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 transdermal patch 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;
or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomer thereof, with the proviso that:
—O—Z—CO 2 H is not
and
—O—Z—CO 2 H does not contain a sugar moiety.
2. The transdermal patch of claim 1 , wherein —O—Z—CO 2 H is
R 7 and R 8 are as defined in claim 1 , and p is an integer from 1 to 9, with the proviso that —O—Z—CO 2 H is not
3. The transdermal patch of claim 2 , wherein both R 7 and R 8 are hydrogen.
4. The transdermal patch of claim 2 , wherein —O—Z—CO 2 H is
and p is an integer from 2 to 9.
5. The transdermal patch 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.
6. The transdermal patch 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).
7. The transdermal patch of claim 1 , wherein the compound of Formula (II) is selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomer thereof.
8. The transdermal patch of claim 1 , further comprising a drug reservoir and a semi-permeable membrane.
9. The transdermal patch of claim 1 , further comprising a drug/polymer matrix.
10. The transdermal patch of claim 1 , further comprising a chemical permeation enhancer.
11. A kit 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;
or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomer thereof, with the proviso that:
—O—Z—CO 2 H is not
and
—O—Z—CO 2 H does not contain a sugar moiety; and
instructions for administering the compound to treat a medical condition responsive to treatment with treprostinil.
12. The kit of claim 11 , wherein —O—Z—CO 2 H is
R 7 and R 8 are as defined in claim 11 , and p is an integer from 1 to 9, with the proviso that —O—Z—CO 2 H is not
13. The kit of claim 12 , wherein both R 7 and R 8 are hydrogen.
14. The kit of claim 12 , wherein —O—Z—CO 2 H is
and p is an integer from 2 to 9.
15. The kit of claim 11 , 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.
16. The kit of claim 11 , 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).
17. The kit of claim 11 wherein the compound of Formula (II) is selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, polymorph or stereoisomer thereof.
18. The kit of claim 11 , 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 11 , wherein the medical condition is pulmonary arterial hypertension.
20. The kit of claim 11 , further comprising a transdermal patch comprising the compound of Formula (II).