Granted Patent
B2
US 12,285,491 · App. 17/835,081 · Granted Apr 29, 2025
Conjugation linkers, cell binding molecule-drug conjugates containing the linkers, methods of making and uses such conjugates with the linkers
Inventors:
Yongxin Robert Zhao (Hangzhou, CN); Qingliang Yang (Hangzhou, CN); Yuanyuan Huang (Hangzhou, CN); Shun Gai (Hangzhou, CN); Hangbo Ye (Hangzhou, CN); Linyao Zhao (Hangzhou, CN); Chengyu Yang (Hangzhou, CN); Huihui Guo (Hangzhou, CN); Xiaomai Zhou (Hangzhou, CN); Hongsheng Xie (Hangzhou, CN); Haifeng Zhu (Hangzhou, CN); Yifang Xu (Hangzhou, CN); Qianqian Tong (Hangzhou, CN); Junxiang Jia (Hangzhou, CN); Minjun Cao (Hangzhou, CN); Wenjun Li (Hangzhou, CN); Shuihong Gao (Hangzhou, CN); Zhixiang Guo (Hangzhou, CN); Lu Bai (Hangzhou, CN); Chen Li (Hangzhou, CN); Yanlei Yang (Hangzhou, CN); Chunyan Wang (Hangzhou, CN); Zhichang Ye (Hangzhou, CN)
Assignee:
HANGZHOU DAC BIOTECH CO., LTD.
A61K47/6803A61K47/68031A61K47/68035A61K47/6829A61K47/6831A61K47/6855A61K47/6863A61K47/6883A61K47/6889
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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.
Claims (23)
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.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jun 8, 2022
From: 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
To: HANGZHOU DAC BIOTECH CO., LTD.
Reel/Frame 060133/0265 →
Continuity (2)
Division
16348749
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