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WO2025149012A1 - Dérivé de dolastatine, son procédé de préparation et son utilisation - Google Patents

Dérivé de dolastatine, son procédé de préparation et son utilisation

Info

Publication number
WO2025149012A1
WO2025149012A1 PCT/CN2025/071652 CN2025071652W WO2025149012A1 WO 2025149012 A1 WO2025149012 A1 WO 2025149012A1 CN 2025071652 W CN2025071652 W CN 2025071652W WO 2025149012 A1 WO2025149012 A1 WO 2025149012A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
antibody
pharmaceutically acceptable
added
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/071652
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English (en)
Chinese (zh)
Inventor
黄云生
李耀武
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hangzhou Adcoris Biopharma Co Ltd
Original Assignee
Hangzhou Adcoris Biopharma Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hangzhou Adcoris Biopharma Co Ltd filed Critical Hangzhou Adcoris Biopharma Co Ltd
Publication of WO2025149012A1 publication Critical patent/WO2025149012A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/515—Complete light chain, i.e. VL + CL

Definitions

  • Dolastatin-10 derivatives also known as auristatins
  • MMAE monomethyl auristatin E
  • MMAF monomethyl auristatin F
  • the present invention optimizes the N-terminus or C-terminus of the Dolastatin structure, including dimethylation, replacement, cyclization and other modifications of the N-methyl Valine at the N-terminus of Dolastatin, or modification of the phenethyl skeleton at the C-terminus of Dolastatin.
  • These compounds are characterized by having good activity in inhibiting cell microtubule aggregation, leading to tumor cell apoptosis, and can therefore be used in the development of antibody-drug conjugates and the treatment of tumors.
  • N,N-dimethylvaline at the N-terminus of Dolastatin-10 can be modified or replaced without significantly affecting its activity.
  • the phenethyl group at the C-terminus can also be modified without significantly affecting its biological activity.
  • M is selected from Any of the following:
  • R 1 and R 2 are each independently selected from any one of C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
  • R 3 is selected from any one of hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
  • R 5 is selected from any one of hydrogen, hydroxy, C 3 -C 6 cycloalkyl or -O-NR 6 -C 1 -C 6 alkyl;
  • n1 and m2 are each independently selected from 0, 1 or 2.
  • R 1 and R 2 are each independently selected from hydrogen, halogen-substituted or unsubstituted methyl, ethyl, propyl, isopropyl, butyl or isobutyl;
  • n1 and m2 are each independently selected from 1 or 2.
  • R 4 is selected from methyl, -CH 2 -NH-O-CH 3 or -CH 2 -O-NH-CH 3 .
  • R 5 is selected from hydrogen, hydroxyl or -O-NH-C 1 -C 6 alkyl.
  • the present invention provides the following compounds or pharmaceutically acceptable salts, stereoisomers or prodrugs thereof:
  • the present invention provides an antibody-drug conjugate of the aforementioned compound.
  • Ab is tumor-associated antigen antibody
  • the linker is a hydrophilic linker.
  • the linker is selected from the following structures:
  • the antibody conjugate is obtained by conjugating the following compound to an antibody:
  • Ab is an antibody to a tumor-associated antigen or an antigen-binding fragment thereof.
  • the present invention provides a pharmaceutical composition, which comprises the aforementioned compound or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof or the aforementioned antibody-drug conjugate and a pharmaceutically acceptable excipient.
  • the present invention provides the use of the aforementioned compound or its pharmaceutically acceptable salt, stereoisomer or prodrug or the aforementioned antibody-drug conjugate or the aforementioned pharmaceutical composition in the preparation of a drug for inhibiting tumor cell growth or in the preparation of a drug for treating cancer.
  • the tumor cells include any one of esophageal cancer cells, breast cancer cells, gastric cancer cells, and lung cancer cells.
  • the cancer includes any one of esophageal cancer, breast cancer, gastric cancer, and lung cancer.
  • Another aspect of the present invention provides a method for treating cancer, comprising the step of administering a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, or the aforementioned antibody-drug conjugate, or the aforementioned pharmaceutical composition to a patient in need thereof.
  • FIG1 is the LCMS spectrum of antibody-drug conjugate ADC2; A and B are HPLC results, and C and D are MS results.
  • FIG2 is the LCMS spectrum of antibody-drug conjugate ADC4; A and B are HPLC results, and C and D are MS results.
  • FIG3 is an LCMS spectrum of antibody-drug conjugate ADC5; A and B are HPLC results, and C is the MS result.
  • Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, 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 or 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,
  • precursor refers to the form in which the compound is metabolized or undergoes simple chemical changes in the patient's body after the compound enters the human body by an appropriate administration method and is converted into the compound contained in the general formula 1 of the present invention and the corresponding salt.
  • the precursor of the compound includes, but is not limited to, various carboxylic acid esters, carbonate esters, phosphate esters, sulfate esters, sulfonate esters, amino acid esters, gluconate esters, and various amides, acetals, hemiacetals, carbonate amide esters, and the like.
  • any variable e.g., Rn
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with up to 5 Rs, and each occurrence of R is an independent choice.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred in the present invention.
  • the hydrogen atoms described in the present invention can all be replaced by their isotope deuterium.
  • Substituted means that one or more hydrogen atoms, preferably up to 5, more preferably 1-3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.
  • the medicaments or pharmaceutical compositions of the present invention may be administered orally, topically, parenterally or mucosally (e.g., buccally, by inhalation or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers.
  • the oral route is generally desirable.
  • the active agent may be administered orally in the form of capsules, tablets, etc. (see Remington: The Science and Practice of Pharmacy, 20th Edition).
