WO2023232145A1 - Petite molécule d'homocamptothécines et son utilisation - Google Patents

Petite molécule d'homocamptothécines et son utilisation Download PDF

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WO2023232145A1
WO2023232145A1 PCT/CN2023/098113 CN2023098113W WO2023232145A1 WO 2023232145 A1 WO2023232145 A1 WO 2023232145A1 CN 2023098113 W CN2023098113 W CN 2023098113W WO 2023232145 A1 WO2023232145 A1 WO 2023232145A1
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cancer
formula
antibody
small molecule
alkyl
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Chinese (zh)
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吕伟
程祉扬
周伟
夏广新
朱阳
柯樱
陈娜
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华东师范大学
上海医药集团股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K47/62—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 a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
    • 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
    • C07D491/02—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 two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the invention relates to a high-camptothecin small molecule and its application.
  • Camptothecins are specific inhibitors of DNA topoisomerase I. Camptothecin compounds form a stable Topo I-DNA-CPT ternary complex by combining with the Topo I-DNA cleavable binary complex, which affects the reconnection of DNA and increases Topo I-mediated DNA damage. , ultimately leading to cell death.
  • the traditional camptothecin compound is a five-ring quinoline alkaloid. Its structure contains quinoline ring AB, pyrrole ring C, pyridone ring D and ⁇ -hydroxylactone ring E, of which the 20-position is S configuration.
  • quinoline ring AB quinoline ring
  • pyrrole ring C pyrrole ring C
  • pyridone ring D pyridone ring
  • ⁇ -hydroxylactone ring E of which the 20-position is S configuration.
  • homocamptothecin compounds containing a seven-membered ⁇ -hydroxylactone ring structure could increase the stability of the lactone ring while maintaining antitumor activity (Bailly, C.Crit.Rev.Oncol.Hematol .2003,45,91).
  • Diflomotecan is the first high-camptothecin compound to enter clinical research, showing high in vitro cytotoxicity and good in vivo anti-tumor activity; Diflomotecan's Topo I inhibitory activity is stronger than camptothecin (Kroep, JR; Gelderblom, H. Expert.Opin.Investig.Drugs 2009,18,69).
  • camptothecin Korean Chemical Company LLC 2000,18,69
  • Lu Wei's research group introduced a methoxy group at the ⁇ position of the carboxyl group of the lactone ring to prepare a new homocamptothecin derivative.
  • Methoxy-modified homocamptothecin derivatives maintain high cytotoxic activity, and their related derivatives can reach pM-level tumor inhibitory activity in certain tumor cells, and have shown excellent anti-tumor effects in in vivo anti-tumor experiments.
  • Low toxicity DOI: 10.1016/j.bmc.2015.03.031
  • the high cytotoxic activity embodied by this type of parent core derivative also provides the possibility for high camptothecin derivatives to be used in antibody drug conjugates.
  • homocamptothecin derivatives as ADC effector molecules.
  • the technical problem to be solved by the present invention is to overcome the shortcomings of the single structure of high-camptothecin derivatives and antibody-drug conjugates in the prior art, and to provide a high-camptothecin small molecule, antibody-drug conjugates, and the like. application.
  • the high-camptothecin small molecules and antibody-drug conjugates provided by the invention have good cytotoxic activity and can inhibit the proliferation of tumor cells.
  • the invention provides a homocamptothecin small molecule as shown in formula I or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are independently C 1-6 alkyl, C 1-6 alkoxy or halogen;
  • R 1 and R 2 form with adjacent carbon atoms Indicates the connection position of the parallel ring
  • Carbon atoms marked with "*1" and “*2" independently represent the S configuration, the R configuration, or a mixture thereof.
  • R 1 and R 2 are independently C 1-6 alkyl or halogen
  • R 1 and R 2 form with adjacent carbon atoms Indicates the connection position of the parallel ring
  • Carbon atoms marked with "*1" and “*2" independently represent the S configuration, the R configuration, or a mixture thereof.
  • the pharmaceutically acceptable salt can be trifluoroacetate, hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, acetate, Oxalates, maleates, tartrates, citrates, succinates or malonates, such as trifluoroacetate.
