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WO2024017229A1 - Utilisation de composé de pyrrolotriazine dans la préparation de médicament antitumoral - Google Patents

Utilisation de composé de pyrrolotriazine dans la préparation de médicament antitumoral Download PDF

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Publication number
WO2024017229A1
WO2024017229A1 PCT/CN2023/107850 CN2023107850W WO2024017229A1 WO 2024017229 A1 WO2024017229 A1 WO 2024017229A1 CN 2023107850 W CN2023107850 W CN 2023107850W WO 2024017229 A1 WO2024017229 A1 WO 2024017229A1
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Prior art keywords
cancer
compound
acid
tumor
lymphoma
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Chinese (zh)
Inventor
魏霞蔚
魏于全
姜宁
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Jumbo Drug Bank Co Ltd
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Jumbo Drug Bank Co Ltd
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Priority to CN202380024770.7A priority Critical patent/CN118785912A/zh
Publication of WO2024017229A1 publication Critical patent/WO2024017229A1/fr
Anticipated expiration legal-status Critical
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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
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants

Definitions

  • the invention belongs to the field of medicine, and specifically relates to the application of a pyrrolotriazine compound in the preparation of anti-tumor drugs.
  • Mitogen-activated protein kinase interacting kinase (MAP kinase interacting kinase, MNK) is a serine/threonine protein kinase.
  • the MNK protein is encoded by two genes, MKNK1 and MKNK2.
  • MNK1a, MNK1b and MNK2a, MNK2b There are four subtypes of human MNK, MNK1a, MNK1b and MNK2a, MNK2b, which are expressed by the MNK1 and MNK2 genes respectively (Ahmed M Abdelaziz1, 2020).
  • All four isoforms contain a nuclear localization signal (NLS) and a sequence that binds to eIF4G at the N-terminus, allowing them to enter the nucleus and function, recognizing and binding to downstream eIF4E.
  • the C-termini of MNK1a and MNK2a subtypes have binding sites for MAPK and can be activated by upstream ERK and p38 phosphorylation (Jianling Xie, 2019).
  • the C-terminal nuclear export signal (NES) of MNK1a allows it to be widely present in the cytoplasm, while the other three isoforms mostly exist in the nucleus.
  • MNK protein can specifically phosphorylate Ser209 of eukaryotic translation initiation factor 4E (eIF4E), thereby indirectly regulating mRNA translation (Fukunaga R, 1997).
  • eukaryotic cell translation initiation factor eIF4E can strengthen the transcription of mRNA encoding and regulating cell cycle proteins and oncogenic proteins, thereby causing the upregulation of tumor-related protein expression (Truitt ML, 2015).
  • eIF4E, the skeleton protein eIF4G and the RNA helicase eIF4A form the eukaryotic initiation factor complex eIF4F. Since eIF4E is responsible for the binding of this complex to the 5' end cap structure of mRNA, it plays an irreplaceable regulatory role in the RNA translation process.
  • eIF4E In normal cells, the activity of eIF4E is limited and the transcription of these tumor-related mRNAs is inhibited, while in tumor cells or tissues, high expression or overactivation of eIF4E can cause the upregulation of the transcription levels of these mRNAs (Lama D, 2019).
  • MNK1/2 and eIF4E are the convergence points of the RAS-RAF-MEK-ERK and PI3K-AKT-mTOR signaling pathways and play an important role in signaling pathway conduction.
  • eIF4E, MNK1/2 and eIF4E signaling pathways can affect the synthesis of a variety of chemokines, cytokines and immune checkpoint proteins, thereby regulating immune responses (Gorentla, B.K. 2012).
  • VEGF/VEGFR pathway is the main signaling pathway for tumor angiogenesis.
  • vascular endothelial growth factor (VEGF) family members include VEGF-A, VEGF-B, VEGF-C, VEGF-D and PIGF.
  • VEGF also known as VEGF-A, is the most important stimulator of physiological and pathological angiogenesis.
  • the functions of VEGF include: maintaining the survival of endothelial cells, inducing endothelial cell proliferation and migration, recruiting bone marrow-derived hematopoietic progenitors or stem cells to induce blood vessel formation, and enhancing vascular permeability.
  • VEGF-A has two tyrosine kinase receptors, namely VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1).
  • VEGFR-2 is the main receptor for VEGF to exert its pro-angiogenic effects.
  • a variety of tumor cells and host cells such as platelets, myocytes, and stromal cells can produce VEGF.
  • Hypoxia is an important inducing factor for up-regulation of VEGF expression.
  • Other factors that promote the secretion of VEGF include: low pH; growth factors; inflammatory chemokines; and genetic mutations.