  • the drug component can be combined with a non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water), an anti-settling agent (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), an emulsifier (e.g., lecithin or gum arabic), a non-aqueous carrier (e.g., almond oil, oily esters, ethanol or fractionated vegetable oils), a preservative (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid), etc.
  • Stabilizers such as antioxidants (BHA, BHT, propyl citric acid, sodium ascorbate, citric acid) can also be added to stabilize the dosage form.
  • composition means a composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable ingredient selected from the following depending on the mode of administration and the nature of the dosage form, including but not limited to: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, temperature-sensitive materials, temperature regulators, adhesives, stabilizers, suspending agents, etc.
  • an effective amount refers to a sufficient amount of a non-toxic drug or medicament that can achieve the desired effect.
  • the amount of a given drug depends on many factors, such as a specific dosing regimen, a disease or condition type and its severity, the uniqueness of the subject or host to be treated (e.g., body weight), but, according to specific surrounding conditions, including, for example, a specific drug, route of administration, condition to be treated, and the subject or host to be treated, the dosage can be routinely determined by methods known in the art.
  • Antibodies include full-length immunoglobulin molecules or immunologically active portions of full-length immunoglobulin molecules, i.e., molecules that contain antigen binding sites that immunospecifically bind to target antigens or portions thereof, and these targets include, but are not limited to, cancer cells or cells that produce autoimmune antibodies associated with autoimmune diseases.
  • the term "antibody” is an immunoglobulin molecule that can bind to a specific antigen. It includes two light chains with lighter molecular weight and two heavy chains with heavier molecular weight. The heavy chain (H chain) and the light chain (L chain) are connected by disulfide bonds to form a tetrapeptide chain molecule.
  • the raw materials and equipment used in the specific embodiments of the present disclosure are all known products, which are obtained by purchasing commercially available products.
  • DAR value testing and calculation Based on the RP-HPLC-MS test results, the DAR value of ADC was analyzed using a Waters Acquity UPLC I-Class/Xevo G2-XS QTOF instrument.
  • MS parameter settings capillary voltage 2.50kV, cone voltage 100V, mass analysis range m/z 200 to 4000, MSE collision energy 20 to 45eV, ion source temperature 120°C, nebulization temperature 500°C, nebulization flow rate 1000L/Hr, internal standard leucine enkephalin.
  • the test sample was diluted to 1mg/mL with sample buffer, TCEP was added at a final concentration of 50mmol/L, incubated at 37°C for 20min, and 5uL was injected.
  • the light chain peak was identified and the peak area percentage was calculated, and the sum of the peak areas was 100.
  • the heavy chain peak was identified and the peak area percentage was calculated, and the sum of the peak areas was 100.
  • the weighted peak areas of the heavy chain and light chain were calculated by multiplying the peak area percentage with the corresponding drug load.
  • the ADC prepared uses but is not limited to Nectin-4 antibody.
  • amino acid sequence of the light chain of the nectin-4 antibody is as follows (SEQ ID NO: 2):
  • tert-butyl (3R, 4S, 5R)-3-methoxy-5-methyl-4-(methylamino)heptanoate (8.0 g, 30.84 mmol)
  • DCM 200 mL
  • Fmoc-Val-OH 20.93 g, 61.68 mmol
  • HATU 23.45 g, 61.68 mmol
  • DIPEA 15.94 g, 123.37 mmol, 21.49 mL
  • D1-4 (2.84 g, 3.43 mmol), ACN (30 mL), and DBU (522.75 mg, 3.43 mmol, 513.50 ⁇ L) were added to a 100 mL single-mouth eggplant-shaped bottle in sequence.
  • the mixture was stirred at room temperature for 2 h, and N-cbz-N-2,2,2-trifluoroethylglycine (1 g, 3.43 mmol) and HATU (1.96 g, 5.15 mmol) were added to continue the reaction for 1.5 h.
  • D5-4 (0.8 g, 1.15 mmol) was dissolved in methanol (8 mL), 2,2,2-trifluoroethane-1-amine (0.34 g, 3.45 mmol) and sodium acetate (0.28 g, 3.45 mmol) were added, and the reaction was stirred at room temperature for 4 h.
  • Sodium cyanoborohydride (0.22 g, 3.45 mmol) and acetic acid (0.35 g, 5.75 mmol) were added, and the reaction solution was stirred at room temperature for 2 h.
  • the solvent was evaporated and 10 mL of saturated carbon was added.
  • A1-1 (0.8 g, 802.32 ⁇ mol) was dissolved in ACN (10 mL), and 80% hydrazine hydrate (602.47 mg, 9.63 mmol) was added. The mixture was stirred at room temperature for 12 h. 20 mL of water was added to the reaction solution, and the mixture was extracted with DCM three times. The mixture was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to give A1-2 (750 mg, yield 99.68%, HPLC 93%); LCMS: [M+1] + 844.21 (calculated value 843.51).
  • A4-1 (177.50 mg, 178.88 ⁇ mol) was dissolved in DCM (8 mL) at room temperature, hydrazine hydrate (35.82 mg, 715.53 ⁇ mol) was added, stirred at 30 °C for 26 h, dried by rotation, and purified by reverse phase column chromatography to obtain a light yellow solid A4-2 (119.5 mg, yield 72.83%);
  • nectin-4 antibody (10.0 mg/mL, 10 mg, 0.066 mmol)
  • adjust the pH to 7.2 with 1 M Na 2 HPO 4 solution then add 0.1 M disodium ethylenediaminetetraacetic acid solution (25 ⁇ L)
  • the compound was diluted to 10000nM, 2000nM, 400nM, 80nM, 16nM, 3.2nM, 0.64nM, 0.13nM using culture medium, and the diluted compound was added to a 96-well cell culture plate at 2 ⁇ L per well, with 3 replicates for each concentration, and 2 ⁇ L of diluent was added to each well of the negative control and blank control groups without adding the compound. After the addition was completed, it was returned to the incubator at 37°C and 5% CO2 for further incubation for 72h.
  • the drug was administered intravenously once regularly, and the monitoring was carried out until the 22nd day after administration.
  • the experimental groups are shown in Table 2 below.
  • a growth curve was drawn, and the tumor was finally removed and weighed.
  • GraphPad Prism software was used to analyze the tumor inhibition results ( Figures 5 and 6).
  • DXd-Nectin-4 is It is obtained by coupling with the Nectin-4 antibody described in the examples of this application.

