Glucose-sensitive albumin-binding derivatives

Patent metadata

Field	Value
Publication number	US-2022081451-A1
Application number	US-202117500242-A
Country	US
Kind code	A1
Filing date	Oct 13, 2021
Priority date	Nov 9, 2017
Publication date	Mar 17, 2022
Grant date	—

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

1 . A diboron compound represented by 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 ;
W represents —OH, —NHCH 2 COOH, —NHCH 2 CH 2 COOH, —NHCH 2 CH 2 CH 2 COOH, or —NHCH(COOH)CH 2 CH 2 COOH (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;
wherein m represents an integer in the range of 1 to 4; and
W represents OH, NHCH 2 COOH; NHCH 2 CH 2 COOH; NHCH 2 CH 2 CH 2 COOH; or NHCH(COOH)CH 2 CH 2 COOH (the latter representing an L-gamma-Glu or a D-gamma-Glu residue); 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 —OH, —NHCH 2 COOH, —NHCH 2 CH 2 COOH, —NHCH 2 CH 2 CH 2 COOH, or —NHCH(COOH)CH 2 CH 2 COOH (the latter representing an L-gamma-Glu or a D-gamma-Glu residue); or
wherein 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-diaminopyrrolidine;
wherein,
represents a covalent bond towards R 1 or R 2 ;
R 4 represents —(C═O)(CH 2 ) p (C═O)—W;
wherein p represents an integer in the range of 1 to 4;
W represents —OH, —NHCH 2 COOH, —NHCH 2 CH 2 COOH, —NHCH 2 CH 2 CH 2 COOH, or —NHCH(COOH)CH 2 CH 2 COOH (the latter representing an L-gamma-Glu or a D-gamma-Glu residue); 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 —OH, —NHCH 2 COOH, —NHCH 2 CH 2 COOH, —NHCH 2 CH 2 CH 2 COOH, or —NHCH(COOH)CH 2 CH 2 COOH (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 IIb:

wherein,
one to four Y represents H; and
none, one or two of 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, where W represents —OH, —NHCH 2 COOH, —NHCH 2 CH 2 COOH, —NHCH 2 CH 2 CH 2 COOH, or —NHCH(COOH)CH 2 CH 2 COOH (the latter representing an L-gamma-Glu or a D-gamma-Glu residue).

2 . The diboron compound of claim 1 , represented by Formula I, wherein X represents a linker of Formula Ia:

wherein
represents a covalent bond towards R 1 or R 2 ;
W represents —OH, —NHCH 2 COOH, —NHCH 2 CH 2 COOH, —NHCH 2 CH 2 CH 2 COOH, or —NHCH(COOH)CH 2 CH 2 COOH (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 IIb:

wherein,
one Y represents (a covalent bond representing) the attachment point to the linker X of Formula Ia;
none, one or two of Y represent F, Cl, CF 2 , CF 3 , SF 5 , OCF 3 , SO 2 CH 3 and/or SO 2 CF 3 ; and
the remaining Y represents H.

3 . The diboron compound of claim 1 , represented by Formula I, wherein 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;
wherein m represents an integer in the range of 1 to 4;
W represents OH, NHCH 2 COOH; NHCH 2 CH 2 COOH; NHCH 2 CH 2 CH 2 COOH; or NHCH(COOH)CH 2 CH 2 COOH (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 IIb:

wherein,
one Y represents (a covalent bond representing) the attachment point to the linker X of Formula Ib;
none, one or two of Y represent F, Cl, CF 2 , CF 3 , SF 5 , OCF 3 , SO 2 CH 3 and/or SO 2 CF 3 ; and
the remaining Y represents H.

4 . The diboron compound of claim 1 , represented by Formula I, wherein 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 —OH, —NHCH 2 COOH, —NHCH 2 CH 2 COOH, —NHCH 2 CH 2 CH 2 COOH, or —NHCH(COOH)CH 2 CH 2 COOH (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 IIb:

wherein,
one Y represents (a covalent bond representing) the attachment point to the linker X of Formula Ic;
none, one or two of Y represent F, Cl, CF 2 , CF 3 , SF 5 , OCF 3 , SO 2 CH 3 and/or SO 2 CF 3 ; and
the remaining Y represents H.

5 . The diboron compound of claim 1 , represented by Formula I, wherein 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-diaminopyrrolidine;
wherein,
represents a covalent bond towards R 1 or R 2 ;
R 4 represents —(C═O)(CH 2 ) p (C═O)—W;

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

• C40B30/04

  by measuring the ability to specifically bind a target molecule, e.g. antibody-antigen binding, receptor-ligand binding · CPC title

• A61K47/54

  the modifying agent being an organic compound · CPC title

• G01N2800/042

  Disorders of carbohydrate metabolism, e.g. diabetes, glucose metabolism · CPC title

• C12Q3/00

  Condition responsive control processes (apparatus therefor C12M1/36; controlling or regulating in general G05) · CPC title