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CN-121987815-A - Antitumor compound and preparation method and application thereof

CN121987815ACN 121987815 ACN121987815 ACN 121987815ACN-121987815-A

Abstract

The application relates to an anti-tumor compound and a preparation method and application thereof, in particular to a compound or a tautomer, a meso form, a racemate form, an enantiomer, a diastereoisomer or a mixture form thereof or a pharmaceutically acceptable salt thereof, and a preparation method and application thereof.

Inventors

  • ZHANG YU
  • ZHU ZHONGYUAN
  • HUA HAIQING
  • LI BING
  • LI JIAN
  • Lin Shengchao
  • LI XI
  • SHEN HONGXIA

Assignees

  • 映恩生物制药（苏州）有限公司

Dates

Publication Date
20260508
Application Date
20210929
Priority Date
20200930

Claims (20)

  1. 1. A compound, a mixture thereof, or a pharmaceutically acceptable salt thereof, said compound having the structure: , wherein, The Ab is an antibody, which comprises an antibody light chain variable region VL and an antibody heavy chain variable region VH, the amino acid sequence of the VL is shown as SEQ ID NO. 27, the amino acid sequence of the VH is shown as SEQ ID NO. 31, The average linkage number N a is an integer or fraction selected from 1 to 10.
  2. 2. The compound, mixture form thereof, or pharmaceutically acceptable salt thereof according to claim 1, wherein the Ab comprises an antibody light chain and an antibody heavy chain, wherein the amino acid sequence of the light chain is shown in SEQ ID No. 35 and the amino acid sequence of the heavy chain is shown in SEQ ID No. 39.
  3. 3. The compound, mixture form thereof, or pharmaceutically acceptable salt thereof according to any one of claims 1-2, wherein the average number of linkages N a is an integer or fraction selected from 3 to 8.
  4. 4. The compound, mixture form thereof, or pharmaceutically acceptable salt thereof according to any one of claims 1-2, wherein the average number of linkages N a is an integer or fraction selected from 2 to 6.
  5. 5. The compound, mixture form thereof, or pharmaceutically acceptable salt thereof according to any one of claims 1-2, wherein the average number of linkages N a is an integer or fraction selected from 3 to 5.
  6. 6. The compound, mixture of compounds, or pharmaceutically acceptable salt thereof according to any one of claims 1-2, wherein the average number of linkages N a is 2, 3, 4, 5, or 6.
  7. 7. A compound according to claim 1, in the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, having the structure: the average linkage number N a is an integer or fraction selected from 1 to 10.
  8. 8. A compound according to claim 1, in the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, having the structure: the average linkage number N a is an integer or fraction selected from 1 to 10.
  9. 9. A compound according to claim 1, in the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, having the structure: the average linkage number n is an integer or fraction selected from 1 to 10.
  10. 10. The compound, mixture form thereof, or pharmaceutically acceptable salt thereof according to claim 9, wherein the average linkage number n is an integer or fraction selected from 3 to 8.
  11. 11. The compound, mixture form thereof, or pharmaceutically acceptable salt thereof according to claim 9, wherein the average linkage number n is an integer or fraction selected from 2 to 6.
  12. 12. The compound, mixture form thereof, or pharmaceutically acceptable salt thereof according to claim 9, wherein the average linkage number n is an integer or fraction selected from 3 to 5.
  13. 13. The compound, mixture form thereof, or pharmaceutically acceptable salt thereof according to claim 9, wherein the average number of linkages n is 2, 3, 4, 5, or 6.
  14. 14. A process for preparing a compound of any one of claims 9-13, a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising contacting Sacituzumab with a structure shown below: 。
  15. 15. A pharmaceutical composition comprising a compound of any one of claims 1-13, a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  16. 16. The pharmaceutical composition of claim 15, in the form of a sterile injectable aqueous solution.
  17. 17. Use of a compound according to any one of claims 1 to 13, a mixture thereof or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition according to claim 15 or 16 for the manufacture of a medicament for the treatment of a tumor.
  18. 18. The use of claim 17, wherein the tumor is a tumor associated with Trop2 expression.
  19. 19. The use according to claim 17, wherein the tumor is selected from the group consisting of lung cancer, kidney cancer, urinary tract cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, and esophageal cancer.
  20. 20. The use according to claim 17, said medicament being prepared in a form suitable for oral, intravenous drip, intraperitoneal injection or topical administration.

