Carrier-linked treprostinil prodrugs

1. A carrier-linked treprostinil prodrug of formula (II), or a pharmaceutical salt thereof:

wherein each T is independently selected from structures (i) to (v):

wherein:

dashed lines indicating attachment to the rest of the molecule;

y is an integer ranging of from 1 to 64;

R a1 is selected from the group consisting of:

unsubstituted alkyl, substituted alkyl, unsubstituted phenyl substituted phenyl, unsubstituted naphthyl, substituted naphthyl, unsubstituted indenyl, substituted indenyl, unsubstituted indanyl, substituted indanyl, unsubstituted tetralinyl, substituted tetralinyl, unsubstituted C 3-10 cycloalkyl, substituted C 3-10 cycloalkyl, unsubstituted 4- to 7-membered heterocyclyl, substituted 4- to 7-membered heterocyclyl, unsubstituted 9- to 11-membered heterobicyclyl, and substituted 9- to 11-membered heterobicyclyl;

R a2 is selected from the group consisting of:

H, unsubstituted alkyl, and substituted alkyl;

R a3 and R a4 are independently selected from the group consisting of:

H, unsubstituted alkyl, and substituted alkyl;

n is 0 or 1;

Q is a spacer moiety;

optionally, R a1 and R a3 are joined together with the atoms to which they are attached to form a ring A;

A is selected from the group consisting of:

phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 4- to 7-membered aliphatic heterocyclyl, and 9- to 11-membered aliphatic heterobicyclyl, wherein A is unsubstituted or substituted; and

Z 1 is a carrier comprising a covalently bound polymer; and

wherein R a2 and R a4 are absent if A is an aromatic ring.

2. The carrier-linked treprostinil prodrug of claim 1 ;

wherein R a2 is H.

3. The carrier-linked treprostinil prodrug of claim 1 ;

wherein R a4 is selected from H, C 1-6 alkyl or substituted C 1-6 alkyl.

4. The carrier-linked treprostinil prodrug of claim 1 ;

wherein R a1 and R a3 are joined together with the atoms to which they are attached to form a ring A;

wherein A is selected from the group consisting of: phenyl;

naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 4- to 7-membered aliphatic heterocyclyl, and 9- to 11-membered aliphatic heterobicyclyl; and

wherein A is unsubstituted or substituted.

5. The carrier-linked treprostinil prodrug of claim 1 ;

wherein T is selected from structure (iii).

6. The carrier-linked treprostinil prodrug of claim 1 ;

wherein y is 4, 6, 8, 10, or 12.

7. The carrier-linked treprostinil prodrug of claim 1 ;

wherein the carrier-linked treprostinil prodrug has the structure of formula (II-A):

wherein:

each T is independently selected from structures (i) to (v):

wherein:

dashed lines indicating attachment to the rest of the molecule;

y is an integer ranging of from 1 to 64;

R a2 is selected from H, unsubstituted alkyl, and substituted alkyl;

R a4 is selected from the group consisting of:

H, unsubstituted alkyl, and substituted alkyl;

A is selected from the group consisting of:

phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 4- to 7-membered aliphatic heterocyclyl, and 9- to 11-membered aliphatic heterobicyclyl, wherein A is unsubstituted or substituted;

Q is a spacer moiety; and

Z 1 is a carrier comprising a covalently bound polymer.

8. The carrier-linked treprostinil prodrug of claim 1 ;

wherein Q in formula (II) is selected from the group consisting of:

COOR a9 , OR a9 , C(O)R a9 , C(O)N(R a9 R a9a ), S(O) 2 N(R a9 R a9a ), S(O)N(R a9 R a9a ), S(O) 2 R a9 , S(O)R a9 , N(R a9 )S(O) 2 N(R a9a R a9b ), SR a9 , N(R a9 R a9a ), OC(O)R a9 , N(R a9 )C(O)R a9a , N(R a9 )S(O) 2 R a9a ,N(R a9 )S(O)R a9a , N(R a9 )C(O)OR a9a , N(R a9 )C(O)N(R a9a R a9b ), OC(O)N(R a9 R a9a ), W; C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl;

wherein W, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally substituted with one or more R a10 , which are the same or different;

wherein:

C 1-50 alkyl; C 2-50 alkenyl; and C 2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of:

—W—, —C(O)O—, —O—, —C(O)—, —C(O)N(R a11 )—, —S(O) 2 N(R a11 )—, —S(O)N(R a11 )—, —S(O) 2 —, —S(O)—, —N(R a11 )S(O) 2 N(R a11a )—, —S—, —N(R a11 )—, —OC(O)R a11 , —N(R a11 )C(O)—, —N(R a11 )S(O) 2 —, —N(R a11 )S(O)—, —N(R a11 )C(O)O—, —N(R a11 )C(O)N(R a11a )—, and —OC(O)N(R a11 R a11a );

