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WO2025153047A1 - Dérivé de camptothécine, son procédé de préparation et son utilisation - Google Patents

Dérivé de camptothécine, son procédé de préparation et son utilisation

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Publication number
WO2025153047A1
WO2025153047A1 PCT/CN2025/072935 CN2025072935W WO2025153047A1 WO 2025153047 A1 WO2025153047 A1 WO 2025153047A1 CN 2025072935 W CN2025072935 W CN 2025072935W WO 2025153047 A1 WO2025153047 A1 WO 2025153047A1
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Prior art keywords
substituted acyl
acyl group
reactant
formula
compound represented
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PCT/CN2025/072935
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English (en)
Chinese (zh)
Inventor
赵红宇
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Suzhou Tiling Biopharmaceutical Co Ltd
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Suzhou Tiling Biopharmaceutical Co Ltd
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Publication of WO2025153047A1 publication Critical patent/WO2025153047A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the technical field of pharmaceutical chemistry, and in particular to a camptothecin derivative and a preparation method thereof, and application of the compound in the preparation of antibody-drug conjugates.
  • Camptothecin was first isolated from the plant Camptotheca acuminata of the Davidiaceae family. It has strong cytotoxicity and has good therapeutic effects on malignant tumors such as digestive tract tumors (gastric cancer, colon cancer, rectal cancer), liver cancer, breast cancer, bladder cancer and leukemia.
  • malignant tumors such as digestive tract tumors (gastric cancer, colon cancer, rectal cancer), liver cancer, breast cancer, bladder cancer and leukemia.
  • the main disadvantages of camptothecin are poor solubility and stability, high toxicity and a small safety window, which limits its clinical application.
  • camptothecin derivatives have low cell proliferation inhibition activity and require a higher dose/antibody ratio (DAR) as ADC toxins, which can easily cause ADC instability, resulting in higher production costs, greater synthesis difficulty and a lower safety window. Therefore, more active camptothecin derivatives are of great significance to the design and development of new ADCs.
  • DAR dose/antibody ratio
  • the purpose of the present invention is to overcome the problems of narrow safety window and low activity of camptothecin derivatives in the prior art, and to provide a camptothecin derivative and its preparation method and application.
  • the camptothecin derivative provided by the present invention has higher tumor cell inhibition activity and better safety, and has a larger safety window as an ADC toxin.
  • the present invention provides a camptothecin derivative in a first aspect, wherein the derivative is a compound represented by formula (I) and/or a pharmaceutically acceptable salt thereof:
  • R 1 is at least one selected from H, -NO 2 , -NH 2 , -OH and halogen;
  • R 2 is at least one selected from H, acyl and substituted acyl, and R 1 and R 2 are not H at the same time.
  • the halogen is selected from at least one of F, Cl and Br.
  • the R1 is selected from at least one of H, -NO2 and -NH2 , and R2 is hydrogen or a substituted acyl group.
  • the substituted acyl group is at least one of a hydroxy substituted acyl group and/or an alkoxy substituted acyl group.
  • the hydroxy-substituted acyl group is an ⁇ -hydroxy-substituted acyl group; further, it is an ⁇ -hydroxy-substituted acyl group containing a C1-C6 alkane, and more preferably, it is an ⁇ -hydroxyacetyl group;
  • the alkoxy-substituted acyl group is an alkoxy-substituted acyl group containing a heterocycle and/or an alkoxy-substituted acyl group containing a nitro-substituted imidazole ring, and further preferably, it is an alkoxy-substituted acyl group containing a nitro-substituted imidazole ring, and more preferably, it is a (1-methyl-2-nitro-1H-imidazol-5-yl)methoxyacyl group.
  • the derivative is selected from:
  • the second aspect of the present invention provides a method for preparing a camptothecin derivative, the method comprising the following steps:
  • the reactant is a mixture of a reactant containing a nitro group and a reactant containing a substituted acyl group, or a reactant containing a nitro group;
  • Ra is a nitro group, and Rb is a substituted acyl group or hydrogen;
  • the reactant is a mixture of a reactant containing a nitro group and a reactant containing a substituted acyl group, or a reactant containing a nitro group;
  • Ra is a nitro group, and Rb is a substituted acyl group or hydrogen;
  • the reactant is a mixture of a reactant containing a nitro group and a reactant containing a substituted acyl group, or a reactant containing a nitro group;
  • Ra is a nitro group, and Rb is a substituted acyl group or hydrogen;
  • the amino protecting agent is at least one selected from benzyl chloroformate, di-tert-butyl dicarbonate and 9-fluorenylmethyl chloroformate.
