US2018153847A1PendingUtilityA1
Treprostinil prodrugs
Est. expirySep 26, 2036(~10.2 yrs left)· nominal 20-yr term from priority
A61K 31/216A61P 9/12A61K 31/265A61K 31/27A61K 31/335A61K 31/222A61K 9/0019A61K 31/192A61K 9/0021A61P 11/00A61K 31/221A61K 9/0053A61K 31/195
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Claims
Abstract
Provided are novel prodrugs of treprostinil, as well as methods of making and methods of using these prodrugs.
Claims
exact text as granted — not AI-modified1 . (canceled)
2 . (canceled)
3 . (canceled)
4 . A method of treating pulmonary hypertension comprising administering subcutaneously to a patient suffering from pulmonary hypertension an effective amount of a prodrug of treprostinil, wherein the prodrug converts in whole or in part to treprostinil in vivo following administration and has reduced affinity for one or more of the IP, DP or EP receptors locally at the site of injection as compared to treprostinil.
5 . The method of claim 4 , wherein said administering is continuous subcutaneous administering.
6 . The method of claim 4 , wherein said administering results in no or less pain at a site of the injection compared to administering treprostinil.
7 . A method of treating pulmonary hypertension comprising administering subcutaneously to a patient suffering from pulmonary hypertension an effective amount of a prodrug of treprostinil, wherein the prodrug is a compound having the following formula:
wherein X is OR 9 or NR 1 R 6 ; wherein R 9 is H or C 1 -C 4 alkyl, which may be optionally substituted with a terminal hydroxyl or carboxy group; wherein R 1 is H or C 1 -C 4 alkyl and R 6 is
or wherein R 1 and R 6 are such that NR 1 R 6 is an amide of an amino acid; R 7 is H or C 1 -C 4 alkyl, which may be substituted with a terminal hydroxy or carboxy group; R 8 is H or C 1 -C 4 alkyl; each of R 2 and R 3 is independently selected from H, C 1-4 alkyl,
phosphate and a group, in which OR 2 or OR 3 forms an ester of an amino acid; Y is OR 4 or NR 4 R 5 , each of R 4 and R 5 is independently selected from H and C 1-4 alkyl; with a proviso that all of R 9 , R 2 and R 3 are not H; or
a pharmaceutically acceptable salt of the compound.
8 . The method of claim 4 , wherein the prodrug is a compound having the following formula:
wherein X is OH or NR 1 R 6 , wherein R 1 is H or C 1 -C 4 alkyl and R 6 is
or wherein R 1 and R 6 are such that NR 1 R 6 is an amide of an amino acid; R 7 is H or C 1 -C 4 alkyl, which may be substituted with a terminal hydroxy or carboxy group, R 8 is H or C 1 -C 4 alkyl and each of R 2 and R 3 is independently selected from H, C 1-4 alkyl, or
wherein Y is OR 4 or NR 4 R 5 , wherein each of R 4 and R 5 is independently selected from H and C 1-4 alkyl; with a proviso that when X is OH, both of R 2 and R 3 are not H; or
a pharmaceutically acceptable salt of the compound
9 . The method of claim 8 wherein:
X is OH or
10 . The method of claim 7 , wherein X is OH.
11 . The method of claim 10 , wherein each of R 2 and R 3 is independently selected from C 1-4 alkyl.
12 . (canceled)
13 . The method of claim 10 , wherein each of R 2 and R 3 is independently selected from H, and
14 . The method of claim 13 , wherein one of R 2 and R 3 is
and the other of R 2 and R 3 is H.
15 . The method of claim 14 , wherein Y is OR 4 .
16 . (canceled)
17 . The method of claim 14 , wherein Y is NR 4 R 5 .
18 . (canceled)
19 . (canceled)
20 . (canceled)
21 . The method of claim 10 , wherein at least one of R 2 and R 3 is phosphate.
22 . (canceled)
23 . (canceled)
24 . The method of claim 10 , wherein at least R 2 and R 3 is a group, in which OR 2 or OR 3 forms an ester of an amino acid.
25 . (canceled)
26 . The method of claim 7 , wherein X is NR 1 R 6 and each of R 2 and R 3 are H.
27 . The method of claim 26 , wherein R 1 is H.
28 . The method of claim 27 , wherein R 6 is
29 . (canceled)
30 . (canceled)
31 . The method of claim 27 , wherein R 6 is
32 . (canceled)
33 . The method of claim 26 , wherein NR 1 R 6 is an amide of an amino acid.
34 . The method of claim 7 , wherein X is OR 9 , R 9 is C 1 -C 4 alkyl, which may be optionally substituted with a terminal hydroxyl or carboxy group, R 2 and R 3 are each H.
35 . The method of claim 34 , wherein R 9 is C 1 -C 4 substituted with a terminal hydroxyl group.
36 . The method of claim 4 , wherein the prodrug has one of the following formulas:
37 . A compound or a pharmaceutically acceptable salt thereof, wherein the compound having one of the following formulas:
38 . (canceled)
39 . (canceled)
40 . (canceled)
41 . (canceled)
42 . (canceled)
43 . (canceled)
44 . (canceled)
45 . (canceled)
46 . (canceled)
47 . (canceled)
48 . The method of claim 4 , wherein the patient is a human, wherein said prodrug has a half-life of less than 120 minutes.
49 . (canceled)
50 . (canceled)
51 . The method of claim 48 , wherein said prodrug has the half-life in plasma of less than 15 minutes.Cited by (0)
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