Carrier-linked treprostinil prodrugs

Patent metadata

Field	Value
Publication number	US-10729778-B2
Application number	US-201715418180-A
Country	US
Kind code	B2
Filing date	Jan 27, 2017
Priority date	Aug 12, 2011
Publication date	Aug 4, 2020
Grant date	Aug 4, 2020

Abstract

Prodrugs or a pharmaceutically acceptable salt thereof which comprise a covalent treprostinil carrier conjugate, as well as their pharmaceutical composition, may be used as medicaments, especially for diseases or disorders which can be treated by treprostinil, such as pulmonary arterial hypertension (PAH).

First claim

The invention claimed is:

1. A method of treating, controlling, delaying, or preventing in a mammalian patient in need of the treatment of pulmonary arterial hypertension, comprising:
administering by inhalation to said patient a diagnostically and/or therapeutically effective amount of 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 indicate 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 heterocycyl, 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 method of claim 1 ;
wherein R a2 is H.

3. The method of claim 1 ;
wherein R a4 is selected from H, C 1-6 alkyl or substituted C 1-6 alkyl.

4. The method 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 method of claim 1 ;
wherein T is selected from structure (iii).

6. The method of claim 1 ;
wherein y is 4, 6, 8, 10, or 12.

7. The method 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 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 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 method of claim 1 ;
wherein Q in formula (H) 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 , R a9a , and 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 a11 );

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 a12 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)R a12a , N(R a12 )C(O)N(R a12 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 , 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.

9. The method of claim 8 ;
wherein each -Q- is independently -Q 1a -Q 1 -*, wherein the asterisk indicates the connection to Z′;
wherein:
Q 1a is a bond selected from the group consisting 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 a9a )—, —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,

Assignees

• Hersel Ulrich
• Rau Harald
• Lessmann Torben
• Bisek Nicola
• Maitro Guillaume
• Sprogoee Kennett
• Wegge Thomas
• Keil Oliver
• Zettler Joachim
• Ascendis Pharma As

Inventors

• Hersel Ulrich
• Rau Harald
• Lessmann Torben
• Bisek Nicola
• Maitro Guillaume
• Sprogøe Kennett
• Wegge Thomas
• Keil Oliver
• Zettler Joachim

Classifications

• A61K31/192

  having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid  {(cannabinoids A61K31/658)} · CPC title

• A61K47/645

  Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT · CPC title

• A61K47/641

  Branched, dendritic or hypercomb peptides · CPC title

• C07C59/72 Primary

  containing six-membered aromatic rings and other rings · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title