  • FIG3 is a hydrogen spectrum of compound 3 obtained in Example 3 of the present invention.
  • FIG4 is a hydrogen spectrum of compound 4 obtained in Example 4 of the present invention.
  • FIG5 is a hydrogen spectrum of compound 5 obtained in Example 5 of the present invention.
  • FIG6 is a comparison chart of the weight changes of mice in Test Example 2 of the present invention.
  • FIG. 7 is a comparison diagram of tumor volume changes in Test Example 2 of the present invention.
  • pharmaceutically acceptable salts also include corresponding solvent addition forms or crystal forms, in particular solvates or multiple crystal forms.
  • Solvates contain stoichiometric or non-stoichiometric solvents and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water during crystallization, or alcoholates are formed when the solvent is ethanol.
  • Solvates of the compounds shown in formula (I) can be easily prepared or formed into corresponding solvates according to the method described in the present invention.
  • the compound may contain an unnatural ratio of atomic isotopes on one or more atoms constituting the compound.
  • the compound may be labeled with a radioactive isotope, such as deuterium ( 2H ), tritium ( 3H ) and C-14 ( 14C ).
  • a deuterated compound may be formed by replacing a hydrogen atom with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs generally have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the half-life of drugs in vivo. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention. In the present invention, if not otherwise specified, the use of "or" or "and” means "and/or".
  • the halogen is selected from at least one of F, Cl and Br; the inventors found that when R 1 is F, Cl and Br, the corresponding compound has anti-tumor activity.
  • the side chain of the derivative contains an -OH group that is easy to connect, and has good cell activity, which is suitable as a small molecule toxin for ADC.
  • the ⁇ -hydroxy-substituted acyl group is an ⁇ -hydroxy-substituted acyl group containing C1-C6 alkanes
  • at least one of the ⁇ -hydroxy-substituted acyl group containing C1-C6 straight-chain alkanes, the ⁇ -hydroxy-substituted acyl group containing C1-C6 branched alkanes, and the ⁇ -hydroxy-substituted acyl group containing cycloalkyl groups can be used.
  • the ⁇ -hydroxyl group containing C1-C6 straight-chain alkanes, C1-C6 branched alkanes or cycloalkyl groups can retain the tumor cell inhibitory activity of camptothecin derivatives while optimizing the drugability and inhibitory activity of camptothecin derivatives; more preferably, when the ⁇ -hydroxy-substituted acyl group is an ⁇ -hydroxyacetyl group, the camptothecin derivative has higher tumor cell inhibitory activity and better safety, and has a larger safety window as an ADC toxin.
  • the alkoxy-substituted acyl group is an alkoxy-substituted acyl group containing a heterocycle and/or an alkoxy-substituted acyl group containing a nitro-substituted imidazole ring.
  • the inventors found that after the nitro group of the imidazole ring enters the tumor tissue, it is reduced to an amine group under the catalysis of nitroreductase to form an unstable intermediate, and then a metabolite with better activity is generated through a self-elimination reaction, which has better prodrug properties and better tumor cell inhibition activity.
  • the camptothecin derivative in which the alkoxy-substituted acyl group is (1-methyl-2-nitro-1H-imidazol-5-yl)methoxyacyl generates a more active metabolite exitecan through a self-elimination reaction, has better prodrug properties and better safety, and has a larger safety window as an ADC toxin.
  • cycloalkyl is monocyclic or bicyclic.
  • the ring-forming carbon atoms of cycloalkyl can be optionally oxidized to form oxo or sulfide groups.
  • Cycloalkyl also includes cycloalkylene.
  • cycloalkyl contains 0, 1 or 2 double bonds.
  • cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl).
  • cycloalkyl can be fused with aryl, heteroaryl, cycloalkyl and heterocycloalkyl.
  • heterocycloalkyl refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of a ring structure, and which has at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen and phosphorus. If the heterocycloalkyl contains at least one double bond, then the partially unsaturated heterocycloalkyl may be referred to as “heterocycloalkenyl", or if the heterocycloalkyl contains at least one triple bond, then the partially unsaturated heterocycloalkyl may be referred to as "heterocycloalkynyl".
