Conjugates comprising an GLP-1/glucagon dual agonist, a linker and hyaluronic acid

Patent metadata

Field	Value
Publication number	US-10792367-B2
Application number	US-201715829596-A
Country	US
Kind code	B2
Filing date	Dec 1, 2017
Priority date	Dec 2, 2016
Publication date	Oct 6, 2020
Grant date	Oct 6, 2020

Abstract

The present invention relates to a conjugate or a pharmaceutically acceptable salt thereof comprising an GLP-1/Glucagon receptor agonist, a linker and a hyaluronic acid hydrogel bearing -L1-L2-L-Y—R20 groups, wherein Y represents an GLP-1/Glucagon receptor agonist moiety; and -L is a linker moiety—by formula (Ia),

wherein the dashed line indicates the attachment to one of the amino groups of the GLP-1/Glucagon receptor agonist moiety by forming an amide bond. The invention further relates to pharmaceutical compositions comprising the conjugates as well as their use as a medicament for treating or preventing diseases or disorders which can be treated by GLP-1/Glucagon receptor agonist.

First claim

The invention claimed is:

1. A conjugate comprising a crosslinked hyaluronic acid hydrogel, in which 0.001 to 20 mol % of the monomeric disaccharide units are crosslinked by a crosslinker and 0.2 to 20 mol % of the monomeric disaccharide units bear -L 1 -L 2 -L-Y—R 20 groups, wherein:
L 1 is a C 1-20 alkyl chain comprising a terminal amino group, in which optionally one or more carbon atoms are replaced by a group selected from —O—, N(R 5aa ) and C(O)N(R 5aa ) and which is optionally substituted with one or more groups independently selected from OH and C(O)N(R 5aa R 5aaa ), wherein R 5aa and R 5aaa are independently selected from the group consisting of H and C 1-4 alkyl, and
L 1 is attached to the hydrogel via the terminal amino group forming an amide bond with the carboxy group of the beta-1,3-D-glucuronic acid of the hyaluronic acid;
L 2 is a single chemical bond or is a C 1-20 alkyl chain, in which optionally one or more carbon atoms are replaced by a group selected from —O— and C(O)N(R 3aa ) and which is optionally substituted with one or more groups independently selected from OH and C(O)N(R 3aa R 3aaa ), wherein R 3aa and R 3aaa are independently selected from the group consisting of H and C 1-4 alkyl, and
L 2 is attached to L 1 via a terminal group selected from the group consisting of

wherein L 2 is attached to one position indicated with the dashed line and L 1 is attached to the position indicated with the other dashed line;
L is a linker of formula (Ia),

wherein the dashed line indicates the attachment to the N-Terminus of Y by forming an amide bond,
X is C(R 4 R 4a ) or N(R 4 ),
R 1 , R 1a , are independently selected from the group consisting of H and C 1-4 alkyl,
R 2 , R 2a , are independently selected from the group consisting of H and C 1-4 alkyl,
R 4 , R 4a , are independently selected from the group consisting of H and C 1-4 alkyl, and
wherein L 2 is attached to L in place of one of R 2 , R 2a , R 4 or R 4a ;

Y is a peptide moiety of formula (Ib)

His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-

Gln-X14-Glu-Ser-Lys-Ala-Ala-Gln-Asp-Phe-Ile-Glu-

Trp-Leu-Lys-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-

Pro-Pro-Ser (Ib)

wherein X14 is Lys, wherein the —NH 2 side chain group is functionalized by (S)-4-carboxy-4-hexadecanoylamino-butyryl; or
Y is a peptide moiety of formula (Ic)

His-dSer-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-

Gln-X14-Asp-Glu-Gln-Leu-Ala-Lys-Asp-Phe-Ile-Glu-

Trp-Leu-Lys-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-

Pro-Pro-Ser (Ic)

wherein X14 is Lys, wherein the —NH 2 side chain group is functionalized by (S)-4-carboxy-4-octadecanoylamino-butyryl; and
R 20 is OH or NH 2 ;

or a salt or solvate thereof.

2. The conjugate of claim 1 comprising a crosslinked hyaluronic acid hydrogel, in which 0.001 to 20 mol % of the monomeric disaccharide units are crosslinked by a crosslinker, 0.2 to 20 mol % of the monomeric disaccharide units bear -L 1 -L 2 -L-Y—R 20 groups, and 0.2 to 30 mol % of the monomeric disaccharide units of the crosslinked hyaluronic acid hydrogel bear -L 1 -Z—OH groups, wherein:
L 1 is a C 1-20 alkyl chain comprising a terminal amino group, in which optionally one or more carbon atoms are replaced by a group selected from —O—, N(R 5aa ) and C(O)N(R 5aa ) and which is optionally substituted with one or more groups independently selected from OH and C(O)N(R 5aa R 5aaa ), wherein R 5aa and R 5aaa are independently selected from the group consisting of H and C 1-4 alkyl, and
L 1 is attached to the hydrogel via the terminal amino group forming an amide bond with the carboxy group of the beta-1,3-D-glucuronic acid of the hyaluronic acid;
L 2 is a single chemical bond or is a C 1-20 alkyl chain, in which optionally one or more carbon atoms are replaced by a group selected from —O— and C(O)N(R 3aa ) and which is optionally substituted with one or more groups independently selected from OH and C(O)N(R 3aa R 3aaa ), wherein R 3aa and R 3aaa are independently selected from the group consisting of H and C 1-4 alkyl, and
L 2 is attached to L 1 via a terminal group selected from the group consisting of

wherein L 2 is attached to one position indicated with the dashed line and L 1 is attached to the position indicated with the other dashed line;
Z is a C 1-16 alkyl chain, in which optionally one or more carbon atoms are replaced by a group selected from —O— and C(O)N(R 6aa ); wherein R 6aa is hydrogen or C 1-4 alkyl; or
and Z is

Z is attached to L 1 via a terminal group selected from the group consisting of

wherein Z is attached to one position indicated with the dashed line and L 1 is attached to the position indicated with the other dashed line;
L is a linker of formula (Ia),

wherein the dashed line indicates the attachment to the N-Terminus of Y by forming an amide bond,
X is C(R 4 R 4a ) or N(R 4 ),
R 1 , R 1a , are independently selected from the group consisting of H and C 1-4 alkyl,
R 2 , R 2a , are independently selected from the group consisting of H and C 1-4 alkyl,
R 4 , R 4a , are independently selected from the group consisting of H and C 1-4 alkyl,
wherein L 2 is attached to L in place of one of R 2 , R 2a , R 4 or R 4a ;

Y is a peptide moiety of formula (Ib)

His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-

Gln-X14-Glu-Ser-Lys-Ala-Ala-Gln-Asp-Phe-Ile-Glu-

Trp-Leu-Lys-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-

Assignees

• Sanofi Sa

Inventors

• Kadereit Dieter
• Wagner Michael
• Olpp Thomas
• Meyer Nino
• Bossart Martin
• Evers Andreas
• Sakhaii Peyman
• Dhal Pradeep K
• Konowicz Paul
• Stefano James E
• Poth Nils

Classifications

• C07K14/605

  Glucagons · CPC title

• C07K14/47

  from mammals · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title