4; and

m in each occurrence independently is an integer from 1 to 10;

or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomer thereof, with the proviso that:

both R 1 and R 2 are not hydrogen;

neither —OR 1 nor —OR 2 forms an acetate;

neither —OR 1 nor —OR 2 forms a substituted cyclohexane-ester; and

neither —OR 1 nor —OR 2 forms an ester with or of an amino acid (protected or unprotected), a peptide or a protein.

2. The transdermal patch of claim 1 , wherein:

R 3 in each occurrence independently is C 1 -C 6 alkyl;

R 4 and R 5 in each occurrence independently are hydrogen or C 1 -C 3 alkyl, or R 4 and R 5 and the carbon atom to which they are connected form a cyclopropyl ring;

R 6 in each occurrence independently is hydrogen or R 3 ;

j in each occurrence independently is 0 or 1; and

m in each occurrence independently is 1 or 2.

3. The transdermal patch 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.

4. The transdermal patch of claim 3 , 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.

5. The transdermal patch of claim 1 , wherein R 2 is hydrogen and —OR 1 is derivatized.

6. The transdermal patch of claim 1 , wherein R 1 is hydrogen and —OR 2 is derivatized.

7. The transdermal patch of claim 1 , wherein both —OR 1 and —OR 2 are derivatized, optionally with the same group.

8. The transdermal patch of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:

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

9. The transdermal patch of claim 1 , further comprising a drug reservoir and a semi-permeable membrane.

10. The transdermal patch of claim 1 , further comprising a drug/polymer matrix.

11. The transdermal patch of claim 1 , further comprising a chemical permeation enhancer.

12. A kit comprising:

1) a compound of Formula (I):

wherein R 1 and R 2 independently are hydrogen,

wherein:

R 3 in each occurrence independently is alkyl, -alkylaryl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which may optionally be substituted with one to six substituents independently selected from the group consisting of halide, cyano, nitro, hydroxyl, —SH, —NH 2 , —OR 11 , —SR 11 , —NR 12 R 13 , —C(═O)R 11 , —C(═O)OR 11 , —C(═O)R 11 , —C(═O)NR 12 R 13 , —NR 11 C(═O)R 11 , cycloalkyl, heterocyclyl, aryl, heteroaryl and unsubstituted alkyl, wherein:

R 11 in each occurrence independently is hydrogen, cycloalkyl, heterocyclyl, aryl, heteroaryl or unsubstituted alkyl; and

R 12 and R 13 in each occurrence independently are hydrogen, cycloalkyl, heterocyclyl, aryl, heteroaryl or unsubstituted alkyl, or R 12 and R 13 and the nitrogen atom to which they are connected form a heterocyclic or heteroaryl ring;

R 4 and R 5 in each occurrence independently are hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, or R 4 and R 5 and the carbon atom to which they are connected form a C 3 -C 6 cycloalkyl ring;

R 6 in each occurrence independently is hydrogen, R 3 , —C(═O)R 3 , —C(═O)OR 3 or —C(═O)NR 9 R 10 ; or

R 6 and R 4 or R 5 , together with the atoms to which they are connected, form a heterocyclic ring;

R 9 and R 10 in each occurrence independently are hydrogen, alkyl, -alkylaryl, cycloalkyl, heterocyclyl, aryl or heteroaryl; or

R 9 and R 10 and the nitrogen atom to which they are connected form a heterocyclic or heteroaryl ring;

j in each occurrence independently is an integer from 0 to 4; and

m in each occurrence independently is an integer from 1 to 10;

or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomer thereof, with the proviso that:

both R 1 and R 2 are not hydrogen;

neither —OR 1 nor —OR 2 forms an acetate;

neither —OR 1 nor —OR 2 forms a substituted cyclohexane-ester; and

neither —OR 1 nor —OR 2 forms an ester with or of an amino acid (protected or unprotected), a peptide or a protein; and

2) instructions for administering the compound to treat a medical condition responsive to treatment with treprostinil.

13. The kit of claim 12 , 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.

14. The kit of claim 12 , wherein R 2 is hydrogen and —OR 1 is derivatized.

15. The kit of claim 12 , wherein R 1 is hydrogen and —OR 2 is derivatized.

16. The kit of claim 12 , wherein both —OR 1 and —OR 2 are derivatized, optionally with the same group.

17. The kit of claim 12 , wherein the compound of Formula (I) is selected from the group consisting of:

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

18. The kit of claim 12 , 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 kit of claim 12 , wherein the medical condition is pulmonary arterial hypertension.

20. The kit of claim 12 , further comprising a transdermal patch comprising the compound of Formula (I).