  • the invention provides the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of anti-tumor drugs,
  • R 1 is H, F, Cl, Br or C 1-3 alkyl
  • R 2 and R 3 are each independently H or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally replaced by 1, 2 or 3 substituents independently selected from F, Cl, Br or I replace;
  • R 2 and R 3 are joined together with the carbon atom to which they are attached to form cyclopentyl, cyclohexyl or piperidinyl, wherein said cyclopentyl, cyclohexyl and piperidinyl are optionally replaced by 1, 2 or 3 R replaced by a ;
  • Each R a is independently H, F, Cl, Br or C 1-3 alkyl
  • R 4 is H, F, Cl, Br or C 1-3 alkyl
  • R 5 and R 6 are each independently H, F, Cl, Br, I or C 1-3 alkyl
  • R 7 is pyrrolidinyl, wherein the pyrrolidinyl is optionally substituted by 1, 2 or 3 R b ;
  • Each R b is independently H, F, Cl, Br, I or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally 1, 2 or 3 independently selected from F, Cl, Br or Substituted by the substituent of I;
  • n 1 or 2.
  • each of the above R a is independently H, F, Cl, Br, -CH 3 or -CH 2 CH 3 , and other variables are as defined in the present invention.
  • R 2 and R 3 are each independently H, -CH 3 or -CH 2 CH 3 , and other variables are as defined in the present invention.
  • R 2 and R 3 are connected together with the carbon atoms to which they are connected to form R a and other variables are as defined in the present invention.
  • R 2 and R 3 are connected together with the carbon atoms to which they are connected to form
  • Other variables are as defined in the present invention.
  • R 1 is C 1-3 alkyl, such as methyl.
  • R 2 and R 3 are joined together with the carbon atom to which they are connected to form
  • R 4 is C 1-3 alkyl, such as methyl.
  • R 5 and R 6 are each independently H or methyl; n is 2;
  • R 7 is substituted by 1, 2 or 3 H, F, Cl or methyl
  • the above compound has a structure represented by any of the formulas (I-1) to (I-4):
  • R 1 , R 4 , R 5 , R 6 , R 7 , R a and n are as defined in the present invention.
  • each of the above R b is independently H, F, Cl, Br, I, Other variables are as defined in the present invention.
  • R 7 is stated therein Optionally substituted by 1 or 2 R b , R b and other variables are as defined in the present invention.
  • R 7 is R b and other variables are as defined in the present invention.
  • R 4 is H or -CH 3 , and other variables are as defined in the present invention.
  • the above compound has a structure represented by any of the structural formulas of formula (I-5) to formula (I-9):
  • R 1 , R 5 , R 6 , R a and R b are as defined in the present invention.
  • R 1 is H, F, Cl or Other variables are as defined in the present invention.
  • R 5 and R 6 are each independently H or Other variables are as defined in the present invention. There are also some solutions of the present invention that are derived from any combination of the above variables.
  • the compound represented by formula (I) is selected from the following structures:
  • the pharmaceutically acceptable salt is a salt formed by a compound represented by formula (I) and an inorganic acid.
  • the inorganic acid includes, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, and bicarbonate, Phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, including acetic acid, propionic acid, isobutyric acid, maleic acid, Malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and similar Acids; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such
  • neoplastic includes “hyperproliferative disease,” which refers to excessive growth or proliferation compared to normal cells or unlysed cells, including dysplasia, neoplasia, noncontact suppression, or carcinogenesis.
  • Neoplastic refers to a variety of hyperproliferative diseases, including solid tumors and hematological tumors. These different forms of hyperproliferative diseases are known in the art and have established standards for diagnosis and classification.
  • Exemplary solid tumors include: breast cancer; prostate cancer; colon cancer; rectal cancer; liver cancer; kidney cancer; stomach cancer; bladder cancer; all forms of lung and bronchial cancer; bone marrow cancer; melanoma; neuroblastoma; parenchyma; pus Chest; choriomas; branching tumors; malignant carcinoid syndrome; carcinoid heart disease; cellular carcinoma (e.g., Walker carcinoma, basal cell carcinoma, basal squamous cell carcinoma, Brown-Pearce carcinoma, ductal carcinoma, myxoid carcinoma , non-small cell carcinoma, oat cell carcinoma, synovial cell carcinoma, bronchiolar carcinoma, bronchial carcinoma, squamous cell carcinoma and transitional cell carcinoma); plasmacytoma; reticuloendot
  • Exemplary hematological malignancies include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), chronic eosinophilic leukemia (CEL), myelodysplastic syndrome (MDS), Hodgkin lymphoma, non-Hodgkin lymphoma (NHL) (such as follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma ( DLBCL), chronic lymphocytic leukemia (CLL), or multiple myeloma (MM).
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • CML chronic myelogenous leukemia
  • CEL chronic eosinophilic leukemia
  • MDS myelodysplastic syndrome
  • NHL non-Hodgkin lymphoma
  • NHL non-Hodgkin lympho
  • the tumor is selected from solid tumors or non-solid tumors, such as melanoma, kidney cancer, blood cancer, prostate cancer, colon cancer, rectal cancer, stomach cancer, esophageal cancer, bladder cancer, Head and neck cancer (such as head and neck squamous cell carcinoma), thyroid cancer, breast cancer (such as triple-negative breast cancer), ovarian cancer, cervical cancer, lung cancer (such as non-small cell lung cancer), urothelial cancer, pancreatic cancer, glioblastoma Cytoma, liver cancer, colon adenocarcinoma, astrocytoma, osteosarcoma, myeloma (eg, multiple myeloma), lymphoma (Hodgkin lymphoma, non-Hodgkin lymphoma (eg, follicular lymphoma) (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), diffuse large B-cell lympho
  • solid tumors or non-solid tumors
  • the tumor is selected from the group consisting of kidney cancer, prostate cancer, colon cancer, rectal cancer, gastric cancer, esophageal cancer, thyroid cancer, breast cancer, lung cancer (such as non-small cell lung cancer), ovarian cancer, glioblastoma Cell tumors, liver cancer, lymphoma ⁇ such as chronic lymphocytic leukemia (CLL) ⁇ , leukemia (such as acute myeloid leukemia).
