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

Patent metadata

Field	Value
Publication number	US-11141489-B2
Application number	US-201916665785-A
Country	US
Kind code	B2
Filing date	Oct 28, 2019
Priority date	Dec 2, 2016
Publication date	Oct 12, 2021
Grant date	Oct 12, 2021

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-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 conjugate or the pharmaceutically acceptable salt thereof 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 process for the preparation of a peptide-linker-conjugate or salt or solvate thereof of general formula L 2* -L-Y, comprising the steps of:
(a) assembling the amino acid sequence of the peptide moiety Y with protected reactive functional groups in the side chains using solid phase peptide synthesis (SPPS) on a resin, including D-Ser in position 2, wherein the side chain of lysine at position 14 is protected by a monomethoxytrityl (Mmt) group;
(b) coupling histidine as Fmoc-His(Trt)-OH at position 1;
(c) deprotection of 9-fluorenylmethyloxycarbonyl (Fmoc);
(d) coupling of the linker reagent L of formula (Iaa):

(e) deprotecting the Mmt protecting group at position 14;
coupling Palm-Glu(γOSu)-OtBu or Stea-Glu(γOSu)-OtBu at position 14; and
(g) cleaving the peptide from the resin and deprotection of all protected groups,
wherein:
L 2* is a C 1-20 alkyl chain, which is optionally interrupted by one or more groups independently selected from —O— and C(O)N(R 3aa ) and is optionally substituted with one or more groups independently selected from OH and C(O)N(R 3aa R 3aaa ), and comprises a chemical functional group intended for conjugation to an L 1 group of a functionalized hyaluronic acid, 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;
X is C(R 4 R 4a ) or N(R 4 );
each R 1 , R 1a , R 2a , R 3aa , R 3aaa , R 4 , and R 4a is independently selected from the group consisting of H and C 1-4 alkyl;
PA is OH or an activating group; and
Y is a peptide moiety of formula (Ib):

(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,

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):

(Ic)

His-D-Ser-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,

wherein X14 is Lys, wherein the —NH 2 side chain group is functionalized by (S)-4-carboxy-4-octadecanoylamino-butyryl.

2. The process of claim 1 , wherein:
L 2* is a C 1-6 alkyl chain, which is optionally interrupted by one group selected from —O— and C(O)N(R 3aa );
R 3aa is independently selected from the group consisting of H and C 1-4 alkyl; and
the chemical functional group is selected from thiol and maleimide.

3. The process of claim 1 , wherein L 2* is —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —C(O)NH— or —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 — and comprises a thiol group as chemical functional group.

4. A process for the preparation of a peptide-linker-conjugate or salt or solvate thereof of general formula L 2* -L-Y, comprising the steps of:
(a) assembling the amino acid sequence of the peptide moiety Y with protected reactive functional groups in the side chains in a step-wise manner using SPPS on a resin, including D-Ser in position 2, wherein the side chain of lysine at position 14 is protected by a Mmt group;
(b) coupling histidine as Fmoc-His(Trt)-OH at position 1;
(c) deprotection of Fmoc;
(d) coupling of the linker reagent L of formula (Iab):

(e) deprotecting the Mmt protecting group at position 14;
(f) coupling Palm-Glu(γOSu)-OtBu or Stea-Glu(γOSu)-OtBu at position 14; and
(g) cleaving the peptide from the resin and deprotection of all protected groups,
wherein:
each R 1 , R 1a , R 2 , R 2a , R 3aa , and R 3aaa is independently selected from the group consisting of H and C 1-4 alkyl;
L 2* is a C 1-20 alkyl chain, which is optionally interrupted by one or more groups independently selected from —O— and C(O)N(R 3aa ) and is optionally substituted with one or more groups independently selected from OH and C(O)N(R 3aa R 3aaa ), and comprises a chemical functional group intended for conjugation to an L 1 group of a functionalized hyaluronic acid, 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;
PA is OH or an activating group; and
Y is a peptide moiety of formula (Ib):

(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,

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):

(Ic)

His-D-Ser-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

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

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61K47/36

  Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin · CPC title

• A61K38/1703

  from vertebrates · CPC title

• A61K47/6903

  the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel · CPC title