R a9 , and R a9a , R a9b are independently selected from the group consisting of:

H, W, and C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl;

wherein W, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally substituted with one or more R a10 , which are the same or different;

wherein:

C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of:

W, —C(O)O—, —O—, —C(O)—, —C(O)N(R a11 )—, —S(O) 2 N(R a11 )—, —S(O)N(R a11 )—, —S(O) 2 —, —S(O)—, —N(R a11 )S(O) 2 N(R a11a )—, —S—, —N(R a11 )—, —OC(O)R a11 , —N(R a11 )C(O)—, —N(R a11 )S(O) 2 —, —N(R a11 )S(O)—, —N(R a11 )C(O)O—, —N(R a11 )C(O)N(R a11a )—, and —OC(O)N(R a11 R a11a );

W is selected from the group consisting of:

phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 4- to 7-membered heterocyclyl, and 9- to 11-membered heterobicyclyl;

wherein W is optionally substituted with one or more R a10 , which are the same or different;

R a10 is selected from the group consisting of:

halogen, CN, oxo (═O), COOR a12 , OR a12 , C(O)R a12 , C(O)N(R a12 R a12a ), S(O) 2 N(R a12 R a12a ), S(O)N(R a12 R a12a ), S(O) 2 R a12 , S(O)R a12 , N(R a12 )S(O) 2 N(R a12a R a12b ), SR a12 , N(R a12 R a12a ), NO 2 , OC(O)R a12 , N(R a12 )C(O)R a12a , N(R a12 )S(O) 2 R a12a , N(R a12 )S(O)R a12a , N(R a12 )C(O)OR a12a , N(R a12 )C(O)N(R a12a R a12b ), OC(O)N(R a12 R a12a ), and C 1-6 alkyl;

wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and

R a11 , R a11a , and R a12 , R a12a , R a12b are independently selected from the group consisting of:

H, and C 1-6 alkyl;

wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.

9. The carrier-linked treprostinil prodrug of claim 8 ;

wherein each -Q- is independently -Q 1a -Q-*, wherein the asterisk indicates the connection to Z 1 ;

wherein;

Q 1a is a bond selected from the group sonsisting of:

—C(O)O—, —O—, —C(O)—, C(O)N(R a9a )—, —S(O) 2 N(R a9a )—, —S(O)N(R a9a )—, —S(O) 2 —, —S(O)—, —N(R a9a )S(O) 2 N(R a9b )—, —S—, —N(R a9a )—, —OC(O)—, —N(R a9a )C(O)—, —N(R a9a )S(O) 2 —, —N(R a9a )S(O)—, —N(R a9a )C(O)O—, —N(R a9a )C(O)N(R a9b )—, —OC(O)N(R a9a )—, and —W—,

Q 1 is selected from the group consisting of:

C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl which are optionally substituted with one or more R a10 , which are optionally interrupted, provided that Q 1 is at least C 2 , by one or more groups selected from the group consisting of:

C 3-7 cycloalkyl, 4- to 7-membered heterocyclyl,

wherein each of said group may individually be present one or more times; and which C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl may optionally be terminated at the end connected to Z 1 by a group selected from C 3-7 cycloalkyl, 4- to 7-membered heterocyclyl,

wherein

R a9a is as defined in claim 8 ;

R a10 is selected from the group consisting of:

halogen, CN, oxo (═O), COOR a12 , OR a12 , C(O)R a12 , C(O)N(R a12 R a12a ), S(O) 2 N(R a12 R a12a ), S(O)N(R a12 R a12a ), S(O) 2 R a12 , S(O)R a12 , N(R a12 )S(O) 2 N(R a12a R a12b ), SR a12 , N(R a12 R a12a ), NO 2 , OC(O)R a12 , N(R a12 )C(O)R a12a , N(R a12 )S(O) 2 R a12a , N(R a12 )S(O)R a12a , N(R a12 )C(O)OR a12a , N(R a12 )C(O)N(R a12a R a12b ), OC(O)N(R a12 R a12a ), and C 1-6 alkyl;

wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;

R a12 , R a12a and R a12b are independently selected from the group consisting of:

H, and C 1-6 alkyl;

wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and

R 13 and R 13a are independently selected from the group consisting of:

H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl.