  • the C 1-6 alkylene group is preferably -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 - or -CH(CH 3 )CH 2 -, for example -CH 2 -.
  • the C 1-6 alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.
  • R 1 and R 2 are independently C 1-6 alkoxy
  • the C 1-6 alkoxy is methoxy, -OCH 2 CH 3 , isopropoxy group or tert-butoxy group, such as methoxy group.
  • the halogen is fluorine, chlorine, bromine or iodine, such as fluorine.
  • the homocamptothecin small molecule shown in formula I is selected from any of the following structures:
  • the pharmaceutically acceptable salt of the homocamptothecin small molecule shown in formula I is selected from any of the following structures:
  • the present invention also provides a linker-drug conjugate as shown in formula II,
  • Q is a single amino acid residue, dipeptide residue, tripeptide residue or tetrapeptide residue
  • X is -(OCH 2 CH 2 ) m -, -(CR a R b ) m -, -O(CR a R b ) m , -NH-(CR a R b ) m -CR c R d -or- S(CR a R b ) m -CR c R d -;
  • R a and R b are independently H, D, halogen, C 1-6 alkyl, halo C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, amino , cyano group, nitro group, 3-10 membered cycloalkyl group or 3-10 membered heterocyclic group;
  • R a and R b together with the carbon atoms to which they are connected form a 3-10-membered cycloalkyl group or a 3-10-membered heterocyclyl group;
  • R c and R d are independently H, C 1-6 alkyl, halogen, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, 3-10 membered cycloalkyl, 3-10 heterocycle base, 6-14-membered aryl group or 5-10-membered heteroaryl group;
  • R c and R d together with the carbon atom to which they are connected form a 3-10-membered cycloalkyl group or a 3-10-membered heterocyclyl group;
  • n is independently 0-10;
  • n 1-6;
  • R 1 , R 2 , "*1" and “*2" are defined as above.
  • the heteroatoms in the 3-10-membered heterocyclyl and 5-10-membered heteroaryl are selected from one or more of N, O and S, and the number of heteroatoms For 1-3.
  • Q is a single amino acid residue, a dipeptide residue, a tripeptide residue or a tetrapeptide residue;
  • X is -(OCH 2 CH 2 ) m -, -(CR a R b ) m -, -O(CR a R b ) m , -NH-(CR a R b ) m -CR c R d -or- S(CR a R b ) m -CR c R d -;
  • R a and R b are independently H, D, halogen, C 1-6 alkyl, halo C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, amino , cyano group, nitro group, 3-10 membered cycloalkyl group or 3-10 membered heterocyclic group;
  • R a and R b together with the carbon atoms to which they are connected form a 3-10-membered cycloalkyl group or a 3-10-membered heterocyclyl group;
  • R c and R d are independently H, C 1-6 alkyl, halogen, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, 3-10 membered cycloalkyl, 3-10 heterocycle base, 6-14-membered aryl group or 5-10-membered heteroaryl group;
  • R c and R d together with the carbon atom to which they are connected form a 3-10-membered cycloalkyl group or a 3-10-membered heterocyclyl group;
  • n is independently 0-10;
  • n 1-6;
  • R 1 and R 2 are independently C 1-6 alkyl or halogen
  • R 1 and R 2 form with adjacent carbon atoms Indicates the connection position of the parallel ring
  • Carbon atoms marked with "*1" and “*2" independently represent the S configuration, the R configuration, or a mixture thereof.
  • the single amino acid residue is -Phe-, -Lys-, -Val-, -Ala-, -Cit-, -Leu-, -Ile-, -Arg- or - Trp-.
  • the left side is connected to the amino group in the antibody-drug conjugate represented by formula III through a carbonyl group, and the The NH in a dipeptide residue, a tripeptide residue or a tetrapeptide residue means that the right side of the dipeptide residue, tripeptide residue or tetrapeptide residue is connected to the compound represented by formula III through an amino group Carbonyl linkages in antibody-drug conjugates.
  • R a and R b are independently H.
  • n is independently 5.