Description

Antitumor compound and preparation method and application thereof The application relates to a Chinese patent application with application date of 2021, 09 and 29, application number of 202180018263.3 and the name of an anti-tumor compound, a preparation method and application thereof. Technical Field The application relates to the field of biological medicine, in particular to an anti-tumor compound and a preparation method and application thereof. Background Currently, the small cytotoxic molecule used for antibody drug conjugates may be a camptothecin derivative, which has an anti-tumor effect by inhibiting topoisomerase I. The camptothecin derivatives can be applied to antibody conjugated drugs (ADC). There is still a need to further develop camptothecin derivatives and ADC drugs that are better in therapeutic and/or safety. Disclosure of Invention The application provides a compound or a tautomer, a meso, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which can have one or more effects selected from the group consisting of (1) inhibition activity on proliferation of tumor cells in vitro, (2) targeted inhibition, (3) plasma stability, (4) in vivo tumor inhibition effect, (5) bystander killing effect (Bystander Effect), (6) anti-transporter transport capability, (7) in vivo tumor targeting capability, and (8) good in vivo safety. In one aspect, the present application provides a compound, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said compound comprises a structure according to formula (II-a): Wherein X 1 is saturated C, said X 1 being substituted with R n; Ring A is selected from the group consisting of 3 to 10 membered saturated or partially unsaturated heterocyclyl, and 3 to 10 membered saturated or partially unsaturated carbocyclyl, wherein said ring A is substituted with 0 or at least 1 substituents R 1a; When ring a is a 3 to 10 membered saturated or partially unsaturated carbocyclyl, the ring a is substituted with p L 2, the L 2 is not R n; Or when ring a is a 3 to 10 membered saturated or partially unsaturated heterocyclyl, said ring a is substituted with p L 2; L 2 is-R 2-L3 -, said R 2 is used for direct or indirect attachment of a ligand; l 3 is- (C (R 3a)(R3b))m -, wherein when L 3 comprises methylene units, 0 or at least 1 methylene units of said L 3 are each independently replaced by -N(R4)C(O)-、-C(O)N(R4)-、-C(O)-、-OC(O)-、-C(O)O-、-NR4-、-O-、-S-、-SO-、-SO2-、-P(R4)-、-P(=O)(R4)-、-N(R4)SO2-、-SO2N(R4)-、-C(＝S)-、-C(＝NR4)-、-N＝N-、-C＝N-、-N＝C- or-C (=n 2) -; R 2 is selected from the group consisting of: -O-, - (R 2a) N-, -S-, and-P (=o) (R 2a) -; L 1 is- (C (R 5a)(R5b))n -, wherein when L 1 comprises methylene units, 0 or at least 1 methylene units of said L 1 are each independently replaced by -N(R6)C(O)-、-C(O)N(R6)-、-C(O)-、-OC(O)-、-C(O)O-、-NR6-、-O-、-S-、-SO-、-SO2-、-P(R6)-、-P(=O)(R6)-、-N(R6)SO2-、-SO2N(R6)-、-C(＝S)-、-C(＝NR6)-、-N＝N-、-C＝N-、-N＝C- or-C (=n 2) -; Wherein each R 1a,R2a,R3a,R3b,R4,R5a,R5b,R6,Rn is independently hydrogen, protium, deuterium, tritium, halogen 、-NO2、-CN、-OR、-SR、-N(Ra)(Rb)、-C(O)R、-CO2R、-C(O)C(O)R、-C(O)CH2C(O)R、-S(O)R、-S(O)2R、-C(O)N(Ra)(Rb)、-SO2N(Ra)(Rb)、-OC(O)R、-N(R)SO2R、, or a C 1-6 aliphatic optionally substituted with R; Wherein each R, R a,Rb is independently hydrogen, protium, deuterium, tritium, halogen 、-NO2、-CN、-OH、-SH、-NH2、-C(O)H、-CO2H、-C(O)C(O)H、-C(O)CH2C(O)H、-S(O)H、-S(O)2H、-C(O)NH2、-SO2NH2、-OC(O)H、-N(H)SO2H、, or C 1-6 aliphatic; m, n are each independently selected from integers of at least 0, and p is an integer of at least 1. In one aspect, the present application provides a compound of formula (II-E x) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: , Wherein X 1 is saturated C, said X 1 being substituted with R n; Ring A is selected from the group consisting of 3 to 10 membered saturated or partially unsaturated heterocyclyl, and 3 to 10 membered saturated or partially unsaturated carbocyclyl, wherein said ring A is substituted with 0 or at least 1 substituents R 1a; When ring a is a 3 to 10 membered saturated or partially unsaturated carbocyclyl, the ring a is substituted with p L 2, the L 2 is not R n; Or when ring a is a 3 to 10 membered saturated or partially unsaturated heterocyclyl, said ring a is substituted with p L 2; L 2 is-R 2-L3 -, said R 2 is used for direct or indirect attachment of a ligand; l 3 is- (C (R 3a)(R3b))m -, wherein when L 3 comprises methylene units, 0 or at least 1 methylene units of said L 3 are each independently replaced by -N(R4)C(O)-、-C(O)N(R4)-、-C(O)-、-OC(O)-、-C(O)O-、-NR4-、-O-、-S-、-SO-、-SO2-、-P(R4)-、-P(=O)(R4)-、-N(R4)SO2-、-SO2N(R4)-、-C(＝S)-、-C(＝NR4)-、-N＝N-、-C＝N-、-N＝C- or-C (=n 2) -; R 2 is selected from the group consisting of: -O-, - (R 2a) N-, -S-, and-P (=o) (R 2a) -; L 1 is- (C (R 5a)(R5b))