Methods for preparing antibody drug conjugates

Patent metadata

Field	Value
Publication number	US-11547762-B2
Application number	US-201916354905-A
Country	US
Kind code	B2
Filing date	Mar 15, 2019
Priority date	Oct 5, 2016
Publication date	Jan 10, 2023
Grant date	Jan 10, 2023

Abstract

The subject matter described herein is directed to methods of preparing certain antibody-drug conjugates (ADCs) wherein the antibody is linked to the drug through a linker, wherein the drug contains a heteroaryl group having a secondary nitrogen, and the linker is attached to the drug via the secondary nitrogen. The resulting conjugates are useful in treating various diseases and conditions.

First claim

That which is claimed:

1. A method for preparing an antibody-drug conjugate of Formula I:
Ab-(L1-D) p   I

or a pharmaceutically acceptable salt thereof, wherein
Ab is an antibody;
L1 is a linking moiety with the structure

wherein,
R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of H, optionally substituted branched or linear C 1 -C 5 alkyl, and optionally substituted C 3 -C 6 cycloalkyl, or R 3 and R 4 taken together with the carbon atom to which they are bound form a C 3 -C 6 cycloalkyl
wherein said optionally substituted alkyl or cycloalkyl may be substituted with alkyl, cycloalkyl, aryl, heteroaryl, hydroxyl, nitrile, halo, alkoxy, haloalkoxy, arylalkoxy, acyloxy, alkylthio, sulfonate, amino, alkylamino, acylamino, carbamoyl, alkylcarbamoyl, or nitro;
D is

wherein L1 is covalently bonded to the secondary nitrogen; and
p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
the method comprising:
i. contacting a compound of Formula II
T-L1-D  II

with an antibody, wherein,
L1 and D are as described above,
T is a leaving group having the structure R 5 —S,
wherein R 5 is an optionally substituted pyridine,
wherein an antibody-drug conjugate of Formula I is prepared.

2. The method of claim 1 , wherein T-L1-D has the following formula:

wherein, R 5 is selected from the group consisting of unsubstituted pyridine and nitropyridine.

3. The method of claim 1 , wherein said antibody-drug conjugate of Formula I has the structure:

wherein p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

4. The method of claim 1 , wherein said antibody-drug conjugate of Formula I has the structure:

wherein p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

5. The method of claim 1 , wherein the antibody-drug conjugate of Formula I is selected from the group consisting of:

wherein p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

6. A method for preparing a compound of Formula III:

wherein,
R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of H, optionally substituted branched or linear C 1 -C 5 alkyl, and optionally substituted C 3 -C 6 cycloalkyl, or R 3 and R 4 taken together with the carbon atom to which they are bound form a C 3 -C 6 cycloalkyl ring
wherein said optionally substituted alkyl or cycloalkyl may be substituted with alkyl, cycloalkyl, aryl, heteroaryl, hydroxyl, nitrile, halo, alkoxy, haloalkoxy, arylalkoxy, acyloxy, alkylthio, sulfonate, amino, alkylamino, acylamino, carbamoyl, alkylcarbamoyl, or nitro; and
D is

wherein the carbonyl in Formula III is covalently bonded to the secondary nitrogen in D;
R 5 is selected from the group consisting of optionally substituted pyridine and nitropyridine;
the method comprising:
i. contacting a compound of Formula V:

wherein LG is a leaving group and PG is a protecting group, with a compound, D, to prepare a compound of Formula VI:

and,
ii. deprotecting the compound of Formula VI under acidic conditions to prepare a compound of Formula III:

7. A compound of Formula III:

wherein,
R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of H, optionally substituted branched or linear C 1 -C 5 alkyl, and optionally substituted C 3 -C 6 cycloalkyl, or R 3 and R 4 taken together with the carbon atom to which they are bound form a C 3 -C 6 cycloalkyl ring
wherein said optionally substituted alkyl or cycloalkyl may be substituted with alkyl, cycloalkyl, aryl, heteroaryl, hydroxyl, nitrile, halo, alkoxy, haloalkoxy, arylalkoxy, acyloxy, alkylthio, sulfonate, amino, alkylamino, acylamino, carbamoyl, alkylcarbamoyl, or nitro;
R 5 is selected from the group consisting of optionally substituted pyridine and nitropyridine;
and
D is

wherein the carbonyl in Formula III is covalently bonded to the secondary nitrogen in D.

8. The method of claim 1 for preparing an antibody-drug conjugate of Formula IV:

or a pharmaceutically acceptable salt thereof, wherein
Ab is an antibody;
R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of H, optionally substituted branched or linear C 1 -C 5 alkyl, and optionally substituted C 3 -C 6 cycloalkyl, or R 3 and R 4 taken together with the carbon atom to which they are bound form a C 3 -C 6 cycloalkyl ring,
wherein said optionally substituted alkyl or cycloalkyl may be substituted with alkyl, cycloalkyl, aryl, heteroaryl, hydroxyl, nitrile, halo, alkoxy, haloalkoxy, arylalkoxy, acyloxy, alkylthio, sulfonate, amino, alkylamino, acylamino, carbamoyl, alkylcarbamoyl, or nitro;
D is

wherein the carbonyl in Formula IV is covalently bonded to the secondary nitrogen in D; and
p is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
the method comprising:
i. contacting a compound of Formula V:

with a compound D, wherein LG is a leaving group and PG is a protecting group, to prepare a compound of Formula VI:

ii. contacting the compound of Formula VI with a disulfide R 5 —S—S—R 5 under acidic conditions to prepare a compound of Formula III:

wherein R 5 is an optionally substituted pyridine; and
iii. contacting a compound of Formula III with an antibody to prepare an antibody-drug conjugate of Formula IV.

9. The method of claim 2 wherein the compound of Formula III is selected from:

10. The method of claim 1 wherein the antibody is Anti-HER2 or Anti-B7H4.

Assignees

• Genentech Inc

Inventors

• Pillow Thomas
• DRAGOVICH Peter

Classifications

• A61P5/28

  Antiandrogens · CPC title

• C07K16/2863

  against receptors for growth factors, growth regulators · CPC title

• A61P33/06

  Antimalarials · CPC title

• A61P5/32

  Antioestrogens · CPC title

• C07K16/22

  against growth factors {; against growth regulators} · CPC title