  • n 1
  • linker-drug conjugate represented by Formula II can have the following structure:
  • the present invention also provides an antibody drug conjugate as shown in formula III:
  • G L is the antibody
  • p 1-8;
  • Z is The b end is connected to X, and the a end is connected to G L ;
  • R 1 , R 2 , X, Q, n, "*1" and “*2" are defined as above.
  • G L is an antibody
  • p 1-8;
  • Z is The b end is connected to X, and the a end is connected to G L ;
  • Q is a single amino acid residue, dipeptide residue, tripeptide residue or tetrapeptide residue
  • X is -(OCH 2 CH 2 ) m -, -(CR a R b ) m -, -O(CR a R b ) m , -NH-(CR a R b ) m -CR c R d -or- S(CR a R b ) m -CR c R d -;
  • R a and R b are independently H, D, halogen, C 1-6 alkyl, halo C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, amino , cyano group, nitro group, 3-10 membered cycloalkyl group or 3-10 membered heterocyclic group;
  • R a and R b together with the carbon atoms to which they are connected form a 3-10-membered cycloalkyl group or a 3-10-membered heterocyclyl group;
  • R c and R d are independently H, C 1-6 alkyl, halogen, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl, 3-10 membered cycloalkyl, 3-10 heterocycle base, 6-14-membered aryl group or 5-10-membered heteroaryl group;
  • R c and R d together with the carbon atom to which they are connected form a 3-10-membered cycloalkyl group or a 3-10-membered heterocyclyl group;
  • n is independently 0-10;
  • n 1-6;
  • R 1 and R 2 are independently C 1-6 alkyl or halogen
  • R 1 and R 2 form with adjacent carbon atoms Indicates the connection position of the parallel ring
  • Carbon atoms marked with "*1" and “*2" independently represent the S configuration, the R configuration, or a mixture thereof.
  • G L is a HER2 antibody, such as Trastuzumab.
  • p can be an integer or a decimal, preferably 6.7-7.2, such as 6.8, 6.9 or 7.1.
  • p can be an integer or a decimal, such as 6.7.
  • the a end of Z and G L are connected by a thioether bond.
  • the G L can be obtained by using a disulfide bond-containing antibody (such as Trastuzumab) to reduce the disulfide bond to a thiol group under the action of a reducing agent.
  • the antibody-drug conjugate represented by Formula III can have the following structure:
  • the HER2 antibody is Trastuzumab.
  • Z is connected to the sulfhydryl group contained in the antibody itself after opening the disulfide bond (for example, reducing the disulfide bond of the antibody itself by a reducing agent can open the disulfide bond and generate -SH).
  • -S- is not another external sulfur atom, but the sulfhydryl group contained in the HER2 antibody itself after opening the disulfide bond. -S- formed after joining.
  • the present invention also provides a pharmaceutical composition, which includes the homocamptothecin small molecule represented by Formula I as described above or a pharmaceutically acceptable salt thereof, or the antibody drug represented by Formula III as described above. conjugate, and at least one pharmaceutical excipient.
  • the present invention also provides a homocamptothecin small molecule represented by Formula I as described above, or a pharmaceutically acceptable salt thereof, or an antibody-drug conjugate represented by Formula III as described above.
  • the cancer is preferably Breast cancer, lung cancer, kidney cancer, liver cancer, ovarian cancer, urinary tract cancer, prostate cancer, glioblastoma multiforme, pancreatic cancer, colorectal cancer, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer Cancer, colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, sarcoma, melanoma, bladder cancer , gastric cancer or esophageal cancer, preferably breast cancer.
  • the present invention also provides compounds of the following formula,
  • the compounds of the invention can be formulated as one of the possible isomers or as mixtures thereof, such as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms) form exists.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography. method and/or fractional crystallization method.
  • groups and their substituents may be selected by those skilled in the art to provide stable moieties and compounds.
  • substituents When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes substituents that are chemically equivalent when the structural formula is written from right to left.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to a straight or branched chain alkyl group having the specified number of carbon atoms (eg, C 1 to C 6 ).
  • Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl wait.
  • aryl refers to a cyclic group with a specified number of carbon atoms (for example, C 6 to C 10 ), consisting only of carbon atoms, which is monocyclic or polycyclic, and at least one ring is aromatic ( complies with Huckel's rule).