  • the heterocycloalkyl may include a monocyclic, bicyclic, spirocyclic or polycyclic (e.g., having two fused or bridged rings) ring system.
  • the heterocycloalkyl is a monocyclic group having 1,2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen.
  • the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl may be optionally oxidized to form oxo or sulfide ion groups or other oxidized bonds (e.g., C(O), S(O), C(S) or S(O)2, N-oxides, etc.), or nitrogen atoms may be quaternized.
  • heterocycloalkyl may be connected via ring-forming carbon atoms or ring-forming heteroatoms.
  • heterocycloalkyl contains 0 to 3 double bonds.
  • heterocycloalkyl contains 0 to 2 double bonds.
  • the definition of heterocycloalkyl also includes a portion of an aromatic ring having one or more fused to the heterocycloalkyl ring (i.e., sharing a key with it), such as benzo derivatives of piperidine, morpholine, azacycloheptatriene or thienyl, etc.
  • heterocycloalkyl containing a fused aromatic ring can be connected via any ring-forming atoms, including the ring-forming atoms of the fused aromatic ring.
  • heterocycloalkyl include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanediyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin
  • alkoxy refers to an alkyl group bonded to the rest of the molecule via an ether oxygen atom.
  • Representative alkoxy groups are those having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
  • alkoxy includes unsubstituted and substituted alkoxy groups, especially alkoxy groups substituted by one or more halogens.
  • Preferred alkoxy groups are selected from -OCH3 , -OCF3 , -CHF2O , -CF3CH2O , -i- PrO , -n-PrO, -i-BuO, -n-BuO or -t-BuO.
  • the derivative is selected from:
  • the present invention provides a method for preparing a camptothecin derivative, the method comprising the following steps:
  • the reactant is a mixture of a reactant containing a nitro group and a reactant containing a substituted acyl group, or a reactant containing a nitro group;
  • Ra is a nitro group, and Rb is a substituted acyl group or hydrogen;
  • the compound represented by formula (I) can be prepared by the above preparation method.
  • the compound has high tumor cell inhibitory activity and great clinical value.
  • As an ADC toxin it can further expand the safety window of ADC drugs, and the preparation process is simple and easy to operate.
  • the reactant containing nitro groups is nitric acid; the nitric acid can be used alone or in combination with other reagents, and pure nitric acid, fuming nitric acid and concentrated nitric acid can be used as the reactant for nitro groups; concentrated nitric acid or fuming nitric acid mixed with concentrated sulfuric acid in a certain ratio can also be used as the reactant for nitro groups, and the ratio can be 1:3-6, or a mixing ratio well known to those skilled in the art; nitric acid acetic anhydride solution can also be used as the reactant for nitro groups, and the volume ratio of nitric acid to acetic anhydride is 1:50-70.
  • the ⁇ -hydroxy-substituted acyl group is an ⁇ -hydroxy-substituted acyl group containing C1-C6 alkanes
  • at least one of an ⁇ -hydroxy-substituted acyl group containing C1-C6 straight-chain alkanes, an ⁇ -hydroxy-substituted acyl group containing C1-C6 branched alkanes, and an ⁇ -hydroxy-substituted acyl group containing cycloalkyl groups can be used.
  • the ⁇ -hydroxyl group containing C1-C6 straight-chain alkanes, C1-C6 branched alkanes, or cycloalkyl groups can retain the tumor cell inhibitory activity of camptothecin derivatives while optimizing the drugability and inhibitory activity of camptothecin derivatives.
  • the alkoxy substituted acyl group is an alkoxy substituted acyl group containing a heterocycle and/or an alkoxy substituted acyl group containing a nitro substituted imidazole ring.
  • the alkoxy substituted acyl group when the alkoxy substituted acyl group is an alkoxy substituted acyl group containing a heterocycle and/or an alkoxy substituted acyl group containing a nitro substituted imidazole ring, the alkoxy substituted acyl group can be self-eliminated under the action of a reductase to generate a camptothecin derivative with better tumor cell inhibitory activity. More preferably, when the reactant containing the substituted acyl group is selected from 2-hydroxyacetic acid, phenyl chloroformate and chloroformic acid (1-methyl-2-nitro-1H-imidazol-5-yl) methyl ester, the synthetic route is short, the reaction conditions are simple, and the operation is easy. The synthesized compound has higher tumor cell inhibitory activity and better safety, and has a larger safety window as an ADC toxin.
