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CN-121971644-A - Ligand drug conjugate and preparation method and application thereof

CN121971644ACN 121971644 ACN121971644 ACN 121971644ACN-121971644-A

Abstract

The invention discloses a ligand drug conjugate and a preparation method and application thereof. The present invention provides a compound of formula I, a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt thereof. The antibody drug conjugate has one or more of the following advantages that (1) the antibody drug conjugate has high stability in circulation, reduces the falling off of non-target drugs in non-target cells, (2) the antibody drug conjugate can increase the effective release of bioactive molecules in cells to achieve the aim of synergism and toxicity reduction, (3) the antibody drug conjugate has good tumor tissue targeting property, and (4) the antibody drug conjugate has good treatment effect on tumor animal models.

Inventors

  • YI LEI
  • Lin Shengchao
  • ZHANG YU
  • LI BING
  • YANG JUNJIE
  • HUA HAIQING
  • ZHU ZHONGYUAN

Assignees

  • 映恩生物科技(上海)有限公司

Dates

Publication Date
20260505
Application Date
20240322
Priority Date
20230322

Claims (10)

  1. 1. A compound of formula I or a pharmaceutically acceptable salt thereof: ; Ab is trastuzumab or combretastatin; q is an integer or fraction of 7 to 8; L 1 is Wherein, the a end is connected with Ab, and the b end is connected with L 2 ; l 2 is The carbonyl end is connected with L 3 ; t1 and t3 are each independently 1, 2 or 3, t2 is 0, t5 is 0, and t6 is 1; L 3 is Gly-Gly-Phe-Gly, the left side of the group reading sequence is NH end which is connected with L 2 , the right side of the group reading sequence is carbonyl end which is connected with Tr; tr is Wherein the "1" position is linked to L 3 and the "2" position is linked to TAS-106; r Tr1 and R Tr2 are each independently hydrogen or deuterium; -TAS-106 is 。
  2. 2. The compound of formula I or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein Ab is trastuzumab; Or q is 7.9 or 7.96.
  3. 3. A compound of formula I, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein: l 2 is Wherein the c-terminal is connected with L 1 , and the d-terminal is connected with L 3 .
  4. 4. A compound of formula I, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein: tr is Or (b) Wherein, the e end is connected with L 3 , and the f end is connected with TAS-106; Preferably, tr is Wherein the e end is connected with L 3 , and the f end is connected with TAS-106.
  5. 5. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is any one of the following: , , q is an integer or fraction of 7-8; preferably, the compound of formula I is any one of the following compounds: 。
  6. 6. A compound of formula II or a salt thereof, characterized in that, ; L 1a is ; -TAS-106 is L 2 、L 3 and Tr are as defined in any one of claims 1 to 5.
  7. 7. The compound of formula II, or a salt thereof, as claimed in claim 6, wherein the compound of formula II is the following compound: 。
  8. 8. a pharmaceutical composition or pharmaceutical formulation comprising a compound of formula I as defined in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.
  9. 9. Use of substance S in the manufacture of a medicament for preventing or treating cancer; the substance S is a compound of formula I as defined in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 8, or a pharmaceutical formulation as defined in claim 8; The cancer is lung cancer, gastric cancer, breast cancer or liver cancer; preferably, the lung cancer is small cell lung cancer and non-small cell lung cancer.
  10. 10. Use of substance S in the preparation of a medicament; the substance S is a compound of formula I as defined in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 8, or a pharmaceutical formulation as defined in claim 8; The medicine is used for treating diseases related to a target A, wherein the target A is a target corresponding to trastuzumab or coltrastuzumab; The diseases related to the target A are lung cancer, gastric cancer, breast cancer or liver cancer; preferably, the lung cancer is small cell lung cancer and non-small cell lung cancer.