  • lung cancer such as non-small cell lung cancer
  • ovarian cancer glioblastoma Cell tumors
  • liver cancer lymphoma ⁇ such as chronic lymphocytic leukemia (CLL) ⁇
  • leukemia such as acute myeloid leukemia
  • the tumor is selected from the group consisting of kidney cancer, colon cancer, rectal cancer, gastric cancer, lung cancer (such as non-small cell lung cancer), ovarian cancer, lymphoma, liver cancer, breast cancer, leukemia (such as acute myeloid leukemia) ).
  • the cells are colon cancer CT-26 cells, colon cancer HT-29 cells, colon cancer SW480 cells, lung cancer Calu-3 cells, lung cancer A549 cells, lung cancer H460 cells, and gastric cancer BGC-823 cells.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has an inhibitory effect on VEGFR2, such as p-VEGFR2.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has an inhibitory effect on both eIF4E and VEGFR2, for example, an inhibitory effect on p-eIF4E and p-VEGFR2.
  • the present invention also provides a pharmaceutical composition, including a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and at least one second drug.
  • “Combination” refers to a compound represented by formula (I) and at least one second drug, each of which can be administered continuously, simultaneously or simultaneously (the compound represented by formula (I) can be administered first, or the second drug can be administered first). drug).
  • the mass ratio of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof to the second drug is 1:500 to 500:1, for example, 1 :50 to 50:1 or 1:10 to 10:1, examples are 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 10:3, 4:1, 25:6, 5:1, 25:1.
  • the mass ratio of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof to the second drug is 10:1 to 50:1, for example, 15:1 to 35:1, and examples are 20:1, 25:1, and 30:1.
  • the mass ratio of the compound represented by formula (I) or its pharmaceutically acceptable salt to the second drug is 1 :1 to 20:1, for example, 2:1 to 10:1, for example, 3:1, 4:1, 25:6, 5:1, 6:1, 8:1.
  • the mass ratio of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof to the second drug is 100:1 to 400:1, for example, 150:1 to 300:1, and examples are 200:1 and 250:1.
  • the second drug is selected from immune checkpoint inhibitors, chemotherapy drugs, or targeted drugs.
  • the immune checkpoint inhibitor targets include immunosuppressive signals involving PD-1, PD-L1, PD-L2, CTLA4, CD80, CD86, B7-H3, B7-H4, HVEM, BTLA, At least one of KIR, LAG3, GAL9, TIM3, 2B4, adenosine, A2aR, TGFP, BCL-2 and immunosuppressive cytokines (such as IL-10, IL-35).
  • the immunosuppressive inhibitor component can be a compound, antibody, antibody fragment or fusion polypeptide (eg Fc fusion, eg CTLA4-Fc), antisense molecule, ribozyme or RNAi molecule, or low molecular weight organic molecule.
  • the chemotherapy drug is selected from at least one of the following drugs: antimetabolites/anticancer agents, such as pyrimidine analogs (5-fluorouracil (5-fu), fluuridine, capecitabine azacitabine, gemcitabine, decitabine, azacitidine and cytarabine) and purine analogues, folate antagonists and related immunosuppressants (methotrexate, pemetrexed, mercaptopurine, thioguanine, Pentostatin and 2-chlorodeoxyadenosine (cladribine, fludarabine); coenzymes (tetrahydrofolate); antiproliferative/antimitotic agents, including natural products such as vinca alkaloids (vinblastine) , vincristine and vinorelbine), microtubule disruptors, such as taxanes (paclitaxel, docetaxel), vindesine, nocodazole, eflenox, epoth
  • the immune checkpoint inhibitor is selected from the group consisting of pembrolizumab, nivolumab, camrelizumab, toripalimab, cimepilimab, Valumab, avelumab, sintilimab, tislelizumab, cepalizumab, durvalumab, atezolizumab, envolizumab, sugalizumab, slulimumab, penpilimab, serelizumab, zimberizumab, jepunolizumab, spartalizumab, proglilimab, sugalizumab Cotinizumab, cosibelimab, AUNP-12, relevanizumab, retifalizumab, dotalizumab, cardonizumab, socazolizumab, adebre monoclonal antibody, ipilimum
  • the targeted drug is selected from the group consisting of B-Raf inhibitors (dabrafenib, sorafenib, vemurafenib and dabrafenib), MEK inhibitors (trametid nimetinib, selumetinib, binimetinib, PD-325901, cobimetinib, CI-1040 and PD035901), VEGF/VEGFR inhibitors (such as bevacizumab, ramucirumab, ramucirumab, Tizumab, aflibercept, conbercept, axitinib, cediranib, motesanib, lenvatinib, sunitinib, sorafenib, cabozantinib, Gorfenib, nintedanib, zopanib, osimertinib, fruquintinib, vandet
  • the second drug is preferably cisplatin, paclitaxel, doxorubicin or PD-1.