10. The carrier-linked treprostinil prodrug of claim 1 ;

wherein the carrier-linked treprostinil prodrug is of formula (IIaa):

wherein:

each T is independently selected from structures (i) or (iii):

wherein:

dashed lines indicate attachment to the rest of the molecule;

y is an integer ranging of from 1 to 64;

R a2 is selected from H, unsubstituted alkyl, and substituted alkyl;

R a4 is selected from H, unsubstituted alkyl, and substituted alkyl;

ring A 1 is a C 3-10 cycloalkyl; 4- to 7-membered aliphatic heterocyclyl; or 9- to 11-membered aliphatic heterobicyclyl;

wherein A 1 is unsubstituted or substituted;

Q 1 is selected from C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl which are optionally substituted with one or more R a10 , which are optionally interrupted, provided that Q 1 is at least C 2 , by one or more groups selected from the group consisting of:

C 3-7 cycloalkyl, 4- to 7-membered heterocyclyl,

wherein each of said group may individually be present one or more times; and which C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl may optionally be terminated at the end connected to Z 1 by a group selected from C 3-7 cycloalkyl, 4- to 7-membered heterocyclyl,

wherein:

R a10 is selected from the group consisting of:

halogen, CN, oxo (═O), COOR a12 , OR a12 , C(O)R a12 , C(O)N(R a12 R a12a ), S(O) 2 N(R a12 R a12a ), S(O)N(R a12 R a12a ), S(O) 2 R a12 , S(O)R a12 , N(R a12 )S(O) 2 N(R a12a R a12b ), SR a12 , N(R a12 R a12a ), NO 2 , OC(O)R a12 , N(R a12 )C(O)R a12a , N(R a12 )S(O) 2 R a12a , N(R a12 )S(O)R a12a , N(R a12 )C(O)OR a12a , N(R a12 )C(O)N(R a12a R a12b ), OC(O)N(R a12 R a12a ), and C 1-6 alkyl;

wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;

R a12 , R a12a and R a12b are independently selected from the group consisting of:

H, and C 1-6 alkyl:

wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;

R 13 and R 13a are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl; and

Z 1 is a carrier comprising a covalently bound polymer.

11. The carrier-linked treprostinil prodrug of claim 1 ;

wherein the carrier-linked treprostinil prodrug is of formula (IIab):

wherein:

each T is inde pendently selected from structures (i) or (iii):

wherein:

dashed lines indicate attachment to the rest of the molecule;

y is an integer ranging of from 1 to 64;

R a2 is selected from H, unsubstituted alkyl, and substituted alkyl;

R a4 is selected from H, unsubstituted alkyl, and substituted alkyl;

ring A 1 is a C 3-10 cycloalkyl; 4- to 7 -membered aliphatic heterocyclyl; or 9- to 11-membered aliphatic heterobicyclyl;

wherein A 1 is unsubstituted or substituted;

Q 1 is selected from C 1 50 alkyl, C 2-50 alkenyl, and C 2-50 alkenyl which are optionally substituted with one or more R a10 , which are optionally interrupted, provided that Q 1 is at least C 2 , by one or more groups selected from the group consisting of:

C 3-7 cycloalkyl, 4- to 7-membered heterocyclyl,

wherein each of said group may individually be present one or more times; and which C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl may optionally be terminated at the end connected to Z 1 by a group selected from C 3-7 cycloalkyl, 4- to 7-membered heterocyclyl,

wherein:

Ra a10 is selected from the group consisting of:

halogen, CN, oxo (═O), COOR a12 , OR a12 , C(O)R a12 , C(O)N(R a12 R a12a ), S(O) 2 N(Ra al2 Ra al2a ), S(O)N(Ra 12 R a12a ), S(O) 2 R 12 ,S(O)R 12 , N(R a12 )S(O) 2 N(R a12a R a12b )Sr a12 ,N(R a12 R a12a ), NO 2 , OC(O)R a12 , N(R a12 )C(O)R a12a , N(R a12 )S(O) 2 R a12a , N(R a12 )S(O)R a12a , N(R a12 )C(O)OR a12a , N(R a12 )C(O)N(R a12a R a12b ), OC(O)N(R a12a R a12a ), and C 1-6 alkyl;

wherein C alkyl is optionally substituted with one or more halogen, which are the same or different;

R a12 , R a12a and R a12b are independently selected from the group consisting of:

H, and C 1-6 alkyl;

wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;

R 13 and R 13a are independently selected from H, alkyl, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl; and

Z 1 is a carrier comprising a covalently bound polymer.