Description

Ligand drug conjugate and preparation method and application thereof The application relates to a divisional application of Chinese patent application 2024103370165. The present application claims priority from chinese patent application 2023102888825, whose filing date is 2023, 3 and 22. The application date of the original application is 2024, 03 and 22, the application number is 2024103370165, and the invention creates a kind of ligand drug conjugate and its preparation method and application. Technical Field The invention belongs to the technical field of medicines, and relates to a ligand drug conjugate, a preparation method thereof and application thereof in preventing and/or treating tumor-related diseases. Background Nucleoside antimetabolites are important drugs in cancer chemotherapy, and currently clinically used nucleoside drugs, such as 5-fluorouracil (5-FU), 1- (2-deoxy-2-methylene- β -D-erythronolide) cytosine (DMDC), 2' -deoxy-2 ', 2' -difluorocytosine (gemcitabine), 1- (2-C-cyano-2-deoxy-D-arabino-furanosyl) cytosine (CNDAC), and the like, mainly act on the S phase of tumor cell DNA synthesis. However, chemotherapeutic agents that act only on the S phase are not ideal for inhibiting partial slow-proliferating solid tumors, one of the reasons being that such agents have little chance to bind to non-replicating DNA (i.e., the non-S phase). Thus, nucleoside antitumor drugs are insufficient to inhibit tumor cell DNA synthesis alone. TAS-106 (ECyd, 3' -C-acetylcytidine) is a nucleoside analog (WO 199618636; J.Med. Chem.1996,39, 5005-5011) that inhibits RNA synthesis throughout the cell cycle except M phase by blocking RNA polymerase. In vitro and in vivo studies have shown that TAS-106 has potent antiproliferative activity against a variety of human tumor cells and tumor xenografts (Cancer letters.116 (1997), 225-231; oncology 2013; 85:356-363). The structural formula of TAS-106 is as follows: The antibody-drug-conjugate (ADC) connects monoclonal antibody or antibody fragment with the cytotoxicity drug with bioactivity through stable chemical linker compound, makes full use of the specificity of the antibody on the surface antigen combination of normal cells and tumor cells and the high efficiency of the cytotoxicity drug, and simultaneously avoids the defects of low curative effect, overlarge toxic and side effects of the former and the like. This means that the antibody drug conjugate binds tumor cells precisely and reduces the effect on normal cells compared to conventional chemotherapeutics (Mullard A,(2013)Nature Reviews Drug Discovery,12:329–332;DiJoseph JF,Armellino DC,(2004)Blood,103:1807-1814). The toxins commonly used in ADC are mainly tubulin interference drugs and DNA damage drugs, including camptothecins, MMAE, T-DM1 and the like, and mainly act on the S phase and the G2 phase of DNA synthesis, but the two toxins have respective use limitations (such as weak inhibition effect of the DNA damage drugs on slowly-proliferated tumor cells, large toxicity of the tubulin interference drugs and the like), and in addition, the two toxins are not sensitive to the primary or secondary drug-resistant tumors, and the drugs with new mechanisms are also urgently needed to be used as effective loads of the ADC. While the ADC with the RNA polymerase inhibitor amatoxins as a payload has been in the clinic (HDP-101) at present, preclinical toxicological data indicate that the highest non-severe toxic dose (HNSTD) of amatoxins is low due to their hematotoxicity and hepatorenal toxicity, and thus there is an urgent need to develop new toxins with new mechanisms, expand the types of toxins, and address unmet clinical needs. The invention designs and synthesizes a series of biological conjugates of TAS-106 with remarkable anti-tumor activity, which are used for treating tumor related diseases. Disclosure of Invention The present invention aims to provide a bioconjugate comprising a bio-targeting moiety and a TAS-106 moiety as a cytotoxic agent, which has a good inhibitory capacity against tumor cells. In a first aspect, the present invention provides a compound of formula I, a pharmaceutically acceptable salt, stereoisomer, solvate or solvate of a pharmaceutically acceptable salt thereof: Ab is a ligand that binds to a target (e.g., a small molecule ligand, a protein, an antibody or antigen binding fragment thereof, a polypeptide, a non-protein agent (e.g., sugar, RNA, or DNA)); q is an integer or fraction of 1 to 16 (q is drug loading); L 1（L1 is a linker moiety that reacts with any amino, sulfhydryl or other chemical functional group on the ligand to covalently attach the entire linker-load to the ligand) is 、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、、Or (b); L 2（L2 is a linking unit) is- (C (R L21RL22)n -, Wherein n is a natural number, Any-C (R L21RL22) -in L 2 is each independently optionally replaced by a structural unit ：-Cyr-、-N(RL23)C(O)-、-C(O)N(RL23)-、-C(O)-、-OC(O)-、-C(O)O-、-NRL23-、-O-、-S-、-SO-、-SO2-、-P(R