  • the present invention also provides the use of the pharmaceutical composition in preparing anti-tumor drugs.
  • the present invention provides the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of a drug for treating diseases related to the VEGFR2 signaling pathway.
  • the present invention provides the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of drugs for treating diseases related to eIF4E and VEGFR2 signaling pathways.
  • the present invention provides the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of a drug for regulating immunity.
  • the regulating immunity is preferably to enhance immunity.
  • the present invention also provides a method for treating tumor diseases, which method includes administering to a patient a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a method for joint treatment of tumor diseases, which method includes jointly administering a therapeutically effective amount of formula (I) to a tumor patient.
  • Combination treatments may be administered in any of a variety of ways, such as sequentially or simultaneously.
  • the method includes administering to the patient the pharmaceutical composition.
  • the tumor is selected from solid tumors or non-solid tumors, such as melanoma, kidney cancer, blood cancer, prostate cancer, colon cancer, rectal cancer, gastric cancer, esophageal cancer, bladder cancer, head and neck cancer (such as Head and neck squamous cell carcinoma), thyroid cancer, breast cancer (such as triple-negative breast cancer), ovarian cancer, cervical cancer, lung cancer (such as non-small cell lung cancer), urothelial cancer, pancreatic cancer, glioblastoma, liver cancer , colon adenocarcinoma, astrocytoma, colorectal cancer, osteosarcoma, myeloma (such as multiple myeloma), lymphoma (Hodgkin lymphoma, non-Hodgkin lymphoma (such as follicular lymphoma) (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma
  • the lung cells are lung cancer cells A549 and H460, and the colon cancer cells are SW480 and CT-26.
  • a method for treating diseases related to the VEGFR2 signaling pathway which method includes administering to a patient a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition.
  • a method for treating diseases related to eIF4E and VEGFR2 signaling pathways which method includes administering to a patient a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition.
  • the active compounds are combined or formulated with appropriate pharmaceutically acceptable carriers, diluents or excipients, and can be formulated into preparations in the form of solid, semi-solid, liquid or gas , such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Modes of administration include oral, intraperitoneal, transdermal, subcutaneous, intravenous or intramuscular injection, inhalation, topical, intralesional, infusion; liposome-mediated delivery; topical, intrathecal, gingival pocket, rectal, intrabronchial , nasal cavity, transmucosal, intestinal, eye or ear delivery, or any other method known in the art, can achieve the treatment of tumors;
  • the therapeutically effective amount or dose of the present invention will vary depending on several factors, including the route of administration chosen, the formulation of the composition, patient response, severity of condition, subject's weight, and the judgment of the prescribing physician, e.g. 1-200mg/kg, 40-150mg/kg, such as 50mg/kg. Dosage may be increased or decreased over time as individual patients require. In some cases, patients are initially given low doses and then increased to an effective dose that is tolerated by the patient. In addition, patients may be administered multiple doses over defined time periods, particularly in time increments (e.g., daily, weekly, biweekly, monthly, quarterly, biennially, or the like).
  • the research of the present invention has found that the compound represented by formula (I) has a dual-target inhibitory effect on eIF4E protein and/or VEGFR2 protein when used alone or in combination with other drugs, thereby having a good tumor inhibitory effect.
  • Figure 1 illustrates the dose-response curve of compound 12 corresponding to p-toluenesulfonate and Con-MNK on HCT116 cells.
  • Figure 2 illustrates the dose-response curve of compound 12 corresponding to p-toluenesulfonate and Con-MNK on human colon cancer HCT116 cells.
  • Figure 3 illustrates the body weight changes of tumor-bearing mice in the subcutaneous xenograft tumor model of human colon cancer HT-29 cells during the administration process.
  • Figure 4 illustrates the body weight changes of tumor-bearing mice in the subcutaneous xenograft tumor model of human colon cancer HT-29 cells during the administration process.
  • Figure 5 illustrates the tumor growth inhibition curve of human colon cancer HT-29 cell subcutaneous xenograft tumor model tumor-bearing mice after administration of drugs.
  • Figure 6 illustrates the mean plasma time-concentration plot in Balb/c nude mice after oral administration of 10, 30 and 100 mg/kg p-toluenesulfonate corresponding to compound 12.
  • Figure 7 illustrates the average plasma and tumor concentration profiles of Balb/c nude mice after oral administration of 10 mg/kg p-toluenesulfonate corresponding to Compound 12.
  • Figure 8 illustrates the average plasma and tumor concentration profiles of Balb/c nude mice after oral administration of 30 mg/kg p-toluenesulfonate corresponding to Compound 12.
  • Figure 9 illustrates the average plasma and tumor concentration profiles of Balb/c nude mice after oral administration of 100 mg/kg p-toluenesulfonate corresponding to Compound 12.
  • Figure 10 shows the protein expression of eIF4E and p-eIF4E in xenograft tumor HT-29 tissue after 2h/8h/24h administration.
  • Figure 11 illustrates the protein expression analysis of eIF4E and p-eIF4E in xenograft tumor HT-29 tissue after 2h/8h/24h administration.
