Glucose-sensitive albumin-binding derivatives

Patent metadata

Field	Value
Publication number	US-11767332-B2
Application number	US-202117500242-A
Country	US
Kind code	B2
Filing date	Oct 13, 2021
Priority date	Nov 9, 2017
Publication date	Sep 26, 2023
Grant date	Sep 26, 2023

Abstract

This invention relates to glucose-sensitive albumin-binding diboron conjugates. More particularly the invention provides novel diboron compounds, and in particular diboronate or diboroxole compounds, useful as intermediate compounds for the synthesis of diboron conjugates.

First claim

The invention claimed is:

1. A diboron conjugate represented by the general Formula I′
R 1 ′—X′—R 2 ′

in which Formula I′,
X′ represents a linker of Formula Ia′:

wherein
---- represents a covalent bond towards R 1 ′ or R 2 ′;
D represents a drug substance; and
W′ represents a covalent bond, or a linker selected from the group consisting of —NHCH 2 (C═O)—, —NHCH 2 CH 2 (C═O)—, —NHCH 2 CH 2 CH 2 (C═O)—, and —NHCH(COOH)CH 2 CH 2 (C═O)— (the latter representing an L-gamma-Glu or a D-gamma-Glu residue); or
X′ represents a linker of Formula Ib′:

wherein,
---- represents a covalent bond towards R 1 ′ or R 2 ′; and
R 3 ′ represent —(CH 2 ) m′ (C═O)—W′-D, wherein
m′ represents an integer in the range of 1 to 4;
W′ represents a covalent bond or a linker selected from the group consisting of —NHCH 2 (C═O)—, —NHCH 2 CH 2 (C═O)—, —NHCH 2 CH 2 CH 2 (C═O)—, and —NHCH(COOH)CH 2 CH 2 (C═O)— (the latter representing an L-gamma-Glu or a D-gamma-Glu residue); and
D represents a drug substance; or
X′ represents a linker of Formula Ic′:

which represents a D- or an L-amino acid form; and
wherein,
---- represents a covalent bond towards R 1 ′ or R 2 ′;
n′ represents an integer in the range of 1 to 4;
W′ represents a covalent bond or a linker selected from the group consisting of —NHCH 2 (C═O)—, —NHCH 2 CH 2 (C═O)—, —NHCH 2 CH 2 CH 2 (C═O)—, and —NHCH(COOH)CH 2 CH 2 (C═O)— (the latter representing an L-gamma-Glu or a D-gamma-Glu residue); and
D represents a drug substance; or
X′ represents a linker of Formula Id′:

which represents a R,R or S,S, or R,S or R,S stereoisomer of the 3,4-diamino-pyrrolidine;
wherein,
---- represents a covalent bond towards R 1 ′ or R 2 ′;
R 4 ′ represents —(C═O)(CH 2 ) p′ (C═O)—W′-D; where
W′ represents a covalent bond or a linker selected from the group consisting of —NHCH 2 (C═O)—, —NHCH 2 CH 2 (C═O)—, —NHCH 2 CH 2 CH 2 (C═O)—, and —NHCH(COOH)CH 2 CH 2 (C═O)— (the latter representing an L-gamma-Glu or a D-gamma-Glu residue);
wherein p′ represents an integer in the range of 1 to 4;
and
D represents a drug substance; or
X′ represents a linker of Formula Ie′:

wherein,
--- represents a covalent bond towards R 1 ′ or R 2 ′; or
X′ represents a linker of Formula If′:

wherein,
---- represents a covalent bond towards R 1 ′ or R 2 ′; or
X′ represents a linker of Formula Ig′:

wherein,
--- represents a covalent bond towards R 1 ′ or R 2 ′; or
X′ represents a linker of Formula Ih′:

wherein,
--- represents a covalent bond towards R 1 ′ or R 2 ′; or
X′ represents a linker of Formula Ii′:

wherein,
---- represents a covalent bond towards R 1 ′ or R 2 ′; and
W′ represents a covalent bond or a linker selected from the group consisting of —NHCH 2 (C═O)—, —NHCH 2 CH 2 (C═O)—, —NHCH 2 CH 2 CH 2 (C═O)—, and —NHCH(COOH)CH 2 CH 2 (C═O)— (the latter representing an L-gamma-Glu or a D-gamma-Glu residue); and
R 1 ′ and R 2 ′, which may be identical or different, each represents a group of Formula IIa′ or Formula IIb′:

wherein,
one to four Y′ represents H; and
none, one or two Y′ represents F, Cl, CF 2 , CF 3 , SF 5 , OCF 3 , SO 2 CH 3 and/or SO 2 CF 3 ; and
one Y′ represents (a covalent bond representing) the attachment point to X′ of Formula I′; and
when X′ is Formula Ie′, If′, Ig′ or Ih′, one Y in either R 1 ′ or R 2 ′ represents —(C═O)—W′-D, where W′ represents a covalent bond, or a linker selected from the group consisting of —NHCH 2 (C═O)—, —NHCH 2 CH 2 (C═O)—, —NHCH 2 CH 2 CH 2 (C═O)—, and —NHCH(COOH)CH 2 CH 2 (C═O)— (the latter representing an L-gamma-Glu or a D-gamma-Glu residue); and
wherein D represents a drug substance.

2. A diboron conjugate, wherein the diboron compound according to claim 1 is conjugated to a drug substance via an optional linker.

3. The diboron conjugate of claim 2 , wherein the diboron compound is conjugated to the drug substance via an optional linker by derivatisation of the carboxylic acid moiety of the diboron compound.

Assignees

• Novo Nordisk As

Inventors

• Kruse Thomas
• Kofod-Hansen Mikael
• Muenzel Martin Werner Borchsenius
• Thoegersen Henning
• Sauerberg Per
• Rasmussen Jakob Ewald
• Behrens Carsten
• Hoeg-Jensen Thomas
• Balsanek Vojtech
• Drobnakova Zuzana
• Droz Ladislav
• Havranek Miroslav
• Kotek Vladislav
• Stengl Milan
• Snajdr Ivan
• Drusanova Hana

Classifications

• C07F5/025 Primary

  Boronic and borinic acid compounds · CPC title

• A61K47/54

  the modifying agent being an organic compound · CPC title

• A61K31/69

  Boron compounds · CPC title

• A61K33/00

  Medicinal preparations containing inorganic active ingredients · CPC title

• C12Q1/00

  Measuring or testing processes involving enzymes, nucleic acids or microorganisms (measuring or testing apparatus with condition measuring or sensing means, e.g. colony counters, C12M1/34); Compositions therefor; Processes of preparing such compositions · CPC title