Conjugation linkers, cell binding molecule-drug conjugates containing the linkers, methods of making and uses such conjugates with the linkers

Patent metadata

Field	Value
Publication number	US-12285491-B2
Application number	US-202217835081-A
Country	US
Kind code	B2
Filing date	Jun 8, 2022
Priority date	Nov 14, 2016
Publication date	Apr 29, 2025
Grant date	Apr 29, 2025

Abstract

The present invention relates to linkers having a group of propiolyl, substituted acryl (acryloyl), or disubstituted propanoyl, and using such linkers for the conjugation of compounds, in particular, cytotoxic agents to a cell-binding molecule.

First claim

The invention claimed is:

1. A compound of Formula (XVII) or (XVIII):

wherein
represent a single bond, and “ ” can be an enantiomer or stereoisomer bond when linked to a single or a double bond;
represents either a single bond, or a double bond, or a triple bond;
provided that when represents a single bond, both Lv 1 and Lv 2 are not H; when represents a double bond, either Lv 1 or Lv 2 can be H, but they are not H at the same time; when represents a triple bond, Lv 1 is absent and Lv 2 can optionally be H;
Lv 1 and Lv 2 represent H or same or different leaving group that is optionally substituted by a thiol, and the leaving group is selected from the group consisting of a halide (selected from, fluoride, chloride, bromide, and iodide), methanesulfonyl (mesyl), toluenesulfonyl (tosyl), trifluoromethyl-sulfonyl (triflate), trifluoromethylsulfonate, nitrophenoxyl, N-succinimidyloxyl (NHS), phenoxyl; dinitrophenoxyl; pentafluorophenoxyl, tetrafluorophenoxyl, trifluorophenoxyl, difluorophenoxyl, monofluorophenoxyl, pentachlorophenoxyl, 1H-imidazole-1-yl, chlorophenoxyl, dichlorophenoxyl, trichlorophenoxyl, tetrachlorophenoxyl, N-(benzotriazol-yl) oxyl, 2-ethyl-5-phenylisoxazolium-3′-sulfonyl, phenyloxadiazole-sulfonyl (-sulfone-ODA), 2-ethyl-5-phenylisoxazoliumyl, phenyloxadiazolyl (ODA), or oxadiazolyl
R 1 is a combination of two or more of C 1 -C 8 alkyl; C 2 -C 8 amide and polyethyleneoxy unit of formula (OCH 2 CH 2 ) p or (OCH 2 CH(CH 3 )) p , wherein p is an integer from 1 to about 1000;
T is

wherein is the site of linkage,
m 1 , m 2 , m 3 , m 4 and m 5 are independently an integer from 1 to 10,
L 1 , L 2 , and X 1 , are absent; and
Drug is a selected from the group consisting of tubulysins, calicheamicins, auristatins, maytansinoids, CC-1065 compounds, daunorubicins, doxorubicins, taxanoids (taxanes), cryptophycins, epothilones, benzodiazepine dimers, calicheamicins and enediyne antibiotics, actinomycins, amanitins, azaserines, bleomycins, epirubicins, tamoxifen, idarubicin, dolastatins, auristatins, duocarmycins, geldanamycins, methotrexates, thiotepa, vindesines, vincristines, hemiasterlins, nazumamides, microginins, radiosumins, alterobactins, microsclerodermins, theonellamides, esperam1cms, siRNA, miRNA, piRNA, nucleolytic enzymes, and pharmaceutically acceptable salts and acids of any of the above molecules.

2. The compound according to claim 1 having one of 13, 17, 27, 31, 44, 52, 82, 85, 123, 166, 172, 267, 272, 280, 288, 292, 295, 312, 314, 493, 495, 497, 499, 505 and 507 as shown in below:

wherein , and Drug are defined the same as in claim 1 ; L is absent.

3. The compound of claim 1 , wherein represents a single bond, and Lv 1 and Lv 2 represent Br or I.

4. The compound of claim 1 , wherein represents a double bond, and Lv 1 and Lv 2 represent H or Br.

5. The compound of claim 1 , wherein represents a triple bond, and Lv 2 represent H.

6. The compound of claim 1 , wherein R 1 is *—C 1 -C 8 alkyl-CONH(CH 2 CH 2 O) p —C 1 -C 8 alkyl-CONH-C 1 -C 8 alkyl-CONH-**, p is an integer from 1 to 1000,* is a linking site to T and ** is a linking site to Drug.

7. The compound of claim 6 , wherein R 1 is *—C 1 -C 8 alkyl-CONH(CH 2 CH 2 O) p CH 2 CH 2 CONH(CH(CH 3 ) 2 )CONH—**.

8. The compound of claim 1 , wherein R 1 is *—C 1 -C 8 alkyl-CONH(CH 2 CH 2 O) p —C 1 -C 8 alkyl-CONH-**, p is an integer from 1 to 1000, * is a linking site to T and ** is a linking site to Drug.

9. The compound of claim 1 , wherein m 1 , m 2 , m 3 , and ms are independently an integer from 1 to 10, m 4 is 2.

10. The compound of claim 1 , wherein m 1 , m 3 and m 5 are 1, m 2 and m 4 is 1.

11. The compound of claim 1 , wherein Drug is a benzodiazepine dimer.

Assignees

• Hangzhou Dac Biotech Co Ltd

Inventors

• Zhao Yongxin Robert
• Yang Qingliang
• Huang Yuanyuan
• Gai Shun
• Ye Hangbo
• Zhao Linyao
• Yang Chengyu
• Guo Huihui
• Zhou Xiaomai
• Xie Hongsheng
• Zhu Haifeng
• Xu Yifang
• Tong Qianqian
• Jia Junxiang
• Cao Minjun
• Li Wenjun
• Gao Shuihong
• Guo Zhixiang
• Bai Lu
• Li Chen
• Yang Yanlei
• Wang Chunyan
• Ye Zhichang

Classifications

• A61K47/68035

  the drug being a pyrrolobenzodiazepine · CPC title

• A61K47/68031

  the drug being an auristatin · CPC title

• A61K47/6863

  the tumour determinant being from stomach or intestines cancer cell · CPC title

• A61K47/6855

  the tumour determinant being from breast cancer cell · CPC title

• A61K47/6829

  Bacterial toxins, e.g. diphteria toxins or Pseudomonas exotoxin A · CPC title