  • Figure 12 shows the protein expression of VEGFR2 and p-VEGFR2 in xenograft tumor HT-29 tissue after 2h/8h/24h administration.
  • Figure 13 illustrates the protein expression analysis of p/t-VEGFR2 in xenograft tumor HT-29 tissue after 2h/8h/24h administration.
  • Figure 14 illustrates the effect of the combination of p-toluenesulfonate and 5-fu corresponding to Compound 12 on the tumor volume of human colon cancer SW480 cell Balb/c nude mouse transplanted tumor model.
  • Figure 15 illustrates the tumor growth curve of mouse colon cancer CT-26 cell subcutaneously transplanted tumor model in tumor-bearing mice after administration of drugs.
  • Figure 16 illustrates the inhibition of MNK1 kinase activity by test compounds.
  • Figure 17 illustrates the inhibition of MNK2 kinase activity by test compounds.
  • Figure 18 illustrates the effect of p-toluenesulfonate corresponding to Compound 12 on the tumor volume of the gastric cancer BGC-823 cell Balb/c nude mouse transplanted tumor model.
  • Figure 19 illustrates the effect of p-toluenesulfonate corresponding to Compound 12 on tumor volume in the lung cancer Calu-3 cell Balb/c nude mouse transplant tumor model.
  • Figure 20 illustrates the inhibition of HUVEC cells by the p-toluenesulfonate corresponding to Compound 12.
  • Figure 21 illustrates the effect of the combination of p-toluenesulfonate and cisplatin corresponding to compound 12 on the tumor volume of the lung cancer A549 cell Balb/c nude mouse transplant tumor model.
  • Figure 22 illustrates the effect of the combination of p-toluenesulfonate and paclitaxel corresponding to compound 12 on the tumor volume of the lung cancer H460 cell Balb/c nude mouse transplanted tumor model.
  • Figure 23 illustrates the tumor growth inhibition curve of human ovarian cancer ES2 cell subcutaneous xenograft tumor model tumor-bearing mice after administration of drugs.
  • Figure 24 illustrates the body weight changes of human ovarian cancer ES2 cell subcutaneous xenograft tumor model tumor-bearing mice during the administration process.
  • Figure 25 illustrates the effect of the combination of p-toluenesulfonate corresponding to Compound 12 and cisplatin or paclitaxel on the tumor volume of the human ovarian cancer ES2 cell subcutaneous xenograft model.
  • Figure 26 illustrates the tumor growth curves of p-toluenesulfonate corresponding to compound 12 used alone and in combination with doxorubicin on human DLBCL cell SU-DHL-6 xenograft tumors.
  • Figure 27 illustrates the body weight change curve of p-toluenesulfonate corresponding to compound 12 used alone and in combination with doxorubicin on human DLBCL cell SU-DHL-6 xenograft tumors
  • Figure 28 illustrates the tumor growth curve of p-toluenesulfonate corresponding to Compound 12 on MCL cell JeKo-1 cell xenograft tumors.
  • Figure 29 illustrates the tumor growth curve of compound 12 corresponding to p-toluenesulfonate and PD-1 antibody or PD-1 isotype antibody on the mouse LL2 subcutaneous tumor model.
  • Figure 30 illustrates the body weight change curve of p-toluenesulfonate corresponding to Compound 12 and PD-1 antibody or PD-1 isotype antibody on the mouse LL2 subcutaneous tumor model.
  • Figure 31 illustrates the tumor growth curve of the p-toluenesulfonate corresponding to compound 12 on the Hep G2 nude mouse transplanted tumor model.
  • Figure 32 illustrates the tumor growth curve of the p-toluenesulfonate corresponding to Compound 12 on the MDA-MB-231 nude mouse transplanted tumor model.
  • the compound of formula (I) above is a compound of the following formula:
  • the crude product was purified by high-performance liquid chromatography (hydrochloric acid conditions) to obtain hydrochloric acid of compound 5. Salt.
  • Methanol (5 mL) was added to the crude product, stirred at 15°C for 16 hours, filtered, and the filter cake was washed with methanol (2 mL ⁇ 2) and dried to obtain compound 11.
  • reaction solution is filtered, and the filtrate is concentrated under reduced pressure, diluted with dichloromethane (250 mL), washed with saturated aqueous potassium carbonate solution (75 mL ⁇ 1), the organic phase is collected, and the aqueous phase is extracted with dichloromethane (75 mL ⁇ 9) , the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain colorless oily product 13b.
  • the crude product was purified by high performance liquid chromatography (hydrochloric acid system) to obtain the hydrochloride salt of compound 14.
  • the trifluoroacetate salt of compound 15c (200 mg, 0.554 mmol) was dissolved in tetrahydrofuran (3 mL) and methanol (3 mL), and di-tert-butyl dicarbonate (121 mg, 0.554 mmol) and triethylamine ( 224 mg, 2.21 mmol).
  • the reaction solution was stirred at 25°C for 1 hour.
  • the reaction solution was diluted with water (60mL), extracted with dichloromethane (60mL ⁇ 4), the organic phases were combined, washed with water (200mL ⁇ 1) and saturated brine (200mL ⁇ 1), dried over anhydrous sodium sulfate, and filtered.
