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KR-20260065873-A - Halogen-substituted amide derivative of execan, method of preparation thereof, and applications

KR20260065873AKR 20260065873 AKR20260065873 AKR 20260065873AKR-20260065873-A

Abstract

The present invention relates to the field of biopharmaceuticals and provides a halogen-substituted amide derivative of exatecan, a method for manufacturing the same, and applications thereof. The halogen-substituted amide derivative of exatecan or its pharmaceutically acceptable salt, stereoisomer, or prodrug has excellent cancer cell inhibitory activity and cell membrane permeability activity, and can be utilized in cancer treatment as a monotherapy, combination therapy, or toxic component of antibody-drug conjugates (ADCs).

Inventors

  • 미아오 전웨이
  • 황 윈성

Assignees

  • 항저우 애드코리스 바이오파마 컴퍼니 리미티드

Dates

Publication Date
20260511
Application Date
20240927
Priority Date
20230928

Claims (11)

  1. In the compound of formula (I) or its pharmaceutically acceptable salt, stereoisomer, or prodrug, (I) In the formula, R is a C1 – C6 alkyl, a halogen-substituted C1 – C6 alkyl, , , It is one of the selected from among them; Here, R1 is selected from C1 – C6 alkylenes, and the C1 – C6 alkylene is optionally substituted with one or more substituents selected from halogens, C1 – C6 alkyls, or halogen-substituted C1 – C6 alkyls; A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, characterized in that R2 is selected from halogen, C1 - C6 alkyl, or halogen-substituted C1 - C6 alkyl; and X is selected from amino or imino.
  2. In paragraph 1, R1 is selected from methylene, halogen-substituted methylene, or trifluoromethyl-substituted methylene, and Preferably, a compound or a pharmaceutically acceptable salt, stereoisomer, or prodrug characterized in that R1 is selected from -CHF-, -CHF2- , -CH2- , or -CH( CF3 )-.
  3. In paragraph 1 or 2, R2 is any one selected from halogen, methyl, methylene, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, and heptyl, and preferably, any one of methylene, methyl, ethyl, and isopropyl; A compound or a pharmaceutically acceptable salt, stereoisomer, or prodrug characterized in that the above halogen is selected from -F, -Cl, -Br, and -I, preferably -F.
  4. In any one of paragraphs 1 through 3, A compound or a pharmaceutically acceptable salt, stereoisomer, or prodrug characterized by X being selected from -NH- or -NH2 .
  5. In any one of paragraphs 1 through 4, Is Selected from among; Here, R1 is selected from halogens; preferably, it is F; n is selected from 1, 2, 3, or 4, preferably n is 1; Preferably, R is , , , , or A compound or its pharmaceutically acceptable salt, stereoisomer, or prodrug characterized by being selected from among.
  6. In any one of paragraphs 1 through 5, A compound or a pharmaceutically acceptable salt, stereoisomer, or prodrug characterized in that the compound of formula (I) above is any one of the following compounds:
  7. In a method for manufacturing a compound according to any one of claims 1 to 6, The step of preparing a compound according to any one of claims 1 to 6 by reacting a halogen-substituted carboxylic acid, a carboxylic acid anhydride, an acyl chloride, and an exatecan; Preferably, a method for preparing a compound characterized in that the halogen-substituted carboxylic acid, carboxylic acid anhydride, and acyl chloride are selected from 2-fluoromalonic acid, 2-amino-3,3,3-trifluoropropionic acid, difluoroacetic anhydride, and 2,2-difluoropropionic acid.
  8. It includes a small molecule drug, a linker, and an antibody, Herein, the antibody-drug conjugate is characterized in that the small molecule drug comprises a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.
  9. A pharmaceutical composition characterized by comprising a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, or an antibody-drug conjugate according to claim 8.
  10. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, a compound obtained by a manufacturing method according to claim 7, an antibody-drug conjugate according to claim 8, or a pharmaceutical composition according to claim 9, in application in the manufacture of drugs for cancer treatment, Preferably, the application is characterized in that the cancer includes any one of gastric cancer, esophageal cancer, esophageal cancer, breast cancer, mammary gland cancer, and lung cancer.
  11. The method comprises the step of administering to a patient in need a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, a compound obtained by the manufacturing method according to claim 7, an antibody-drug conjugate according to claim 8, or a pharmaceutical composition according to claim 9; Preferably, a cancer treatment method characterized in that the cancer includes any one of gastric cancer, esophageal cancer, esophageal cancer, breast cancer, mammary gland cancer, and lung cancer.

