Charged linkers and their uses for conjugation

Patent metadata

Field	Value
Publication number	US-10464955-B2
Application number	US-201415118726-A
Country	US
Kind code	B2
Filing date	Feb 28, 2014
Priority date	Feb 28, 2014
Publication date	Nov 5, 2019
Grant date	Nov 5, 2019

Abstract

Cell binding agent-drug conjugates comprising phosphinate-based charged linkers and methods of using such linkers and conjugates are provided.

First claim

What is claimed is:

1. A charged linker of formula (I)

wherein:
Y represents a functional group selected from the group consisting of an unsubstituted or substituted N-hydroxysuccinimide ester, p-nitrophenyl ester, dinitrophenyl ester, pentafluorophenyl ester, pyridyldisulfide, nitropyridyldisulfide, unsubstituted maleimido, β-maleimidopropionamido, haloacetate and carboxylic acid halide;
Z is different from Y and represents a thiol, pyridyldisulfide, —ONH 2 , carboxy, aldehyde, ketone, azide, unsubstituted or substituted maleimido, haloacetyl, hydrazine, halogen, or hydroxy group;
M is H, Na, K, N + R 1 R 2 R 3 or a pharmaceutical salt thereof;
R 1 is a linear alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms, polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to about 1000, or a combination thereof;
R 2 is absent;
R 3 is a linear alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms, polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to about 1000, or a combination thereof;
R 4 , and R 5 , are the same or different and are absent, H, a linear alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms, or a combination thereof.

2. The charged linker of claim 1 , wherein Y represents an unsubstituted or substituted N-hydroxysuccinimide ester, or an unsubstituted maleimido.

3. The charged linker of claim 1 , wherein Z is pyridyldisulfide, —ONH 2 , ketone, azide, or unsubstituted or substituted maleimido.

4. The charged linker of claim 1 , wherein R 1 and R 3 are the same or different and are a polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to 100.

5. The charged linker of claim 1 , wherein R 1 and R 3 are the same or different and are a linear alkyl having from 1 to 6 carbon atoms.

6. The charged linker of claim 1 , wherein R 3 is a polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to 100 or a linear alkyl having from 1 to 6 carbon atoms, and R 4 and R 5 are absent.

7. The charged linker of claim 1 , wherein R 3 is a polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to about 1000, and R 4 and R 5 are absent.

8. The charged linker of claim 7 , wherein p is an integer from 1 to 24.

9. The charged linker of claim 1 , wherein M is H.

10. The charged linker of claim 1 , wherein
Y represents an unsubstituted or substituted N-hydroxysuccinimide ester, or an unsubstituted maleimido;
Z is pyridyldisulfide, azide, or unsubstituted or substituted maleimido;
R 1 and R 3 are the same or different and are a linear alkyl having from 1 to 6 carbon atoms;
R 4 and R 5 are absent; and
M is H.

11. The charged linker of claim 1 , wherein
Y represents an unsubstituted or substituted N-hydroxysuccinimide ester, or an unsubstituted maleimido;
Z is pyridyldisulfide, —ONH 2 , ketone, azide, or unsubstituted or substituted maleimido;
R 1 and R 3 are the same or different and are a linear alkyl having from 1 to 6 carbon atoms;
R 4 and R 5 are absent; and
M is H.

12. The charged linker of claim 1 , wherein
Y represents an unsubstituted N-hydroxysuccinimide ester, or an unsubstituted maleimido;
Z is pyridyldisulfide, —ONH 2 , ketone, azide, or unsubstituted maleimido;
R 1 and R 3 are the same or different and are a linear alkyl having from 1 to 6 carbon atoms;
R 4 and R 5 are absent; and
M is H.

13. The charged linker of claim 1 , wherein
Y represents an unsubstituted or substituted N-hydroxysuccinimide ester, or an unsubstituted maleimido;
Z is pyridyldisulfide, azide, or unsubstituted or substituted maleimido;
R 1 is a linear alkyl having from 1 to 6 carbon atoms;
R 3 consists of a linear alkyl having from 1 to 6 carbon atoms and a polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to 24;
R 4 and R 5 are absent; and
M is H.

14. The charged linker of claim 1 , wherein
Y represents an unsubstituted or substituted N-hydroxysuccinimide ester, or an unsubstituted maleimido;
Z is pyridyldisulfide, —ONH 3 , ketone, azide, or unsubstituted or substituted maleimido;
R 1 is a linear alkyl having from 1 to 6 carbon atoms;
R 3 consists of a linear alkyl having from 1 to 6 carbon atoms and a polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to 24;
R 4 and R 5 are absent; and
M is H.

15. The charged linker of claim 1 , wherein
Y represents an unsubstituted N-hydroxysuccinimide ester, or an unsubstituted maleimido;
Z is pyridyldisulfide, —ONH 2 , ketone, azide, or unsubstituted maleimido;
R 1 is a linear alkyl having from 1 to 6 carbon atoms;
R 3 consists of a linear alkyl having from 1 to 6 carbon atoms and a polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to 24;
R 4 and R 5 are absent; and
M is H.

16. The charged linker of claim 1 , wherein R 1 and R 3 are the same or different and are a linear alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms, or polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to about 1000.

Assignees

• Hangzhou Dac Biotech Co Ltd

Inventors

• Zhao Robert Yongxin
• Li Xing
• Huang Yuangyuang
• Yang Qingliang

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title