  • the filtrate was concentrated under reduced pressure, and the crude product was purified by high-performance liquid chromatography (neutral conditions) to obtain compound 15d.
  • the hydrochloride of compound 15 (30 mg, 0.049 mmol) was dissolved in anhydrous methanol (3 mL), and aqueous formaldehyde solution (6.39 mg, 78.7 ⁇ mol, purity: 37%) and sodium cyanoborohydride (6.60 mg,0.105mmol).
  • the reaction solution was stirred at 10°C for 1 hour.
  • the reaction solution was quenched by adding water (20 mL), concentrated under reduced pressure to remove methanol, filtered, and washed with methanol (3 mL ⁇ 2).
  • the crude product was purified by high performance liquid chromatography (hydrochloric acid conditions) to obtain the hydrochloride salt of compound 16.
  • Cell culture Digest and isolate the cells in the T75 culture flask, resuspend in culture medium, count, adjust the cell concentration with culture medium to 2 ⁇ 10 5 cells/mL, add 100 ⁇ L of cell suspension to the 96-well plate, and incubate at room temperature. After leaving for 10 minutes, place it in a 37°C, 5% CO 2 incubator for overnight culture. Then place the cell plate back into the incubator for 3 hours. After 3 hours, remove the culture medium, add 50 ⁇ L 1X lysis buffer to each well, and rotate for 10 min at room temperature. Add 10 ⁇ L of lysis solution to the 384-well assay plate. Add 5 ⁇ L acceptor mix to each well, seal the plate with sealing film, and incubate at room temperature for 1 hour.
  • Cell culture Human colon cancer HT-29 cells (ATCC, product number: HTB-38) are cultured in vitro.
  • the culture conditions are McCoy's 5a medium plus 10% fetal bovine serum, 100U/mL penicillin and 100 ⁇ g/mL streptomycin. , cultured in 37°C 5% CO2 incubator. Passage was performed twice a week with routine digestion treatment with trypsin-EDTA. When the cell saturation is 80%-90% and the number reaches the required number, cells are collected, counted, and inoculated.
  • HT-29 cells were subcutaneously inoculated into the right back of each mouse. When the average tumor volume reached 154 mm 3 , random groups were divided according to tumor volume.
  • Tissuelyser LT uses the highest frequency to disrupt tissue for 5 minutes.
  • Electrophoresis 80 volts, 30 minutes, then 120 volts, 90 minutes.
  • Transfer Use iBlot2 transfer kit and transfer apparatus to transfer: for proteins with a molecular weight less than 100KDa, run the P3 program for 7 minutes; for proteins with a molecular weight greater than 100KDa, run the P3 program for 15 minutes.
  • Blocking Place the membrane in blocking solution (5% skim milk prepared with 1xTBST) for 1 hour at room temperature with shaking.
  • Chemiluminescence Add the HRP substrate in the West Femto Ultra-Sensitive Chemiluminescence Kit to the membrane.
  • AlphaviewSA software was used to perform relative quantification of the density intensity of the immunoblot chemiluminescent bands.
  • the average tumor volume in the vehicle control group was 1670mm 3 .
  • the average tumor volumes of the 10mg/kg, 30mg/kg, and 100mg/kg treatment dose groups of compound 12 corresponding to p-toluenesulfonate were 860mm 3 , 719mm 3 and 652mm 3 respectively, and the T/C were 51.72%, 43.56% and 38.89%, TGI are 53.46%, 62.69% and 67.16% respectively.
  • the p-toluenesulfonate corresponding to compound 12 showed a dose-dependent anti-tumor effect, and had a significant inhibitory effect on tumor growth at three concentrations, with statistical differences (p ⁇ 0.05 ).
  • Each dose group of the compound could significantly inhibit p-eIF4E protein expression at different time points.
  • Each dose group had a certain inhibitory effect on VEGFR2 and p-VEGFR2 protein expression 2h and 8h after administration.
  • 5-fu was formulated with DPBS to 3 mg/mL.
  • the specific preparation method is: weigh 30mg5-fu and add 10mL DPBS, vortex until clear, mark G2, G4-2, G5-2, G6-2, ready for use.
  • the corresponding compound of the present invention was formulated at 10 mg/mL.
  • the specific preparation method is: weigh 299.88mg compound and add 2.8mL NMP, vortex until clear, then add 2.8mL Solutol and vortex, then add 22.4mL water, vortex until uniform, marked as G3, G6-1 , prepared once a week.
  • the corresponding compound of the present invention was formulated at 1 mg/mL.
  • the specific preparation method is: weigh 14.99mg compound and add 1.4mL NMP, vortex until clear, then add 1.4mL Solutol and vortex, then add 11.2mL water, vortex until uniform, mark it as G4-1, every week Prepare once.
  • the corresponding compound of the present invention was formulated at 3 mg/mL.
  • the specific preparation method is: weigh 14.99 ⁇ 3mg compound and add 1.4mL NMP, vortex until clear, then add 1.4mL Solutol and vortex, then add 11.2mL water, vortex until uniform, mark it as G5-1. Prepare once a week.