  • Aryl groups are connected to other segments in the molecule through aromatic rings or non-aromatic rings.
  • Aryl groups include, but are not limited to, phenyl, naphthyl, and the like.
  • the "-" at the end of a group means that the group is connected to other fragments in the molecule through this site.
  • alkylene as a group or part of another group, means a saturated divalent hydrocarbon radical obtained by removing two hydrogen atoms from a saturated linear or branched hydrocarbon radical; that is, One of the hydrogens in the alkyl group is substituted, alkyl being as defined above.
  • alkylene groups include methylene (-CH 2 -), ethylene ⁇ including -CH 2 CH 2 - or -CH(CH 3 )- ⁇ , isopropylene ⁇ including -CH(CH 3 )CH 2 -or-C(CH 3 ) 2 - ⁇ and so on.
  • alkoxy refers to -O-alkyl, alkyl being as defined above.
  • cycloalkyl refers to a saturated monocyclic cyclic group having a specified number of carbon atoms (eg, C 3 to C 6 ) and consisting only of carbon atoms. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • heterocyclyl refers to a group having a specified number of ring atoms (e.g., 5 to 10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified heteroatom species (among N, O, and S). one or more) cyclic groups, which are monocyclic, bridged or spirocyclic, and each Each ring is saturated.
  • Heterocycloalkyl groups include, but are not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuryl, morpholinyl, piperidinyl, and the like.
  • heteroaryl refers to a specified number of heteroatoms (such as 1, 2 or 3) and a specified heteroatom species (among N, O and S) with a specified number of ring atoms (e.g., 5 to 10 members).
  • one or more) cyclic groups which are monocyclic or polycyclic, and at least one ring is aromatic (in compliance with Huckel's rule).
  • the heteroaryl group is connected to other segments in the molecule through an aromatic ring or a non-aromatic ring.
  • Heteroaryl groups include, but are not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, and the like.
  • pharmaceutically acceptable salt refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively nontoxic, safe, and suitable for use by a patient) acid or base.
  • base addition salts can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, ammonium salts, etc.
  • acid addition salts can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent.
  • Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochlorides, sulfates, mesylates, etc.
  • pharmaceutical excipients refers to the excipients and additives used in the production of drugs and preparation of prescriptions. It is all substances other than active ingredients included in pharmaceutical preparations.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive and progressive effect of the present invention is that the present invention provides a class of high-camptothecin small molecules with novel structures and their antibody-drug conjugates, which can inhibit the proliferation of tumor cells.
  • Figure 1 shows the effects of HER2-CZY-8 and HER2-L-4 on the proliferation ability of NCl-N87 tumor cells in Experimental Example 2.
  • Figure 2 shows the anti-tumor efficacy test results of the antibody drug conjugate in Experimental Example 3 on the animal model of subcutaneous transplantation of NCI-N87 cells in NOG mice.
  • Figure 3 shows the body weight changes in the animal model of subcutaneous transplantation of NCI-N87 cells in NOG mice in Experimental Example 3.
  • DCC represents dicyclohexylcarbodiimide
  • DMAP represents dimethylaminopyridine
  • DIPEA represents diisopropylethylamine
  • DMF represents N,N-dimethylformamide
  • PBS represents phosphate buffered saline solution.
  • step 1
  • Dissolve compound 1b (2.7g, 13.4mmol) in 20mL anhydrous dichloromethane, add DCC (5.5g, 26.8mmol), DMAP (160mg, 1.3mmol) in sequence, and add monoethyl malonate in an ice-water bath.
  • Ester (2.4 mL, 20.1 mmol) was slowly dropped into the system, and after the addition was completed, the reaction was carried out at room temperature for 12 hours. After the reaction is completed, filter and spin the filtrate to dryness to obtain 4.0 g of crude product, which is dissolved in 20 mL of ethanol. Add sodium ethoxide (1.4g, 20.6mmol) to the system in batches, and continue the reaction at room temperature for 2 hours.