  • the reduction reaction includes contacting the compound represented by formula (III) with a reducing agent;
  • the reducing agent can be tetrahydroxydiboron, sodium borohydride, lithium aluminum tetrahydride or hydrogen gas alone, or different reducing agents can be selected according to the substituent groups.
  • Catalysts such as 4,4'-bipyridine, Raney nickel (Raney Ni), palladium carbon, platinum carbon, etc. can also be added to the reduction reaction system to shorten the reaction process.
  • the reducing agent is tetrahydroxydiboron and/or sodium borohydride
  • the reduction effect is better.
  • 4,4'-bipyridine can be added as a catalyst to shorten the reduction reaction time.
  • the substitution reaction comprises:
  • the conditions of the substitution reaction at least meet the following requirements: inert gas protection, the inert gas is selected from xenon, argon or nitrogen, the temperature is -4-0°C, specifically -4°C, -3°C, -2°C, -1°C, 0°C, or any value between the above two values, the time is 50-70min, specifically 50min, 55min, 60min, 65min, 70min, or any value between the above two values;
  • the conditions of the substitution reaction at least meet the following requirements: inert gas protection, the inert gas is selected from xenon, argon or nitrogen, the temperature is 25-30°C, specifically 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, or any value between the above two values, and the time is 120-130min, specifically 120min, 121min, 122min, 123min, 124min, 125min, 126min, 127min, 128min, 129min, 130min, or any value between the above two values;
  • the conditions of the reduction reaction at least meet the following requirements: inert gas protection, the inert gas is selected from xenon, argon or nitrogen, the temperature is 20-25°C, specifically 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, or any value between the above two values, and the time is 4-10min, specifically 4min, 5min, 6min, 7min, 8min, 9min, 10min, or any value between the above two values.
  • the reaction solvent used in the above preparation method can be ethyl acetate (EA), dimethylformamide (DMF), dichloromethane (DCM) and 1,2-dichloroethane (DCE) or a reaction solvent known to those skilled in the art; after the above reaction is completed, the target compound is obtained by post-treatment.
  • EA ethyl acetate
  • DMF dimethylformamide
  • DCM dichloromethane
  • DCE 1,2-dichloroethane
  • the post-treatment process includes quenching, extraction, washing and purification, wherein water can be selected as a quenching agent for the quenching reaction, and the amount is about 100-500mL, and the amount can be appropriately expanded or reduced according to the amount of the reactants; methanol, acetonitrile, tetrahydrofuran, ethyl acetate, dichloromethane and other solvents can be used for extraction, and the amount of the extractant is about 300-500mL, and the amount can be appropriately expanded or reduced according to the amount of the reactants; washing can be carried out by washing the extractant with saturated salt water, saturated sodium carbonate aqueous solution and saturated sodium bicarbonate aqueous solution, and after washing, anhydrous sodium sulfate or anhydrous magnesium sulfate and other reagents can be used for drying; before purification, a small amount of crude product solution is obtained by vacuum concentration and then purified by silica gel column, or directly purified by preparative liquid chromatography (
  • Catalysts and reaction aids can be palladium carbon Pd/C, 4,4'-bipyridine, triethylamine (TEA or Et3N), N,N-diisopropylethylamine (DIEA) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), etc.
  • reaction a small amount of reactants can be extracted by syringe for thin layer chromatography (TLC) analysis or liquid chromatography-mass spectrometry (LC-MS) analysis, and the reaction can be quenched after the reaction is confirmed to be completed.
  • TLC thin layer chromatography
  • LC-MS liquid chromatography-mass spectrometry
  • a specific method for introducing a halogen substituent is: converting an amine group into a halogen by a Sandmeyer reaction. Specifically, under the action of CuCN, the corresponding benzonitrile is obtained, and then treated with CuCl or CuBr to obtain the corresponding halogenated derivative. Alternatively, an iodinated derivative is obtained by heating with sodium iodide, and then treated with silver tetrafluoroborate to obtain a diazonium fluoroborate, and then heated to obtain a fluorinated derivative.
  • a specific method for introducing a hydroxyl substituent is as follows: a halogen atom-substituted compound and an amino compound are subjected to a Buchwald-Hartwig coupling reaction to obtain a substituted amino compound, and finally a hydroxyl-substituted compound in which Ra is a hydroxyl group is obtained by deprotection and hydrochloric acid acidification.