  • Tumor volume was measured twice weekly. And calculate the tumor inhibition rate TGI (%).
  • TGI (%) [(1-average tumor volume at the end of treatment group administration-average tumor volume at the end of treatment group administration)/(average tumor volume at the end of treatment group for solvent control group-solvent control group group administration) average tumor volume)] ⁇ 100%.
  • TV 1 is the tumor volume on the day of group administration
  • TV n is the tumor volume on the day of measurement.
  • T/C% RTV t /RTV c ⁇ 100%
  • RTV t is the average relative tumor volume of the treatment group
  • RTV c is the average relative tumor volume of the vehicle control group.
  • Cell culture Mouse colon cancer CT-26 cells were cultured in vitro. The culture conditions were McCoy's 5a medium plus 10% fetal bovine serum, 100U/mL. Penicillin and 100 ⁇ g/mL streptomycin were cultured in a 37°C, 5% CO2 incubator. Passage was performed twice a week with routine digestion treatment with trypsin-EDTA. When the cell saturation is 80% to 90% and the number reaches the required number, cells are collected, counted, and inoculated.
  • CT-26 cells were subcutaneously inoculated into the right hind limb of each mouse. Group administration began when the tumor volume reached approximately 70 mm 3 on the 9th day after inoculation.
  • Tumor diameter was measured three times a week using vernier calipers.
  • the tumor inhibitory effect of the compound was evaluated by TGI (%) or tumor proliferation rate T/C (%).
  • TGI (%) reflects the tumor growth inhibition rate.
  • TGI (%) [(1-(average tumor volume at the end of treatment in a certain treatment group - average tumor volume at the beginning of treatment in the treatment group))/(average tumor volume at the end of treatment in the solvent control group - start of treatment in the solvent control group) average tumor volume)] ⁇ 100%.
  • T/C% TRTV/CRTV ⁇ 100% (TRTV: average RTV of the treatment group; CRTV: average RTV of the negative control group).
  • the relative tumor volume (RTV) of a single mouse is calculated based on the results of tumor measurement.
  • Tweight and Cweight represent the tumor weight of the drug administration group and the vehicle control group, respectively.
  • the p-toluenesulfonate monotherapy group corresponding to Compound 12 has a certain anti-tumor effect at a dose of 10-40mg/kg.
  • the tumor volume is 1057mm 3
  • T/C is 57.76%
  • TGI is 45.77%
  • p 0.051
  • There is a significant anti-tumor effect at the dose of 90mg/kg the tumor volume is 922mm 3
  • T/C is 47.26%
  • TGI is 53.20%
  • p 0.026.
  • the effect p 0.009, and it has better anti-tumor effect compared with the PD-1 monotherapy group.
  • Buffer 20mM Hepes (pH 7.5), 10mM MgCl 2 , 1mM EGTA, 0.02% Brij35, 0.02mg/ml BSA, 0.1mM Na 3 VO 4 , 2mM DTT, 1% DMSO
  • Kinase activity data are expressed as the percentage of remaining kinase activity in the test sample relative to the vehicle control (dimethyl sulfoxide).
  • BGC-823 cells were cultured in RPMI-1640 culture medium containing 10% fetal bovine serum (FBS) and 1% PS. BGC-823 cells in the logarithmic growth phase were collected, resuspended in HBSS to 5 ⁇ 10 6 /mL, and transplanted subcutaneously into BALB/c Nude mice under sterile conditions. Each mouse was inoculated with 5 ⁇ 10 5 /0.1mL. cell.
  • FBS fetal bovine serum
  • mice On the 10th day after vaccination, when the average tumor volume of the grouped mice reached 157.27 mm 3 , they were randomly divided into 3 groups according to tumor volume, with 6 mice in each group.
  • Tumor volume measurement Use vernier calipers to measure twice a week.
  • TGI% [1-T/C] ⁇ 100.
  • T/C% (delta T/T 0 ) ⁇ 100.
  • the relative tumor volume (RTV) is calculated based on the results of tumor measurement.
  • Tumor weight can be calculated by the relative tumor proliferation rate T/C (%).
  • T/C% Tweight/Cweight ⁇ 100% (Tweight: average tumor weight of the treatment group; Cweight: average tumor weight of the control group).
  • the p-toluenesulfonate (50mg/kg) corresponding to Compound 12 was The tumor growth inhibition rates TGI (%) of the drug group and the p-toluenesulfonate (150 mg/kg) administration group corresponding to compound 12 were 39.79% and 50.14%, respectively. Both the p-toluenesulfonate corresponding to compound 12 (50 mg/kg) and the p-toluenesulfonate corresponding to compound 12 (150 mg/kg) had statistically significant inhibitory effects on tumor growth (P ⁇ 0.05). At the same time, the anti-tumor efficacy of p-toluenesulfonate corresponding to compound 12 is positively correlated with the dosage. ( Figure 18)
  • Calu-3 cells were cultured in MEM medium containing 10% fetal bovine serum (FBS) and 1% PS. Calu-3 cells in the logarithmic growth phase were collected, resuspended in HBSS to 1 ⁇ 10 8 /mL, and transplanted subcutaneously into BALB/c Nude mice under sterile conditions. Each mouse was inoculated with 1 ⁇ 10 7 /0.2mL ( Contains 25% Matrigel) cells.