12. The carrier-linked treprostinil prodrug of claim 1 ;

wherein the carrier-linked treprostinil prodrug is of formula (IIac) or (IIad):

wherein

each T is independently selected from structures (i) or (ii):

Z 1 is a carrier comprising a covalently bound polymer;

y is an integer ranging of from 1 to 64;

x is selected from 2, 3, 4, 5, 6, 7 or 8; and

X 1 is selected from C 1-15 alkyl, C 2-15 alkenyl and C 2-15 alkynyl, which are optionally substituted or interrupted by one or more groups selected from the group consisting of:

C 3-7 cycloalkyl, 4- to 7-membered heterocycyl,

wherein R 13 and R 13a are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl.

13. The carrier-linked treprostinil prodrug of claim 1 ;

wherein the carrier-linked treprostinil prodrug is of formula (IIb):

wherein:

X 1 is selected from C 1-15 alkyl, C 2-15 alkenyl and C 2-15 alkynyl, which are optionally substituted or interrupted by one or more groups selected from the group consisting of:

C 3-7 cycloalkyl, 4- to 7-membered heterocyclyl,

wherein:

R 13 and R 13a are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl;

y is an integer ranging of from 1 to 64;

x is selected from 2, 3, 4, 5, 6, 7 or 8; and

Z 1 is a carrier comprising a covalently bound polymer.

14. The carrier-linked treprostinil prodrug of claim 12 ;

wherein x is 6.

15. The carrier-linked treprostinil prodrug of claim 1 ;

wherein the carrier-linked treprostinil prodrug has the structure of formula (IIba):

wherein:

y is an integer ranging of from 1 to 64; and

Z 1 is a carrier comprising a covalently bound polymer.

16. The carrier-linked treprostinil prodrug claim 1 ;

wherein the carrier Z 1 has the structure of formula (VII):

B-(-A) n   (VII);

wherein:

B is branching core;

A is a poly(ethylene glycol)-based polymeric chain; and

n is an integer of from 3 to 32.

17. The carrier-linked treprostinil prodrug of claim 1 ;

wherein Z 1 represents a moiety (IIca):

wherein:

t ranges from 80 to 160;

w ranges from 2 to 6; and

dashed lines indicate attachment to the rest of the carrier-linked treprostinil prodrug.

18. The carrier-linked treprostinil prodrug of claim 17 ;

wherein w is 2 or 3.

19. The carrier-linked treprostinil prodrug of claim 1 of

formula (IIc), or a pharmaceutically acceptable salt thereof:

wherein y is 4 and Z 1 represents a moiety (IIca):

wherein:

dashed lines indicate attachment to the rest of the structure of formula (IIc);

t ranges from 80 to 160; and

w is 2 or 3.

20. The carrier-linked treprostinil prodrug of claim 1 ;

wherein R a1 is C 1-6 alkyl or substituted C 1-6 alkyl.

21. The carrier-linked treprostinil prodrug of claim 1 ;

wherein R a3 is H, C 1-6 alkyl or substituted C 1-6 alkyl.

22. A pharmaceutical composition comprising:

a carrier-linked treprostinil prodrug, or a pharmaceutically acceptable salt thereof, as claimed in claim 1 ; and

optionally one or more pharmaceutically acceptable excipients.

23. The pharmaceutical composition as claimed in claim 22 ;

(i) wherein the carrier-linked treprostinil prodrug is sufficiently dosed in the pharmaceutical composition to provide a therapeutically effective amount of treprostinil for at least 12 hours in one application; and/or

(ii) wherein a single dose of the pharmaceutical composition comprises about 2 to about 6 mg of the treprostinil moiety T.

24. A method of treating or preventing a disease or disorder which can be treated and/or prevented by treprostinil comprising the step of:

administering the prodrug, or the pharmaceutically acceptable salt thereof, as claimed in claim 1 .

25. The method as claimed in claim 24 ;

wherein the disease or disorder is pulmonary arterial hypertension.

26. A method of treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of one or more conditions comprising:

administering to said patient a diagnostically and/or therapeutically effective amount of the carrier-linked treprostinil prodrug, or a pharmaceutically acceptable salt thereof, as claimed in claim 1 .

27. The method, as claimed in claim 26 ;

wherein administration of the water-soluble carrier-linked prodrug, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

topical, enteral, parenteral, inhalation, injection, infusion, intraarticular, intradermal, subcutaneous, intramuscular, intravenous, intraosseous, intraperitoneal, intrathecal, intracapsular, intraorbital, intracardiac, transtracheal, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, intraventricular and intrasternal administration.

28. The carrier-linked treprostinil prodrug as claimed in claim 1 ;

wherein R a1 and R a3 are joined together with the atoms to which they are attached to form a ring A; and

wherein A is selected from the group consisting of:

cyclopropane, cyclobutane, cyclopentane, cyclohexane, and cycloheptane.