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  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Cell Biology (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne le domaine de la biomédecine. Plus particulièrement, l'invention concerne un dérivé de dolastatine, ou un sel, un stéréoisomère ou un promédicament pharmaceutiquement acceptable de celui-ci, son procédé de préparation et son utilisation dans la préparation d'un médicament antitumoral. Le dérivé de dolastatine est tel que représenté par la formule (I), les définitions des groupes dans la formule étant décrites en détail dans la description. Le dérivé de dolastatine a une activité antitumorale relativement bonne.
PCT/CN2025/071652 2024-01-12 2025-01-10 Dérivé de dolastatine, son procédé de préparation et son utilisation Pending WO2025149012A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202410052116.3 2024-01-12
CN202410052116.3A CN117964682A (zh) 2024-01-12 2024-01-12 Dolastatin衍生物及其制备方法和应用

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WO2025149012A1 true WO2025149012A1 (fr) 2025-07-17

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Publication number Priority date Publication date Assignee Title
CN117964682A (zh) * 2024-01-12 2024-05-03 杭州爱科瑞思生物医药有限公司 Dolastatin衍生物及其制备方法和应用

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BURKE, P.J. ET AL.: "Development of Novel Quaternary Ammonium Linkers for Antibody-Drug Conjugates", MOLECULAR CANCER THERAPEUTICS, vol. 15, no. 5, 31 May 2016 (2016-05-31), XP055456299, DOI: 10.1158/1535-7163.MCT-16-0038 *

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