  • an amino-substituted compound is mixed with nitrous acid and subjected to a Sandmeyer reaction to obtain a hydroxyl-substituted compound in which Ra is a hydroxyl group.
  • the compound represented by formula (I) can be prepared by the method of general reaction scheme 1-3.
  • the amino group is protected by an amino protecting agent di-tert-butyl dicarbonate ((Boc) 2 O) to obtain compound 1B, which is then subjected to a substitution reaction with a reactant containing a nitro group, using a mixed acid of nitric acid (HNO 3 ) and acetic anhydride (Ac 2 O) as the reactant containing a nitro group to obtain compound 1C; after the substitution reaction with the reactant containing a nitro group is completed, the Boc protecting group of the amino group of compound 1C is removed by trifluoroacetic acid (TFA) to obtain compound 1; compound 1 is subjected to a substitution reaction with a reactant containing a substituted acyl group, using 2-hydroxyacetic acid as the reactant containing a substituted acyl group to obtain compound 2; compound 2 is subjected to a contact reaction with a reducing agent, using tetrahydroxydiboron as the
  • Compound 1C is directly contacted with a reducing agent, tetrahydroxydiboron, to obtain compound 1D, and the Boc protecting group of the amino group of compound 1D is removed by trifluoroacetic acid (TFA) to obtain compound 4;
  • a reducing agent tetrahydroxydiboron
  • TFA trifluoroacetic acid
  • compound 1F was obtained by reaction with phenyl chloroformate, and then coupled with (1-methyl-2-nitro-1H-imidazol-5-yl)methanol to obtain compound 5.
  • the 8-nitro group in compound 2 is reduced to an amine group under the catalysis of nitroreductase to generate the active substance compound 3;

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Abstract

La présente invention relève du domaine technique de la chimie médicale. La présente invention concerne un dérivé de camptothécine, son procédé de préparation et son utilisation. Le dérivé est un composé tel que représenté dans la formule (I) et/ou un sel pharmaceutiquement acceptable de celui-ci, R1 étant choisi parmi H, -NO2, -NH2, -OH et halogène ; R2 est choisi parmi H, acyle et acyle substitué ; et R1 et R2 ne sont pas H en même temps. Le procédé de préparation du dérivé de camptothécine comprend les étapes suivantes consistant à : effectuer une réaction de substitution sur un composé tel que représenté dans la formule (II) et un réactif pour obtenir un composé tel que représenté dans la formule (III), le réactif étant un réactif contenant un nitro et/ou un réactif contenant un acyle substitué, Ra étant nitro et hydrogène, et Rb étant choisi parmi au moins l'un parmi acyle, acyle substitué et hydrogène. Le dérivé de camptothécine a une activité inhibitrice des cellules tumorales plus élevée et une meilleure sécurité.
PCT/CN2025/072935 2024-01-18 2025-01-17 Dérivé de camptothécine, son procédé de préparation et son utilisation Pending WO2025153047A1 (fr)

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CN202410077258.5A CN117986269A (zh) 2024-01-18 2024-01-18 喜树碱衍生物及其制备方法和应用
CN202410077258.5 2024-01-18

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CN117986269A (zh) * 2024-01-18 2024-05-07 苏州提领生物制药有限公司 喜树碱衍生物及其制备方法和应用

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WO2022236136A1 (fr) * 2021-05-07 2022-11-10 ALX Oncology Inc. Dérivés d'exatecan et conjugués anticorps-médicament de ceux-ci
CN115850291A (zh) * 2021-09-24 2023-03-28 石药集团巨石生物制药有限公司 喜树碱衍生物及其用途
WO2023217064A1 (fr) * 2022-05-09 2023-11-16 同宜医药（苏州）有限公司 Dérivé de camptothécine, conjugué anticorps-médicament, composition pharmaceutique à base de celui-ci et utilisation associée
CN118878548A (zh) * 2023-04-30 2024-11-01 泰诚思(上海)生物医药有限公司 喜树碱衍生物、其制备方法及用途、抗体药物偶联物及其应用
CN117986269A (zh) * 2024-01-18 2024-05-07 苏州提领生物制药有限公司 喜树碱衍生物及其制备方法和应用

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