Chemoselective thiol-conjugation with alkene or alkyne-phosphonothiolates and -phosphonates

Patent metadata

Field	Value
Publication number	US-12453779-B2
Application number	US-201916977680-A
Country	US
Kind code	B2
Filing date	Mar 6, 2019
Priority date	Mar 7, 2018
Publication date	Oct 28, 2025
Grant date	Oct 28, 2025

Abstract

Disclosed are novel conjugates and processes for the preparation thereof. A process for the preparation of alkene-or alkyne-phosohonothiolates and -phosphonates comprises the step of: reacting a compound of formula (I) with a thiol-containing molecule of formula (II) wherein represents an amino acid, a peptide, a protein, an antibody, a nucleotide, an oligonucleotide, a saccharide, a polysaccharide, a polymer, an optionally substituted C 1 -C 8 -alkyl, an optionally substituted phenyl, or an optionally substituted aromatic 5- or 6-membered heterocyclic system; resulting in a compound of formula (III).

First claim

The invention claimed is:

1. A compound of formula (III)

wherein
represents a bond and X represents (R 3 R 4 )C, wherein R 3 and R 4 independently represent H or C 1 -C 8 -alkyl; or
represents a double bond and X represents R 3 C, wherein R 3 represents H or C 1 -C 8 -alkyl; and
Y represents S;
R 1 represents an optionally substituted aliphatic or aromatic residue;
represents an aliphatic or aromatic residue; and
represents an amino acid, a peptide, a protein, an antibody, or a nucleotide.

2. The compound according claim 1 , wherein R 1 represents C 1 -C 8 -alkyl optionally substituted with at least one of (C 1 -C 8 -alkoxy) n wherein n is 1, 2, 3, 4, 5 or 6, F, Cl, Br, I, —NO 2 , —N(C 1 -C 8 -alkyl)H, —NH 2 , —N 3 , —N(C 1 -C 8 -alkyl) 2 , ═O, C 3 -C 8 -cycloalkyl, —S—S—(C 1 -C 8 -alkyl), hydroxy-(C 1 -C 8 -alkoxy)n wherein n is 1, 2, 3, 4, 5 or 6, C 2 -C 8 -alkenyl, or C 2 -C 8 -alkynyl; or
R 1 represents phenyl optionally independently substituted with at least one of C 1 -C 8 -alkyl, (C 1 -C 8 -alkoxy)n wherein n is 1, 2, 3, 4, 5 or 6, F, Cl, I, Br, —NO 2 , —N(C 1 -C 8 -alkyl)H, —NH 2 , or —N(C 1 -C 8 -alkyl) 2 ; or
R 1 represents a 5- or 6-membered heteroaromatic system; or
R 1 represents C 1 -C 8 -alkyl, C 1 -C 8 -alkyl substituted with —S—S—(C 1 -C 8 -alkyl), C 1 -C 8 -alkyl substituted with (C 1 -C 8 -alkoxy) n wherein n is 1, 2, 3, 4, 5 or 6, C 1 -C 8 -alkyl substituted with optionally substituted phenyl; or phenyl; or phenyl substituted with —NO 2 .

3. The compound according to claim 1 , wherein R 1 represents methyl, ethyl, propyl or butyl.

4. The compound according to claim 1 , wherein R 1 represents

with n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

with n=0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, wherein # represents the position of O.

5. The compound according to claim 1 , wherein represents an antibody, a protein, or a tripeptide.

6. The compound according to claim 2 , wherein the 5- or 6-membered heteroaromatic system is pyridyl.

7. The compound according to claim 3 , wherein R 1 represents methyl or ethyl.

8. The compound according to claim 5 , wherein when represents an antibody, the antibody is an lgG-antibody.

9. The compound according to claim 8 , wherein the IgG-antibody is Cetuximab, Trastuzumab or Brentuximab.

10. The compound of claim 5 , wherein the tripeptide is a peptide of formula (VIII)

or of formula (IX)

wherein # represents the position of S.

11. The compound of claim 1 , wherein the aliphatic or aromatic residue comprises a linker-drug conjugate.

Assignees

• Forschungsverbund Berlin Ev
• Univ Muenchen Ludwig Maximilians

Inventors

• Hackenberger Christian
• Baumann Alice Leonie
• Kasper Marc-André
• Byrne Stephen
• Helma-Smets Jonas
• Leonhardt Heinrich
• Stoscheck Tina
• Gerlach Marcus
• Schumacher Dominik

Classifications

• A61K47/68031

  the drug being an auristatin · CPC title

• C07F9/4071 Primary

  the ester moiety containing a substituent or a structure which is considered as characteristic · CPC title

• C07F9/4015

  Esters of acyclic unsaturated acids · CPC title

• A61K47/6889

  Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment · CPC title

• A61K47/6849 Primary

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title