  • compound 1h (380mg, 0.95mmol), compound 1i ((240mg, 0.95mmol) and triphenylphosphorus (300mg, 1.14mmol) were dissolved in 20mL of anhydrous dichloromethane, and added to the solution in an ice-water bath. Diethyl azodicarboxylate (180 ⁇ L, 1.14 mmol) was added dropwise to the system. After the dropwise addition was completed, the system was moved to room temperature to react for 6 hours. After the reaction was completed, the solvent was spin-dried to obtain a crude product, which was subjected to column chromatography (dichloromethane).
  • compound 1j 250mg, 0.39mmol
  • palladium acetate 90mg, 0.39mmol
  • potassium acetate 155mg, 1.58mmol
  • tris(o-methylphenyl)phosphorus 120mg, 0.39mmol
  • tetrakis Butylammonium chloride 110 mg, 0.39 mmol
  • MS (ESI) m/z 554.4 (M+H + ).
  • GX-1 50 mg, 0.09 mmol
  • glycolic acid 10 mg, 0.14 mmol
  • DIPEA 32 ⁇ L, 0.27 mmol
  • step 1
  • compound 2g (380mg, 0.93mmol), compound 1i (240mg, 0.95mmol) and triphenylphosphorus (300mg, 1.14mmol) were dissolved in 20mL anhydrous dichloromethane, and the system was added to the system under an ice-water bath. Diethyl azodicarboxylate (180 ⁇ L, 1.14 mmol) was added dropwise. After the dropwise addition was completed, the system was moved to room temperature and allowed to react for 6 hours.
  • step 1
  • TCEP tris(2carboxyethyl)phosphine
  • Dissolve compound CZY-8 (1.32 mg, 1014 nmol) in 50 ⁇ L DMSO, add it to the above reaction solution, place it in a water bath oscillator, shake at 25°C for 3 hours, and then stop the reaction.
  • the reaction solution was desalted and purified using a Sephadex G25 gel column (mobile phase: 0.05M PBS buffer aqueous solution with a pH of 6.5, containing 0.001M EDTA) to obtain a PBS buffer solution of the conjugate HER2-CZY-8 (1.1mg/ mL, 7.5mL), store at 4°C.
  • Purity detected by SEC-HPLC 96.68%, and the average drug loading (DAR) calculated by RP-HPLC was 6.7.
  • Inhibition rate (%) [1-(OD administration well -OD negative control well )/(OD positive control well -OD negative control well )] ⁇ 100%.
  • the antibody drug conjugate HER2-GGFG-DXd whose CAS number is 1826843-81-5, was purchased from Hangzhou Haoyang Biotechnology Co., Ltd.
  • cell culture was performed, and the tumor cell lines were cultured in an incubator at 37°C and 5% CO2. Passage regularly and use cells in the logarithmic growth phase for plating. Stain cells with trypan blue and count viable cells, and adjust the cell concentration to an appropriate concentration. Add 135 ⁇ L of cell suspension to each well of the culture plate, add culture medium without cells in the blank control air, and incubate the culture plate overnight in an incubator at 37°C, 5% CO2, and 100% relative humidity. Prepare a 100X antibody dilution master plate: dilute the antibody in PBS from the highest concentration to the lowest concentration.
  • Adding medicine Take 15 ⁇ L of 10X antibody working solution and add it to the cell culture plate. Add 15 ⁇ L of PBS-cell culture medium mixture to the vehicle control and blank control. Place the 96-well cell plate back into the incubator for 6 and 7 days.
  • Cell viability was then detected using the CellTiter-Glo luminescence method: Melt the CellTiter-Glo buffer and bring it to room temperature, and simultaneously bring the CellTiter-Glo substrate to room temperature.
  • Prepare CellTiter-Glo working solution by adding CellTiter-Glo buffer to a bottle of CellTiter-Glo substrate to dissolve the substrate. Vortex slowly to fully dissolve. Take out the cell culture plate and let it equilibrate to the chamber for 30 minutes. temperature. Add 75 ⁇ L (equivalent to half the volume of cell culture medium in each well) of CellTiter-Glo working solution to each well. Wrap the cell plate with aluminum foil to protect it from light.