Description

Halogen-substituted amide derivative of execan, method of preparation thereof, and applications The present application claims priority to Chinese patent application number 2023112892206, with a filing date of September 28, 2023, and the present application incorporates the full text of the said Chinese patent application. The present invention relates to the field of biopharmaceuticals, and specifically to amide derivatives of halogen-substituted execan and methods for their preparation and applications. Exatecan is a derivative of the natural product camtothecin, which has inhibitory activity against topoisomerase Top1 and, in particular, exhibits a potent inhibitory effect on complexes formed by Top1-DNA. Camtothecin is a drug with broad-spectrum antitumor activity that demonstrates significant efficacy against gastric cancer, pharyngeal cancer, lung cancer, and bladder cancer. Among these, irinotecan and topotecan are approved and used in several countries for the treatment of various cancers. Belotecan, a camtothecin derivative, is approved and used in Korea for the treatment of small cell lung cancer (SCLC) and ovarian cancer. However, the major drawbacks of camtothecin-class anticancer drugs are toxicity, poor solubility, and drug resistance in tumor cells. I. Definition Unless otherwise specified, scientific and technical terms used in this document have the meanings commonly understood by a person skilled in the art. Furthermore, related terms and laboratory operation steps used in this document refer to terms and general steps widely used in the relevant field. In addition, to better understand the invention, definitions and interpretations of related terms are provided as follows. Unless otherwise noted, the terms used in this document, such as “include,” “include,” “have,” “contain,” and their equivalent grammatical forms, should be understood in an open and non-restrictive sense, and, for example, other unlisted elements or steps are not excluded. The compounds of the present invention may be asymmetric and may have, for example, one or more stereoisomers. Unless otherwise noted, all stereoisomers include, for example, both symmetry isomers and asymmetric isomers. The above stereoisomers include geometric isomers (e.g., cis, trans structures) and optical isomers (e.g., symmetry isomers), and refer to therapeutic agents composed of monomers, racemic mixtures, racemate mixtures, and pharmaceutically acceptable salts thereof. The compounds containing asymmetric carbon atoms of the present invention may be isolated in an optically active pure form or in a racemate form. The optically active pure form may be isolated from a racemate mixture or synthesized using chiral raw materials or chiral reagents. Racemates, asymmetric isomers, and symmetry isomers are all included within the scope of the present invention. The compound of the present invention further comprises a tautomeric form. The tautomeric form results from an exchange and proton transfer between a single bond and an adjacent double bond. In this document, “pharmaceuticalally acceptable salts” means salts formed with the relevant amine compounds and inorganic or organic acids, or salts formed with the relevant carboxylic acid compounds and alkali metals or alkaline earth metals, or salts formed with organic amines. Herein, inorganic acids include, but are not limited to, hydrochloric acid, hydrobromide, hydroiodide, sulfuric acid, phosphoric acid, etc.; organic acids include, but are not limited to, acetic acid, propionic acid, butyric acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, succinic acid, lactic acid, citric acid, succinic acid, gluconic acid, maleic acid, fumaric acid, tartaric acid, etc.; alkali metal and alkaline earth metal salts include, but are not limited to, sodium, potassium, calcium, magnesium salts, etc. Organic amine salts include, but are not limited to, salts composed of ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, tert-butylamine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, morpholine, piperidine, piperazine, amino acids, etc. In this document, “precursor” means that after a compound enters the human body by an appropriate method of administration, the precursor compound is converted into the form of a compound included in General Formula 1 of the present invention and its corresponding salt through metabolism or simple chemical changes within the patient’s body. The precursors of the compound include, but are not limited to, various forms such as carboxylates, carbonates, phosphates, sulfates, sulfonates, amino acid esters, gluconates, and various amides, acetals, hemiacetals, carbamide esters, etc. The numerical ranges in this document refer to each integer within the specified range. For example, “ C1 - C6 ” means that this radical can have 1 carbon atom, 2 carbon