  • IR inhibition rate
  • the positive control antibody Trastuzumab (HER2 antibody, CAS: 180288-69-1) was purchased from Hangzhou Haoyang Biotechnology Co., Ltd.).
  • the solvent control is DMSO, and 20uL RPMI1640medium/10% FBS is added to the blank control.
  • Example 3 Anti-tumor efficacy test of HER2-CZY-8 on the animal model of subcutaneous transplantation of NCI-N87 cells in NOG mice:
  • NCI-N87 cells were subcutaneously inoculated into NOG mice to determine the anti-tumor effect of HER2-CZY-8.
  • NOG mice Female NOG mice (6 weeks old) were purchased from Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd. Mice were acclimated for 7 days upon arrival before the study began.
  • NCI-N87 cells Human breast cancer NCI-N87 cells (ATCC source, Cat. No. CRL-5822), perform routine subculture according to the instructions; resuspend the cells in serum-free medium and adjust the cell density. On day 0, the cell suspension is subcutaneously inoculated to The NCI-N87 tumor-bearing mouse model was established by subcutaneous injection into the right axilla of female NOG mice.
  • TGI (%) [1-(Ti-T0)/(Vi-V0) ] ⁇ 100; where Ti: mean tumor volume in the treatment group, T0: mean tumor volume in the treatment group on D0, Vi: mean tumor volume in the same type control group, V0: mean tumor volume in the same type control group on day D0 .
  • Tumor volume measurement: Vernier calipers were used to measure the long diameter (a) and wide diameter (b) of the tumor. The tumor volume was calculated according to the following formula: TV 1/2 ⁇ a ⁇ b 2 . Body weight was measured using an electronic balance. Table 5 shows the dosage and mode of administration.
  • QW means once a week
  • BIW means twice a week
  • HER2-CZY-8 significantly inhibits the growth of tumors in the animal model of subcutaneously transplanted NCI-N87 cells in NOG mice, and has no significant effect on the body weight of NOG mice.

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Abstract

La présente invention concerne une petite molécule d'homocamptothécines et son utilisation. La présente invention concerne en particulier une petite molécule d'homocamptothécine telle que représentée dans la formule (I) ou un sel pharmaceutiquement acceptable de celle-ci, et un conjugué anticorps-médicament de celle-ci; et celle-ci peut inhiber la prolifération de cellules tumorales.
PCT/CN2023/098113 2022-06-02 2023-06-02 Petite molécule d'homocamptothécines et son utilisation WO2023232145A1 (fr)

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WO2021190602A1 (fr) * 2020-03-25 2021-09-30 江苏恒瑞医药股份有限公司 Procédé de préparation d'un conjugué anticorps-médicament
CN114456186A (zh) * 2020-10-12 2022-05-10 四川百利药业有限责任公司 一种喜树碱类衍生物及其配体-药物偶联物

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CN1192740A (zh) * 1995-06-21 1998-09-09 科学研究与运用咨询公司 新的喜树碱类似物、其制备方法和药物应用及其药物组合物
CN1241191A (zh) * 1996-12-20 2000-01-12 科学研究与运用咨询公司 喜树碱的新的类似物,及作为药物的用途及其药物组合物
CN1241192A (zh) * 1996-12-20 2000-01-12 科学研究与运用咨询公司 喜树碱的前药形式和类似物,及其药物用途
CN112138171A (zh) * 2019-06-28 2020-12-29 上海复旦张江生物医药股份有限公司 抗体偶联药物、其中间体、制备方法及应用
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WO2021190602A1 (fr) * 2020-03-25 2021-09-30 江苏恒瑞医药股份有限公司 Procédé de préparation d'un conjugué anticorps-médicament
CN114456186A (zh) * 2020-10-12 2022-05-10 四川百利药业有限责任公司 一种喜树碱类衍生物及其配体-药物偶联物

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117679529A (zh) * 2024-01-30 2024-03-12 成都中医药大学 核酸适配体-多价药物偶联物及其制备方法与应用
CN117679529B (zh) * 2024-01-30 2024-05-03 成都中医药大学 核酸适配体-多价药物偶联物及其制备方法与应用

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