  • FBS fetal bovine serum
  • Tumor volume measurement Use vernier calipers to measure twice a week.
  • TGI% [1-T/C] ⁇ 100.
  • T/C% (delta T/T 0 ) ⁇ 100.
  • the relative tumor volume (RTV) is calculated based on the results of tumor measurement.
  • the tumor mass was taken and weighed, and photos were taken.
  • the p-toluenesulfonate (50mg/kg) group corresponding to compound 12 and the p-toluenesulfonate (150mg/kg) corresponding to compound 12 The tumor growth inhibition rates TGI (%) of the two groups were 45.74% and 69.42% respectively. According to the above result analysis, it can be seen that the p-toluenesulfonate (50mg/kg) group corresponding to compound 12 can inhibit tumor growth to a certain extent (P>0.05).
  • the p-toluenesulfonate (150mg/kg) group corresponding to compound 12 showed Statistically significant inhibitory effect on tumor growth (P ⁇ 0.05).
  • the anti-tumor efficacy of the corresponding compound of the present invention is positively correlated with the dosage.
  • the p-toluenesulfonate (50 mg/kg) group corresponding to Compound 12 was able to inhibit the subcutaneous transplantation of Calu-3 human lung cancer cells in mice to a certain extent. growth (P>0.05), and the p-toluenesulfonate (150mg/kg) group corresponding to compound 12 showed statistically significant inhibitory effects on tumor growth (P ⁇ 0.05).
  • IC50 For the determination of IC50, the data was analyzed using XLFit version 5.3 (ID Business Solutions), and the S-shaped dose-response curve (variable slope) was fitted by nonlinear regression analysis based on the mean value of each test concentration. When the top and/or bottom values exceed 10% or fall below -10%, the maximum and minimum limits of the curve may be redefined to 100 and 0, subject to meeting the QC criteria of R2.
  • HUVEC cell line Subculture in RPMI-1640 medium containing 10% fetal bovine serum, 100 u/ml penicillin and 100 mg/ml streptomycin at 37°C and 5% CO2 . Cells in the logarithmic growth phase, growing well, and with cell activity greater than 90% were selected for experiments.
  • HUVEC cells in logarithmic growth phase were used for experiments. Different concentrations of p-toluenesulfonate corresponding to Compound 12 were added to RPMI-1640 culture medium with 10% fetal calf serum, and the cell concentration was adjusted to 5 ⁇ 10 5 ml, each dose concentration is a group, placed in a 37°C, 5% CO 2 incubator for different times (48, 72h), incubated for 4h, and fully dissolved. Select the wavelength of 490nm and measure the absorbance (A) value of each well on an enzyme-linked immunoassay detector.
  • SPSS statistical software was used to conduct t test and one-way analysis of variance (ANOVA).
  • A549 cells were cultured in conventional cell culture medium. H460 cells in the logarithmic growth phase were collected, resuspended, and transplanted subcutaneously into mice under sterile conditions. Each mouse was inoculated with 2 ⁇ 10 7 mL cells.
  • mice were randomly divided into 4 groups according to tumor size, with 5 mice in each group.
  • Tumor volume measurement Use a vernier caliper to measure.
  • TGI% [1-T/C] ⁇ 100.
  • T/C% (delta T/T 0 ) ⁇ 100.
  • the relative tumor volume (RTV) is calculated based on the results of tumor measurement.
  • the tumor mass was taken and weighed, and photos were taken.
  • H460 cells were cultured in conventional cell culture medium. H460 cells in the logarithmic growth phase were collected, resuspended, and transplanted subcutaneously into mice under sterile conditions. Each mouse was inoculated with 1 ⁇ 10 7 mL cells.
  • mice were randomly divided into 4 groups according to tumor size, with 6 mice in each group.
  • Tumor volume measurement Use a vernier caliper to measure.
  • TGI% [1-T/C] ⁇ 100.
  • T/C% (delta T/T 0 ) ⁇ 100.
  • the relative tumor volume (RTV) is calculated based on the results of tumor measurement.
  • the tumor mass was taken and weighed, and photos were taken.
  • the TGIs of the p-toluenesulfonate (12 mg/kg + 50 mg/kg) group corresponding to paclitaxel + compound 12 were 30.17%, 66.24%, and 93.22%, respectively.
  • mice were randomly divided into 3 groups, with 5-8 mice in each group. Drug intervention was started on the 7th day after subcutaneous tumor inoculation.
  • the grouping and administration conditions were as follows:
  • Blank control group 100 ⁇ L normal saline was administered daily;
  • Solvent control group 100 ⁇ L of solvent was administered daily.
  • Drug experimental group The dose is 50 mg/kg, and about 100 ⁇ L of p-toluenesulfonate solution corresponding to Compound 12 is administered daily according to body weight.
  • volume formula long diameter * short diameter * short diameter / 2
  • the mice were sacrificed approximately 3 weeks after administration.
  • mice were randomly divided into 5 groups, with 5-8 mice in each group. Drug intervention was started on the 7th day after subcutaneous tumor inoculation.
  • the grouping and administration conditions were as follows:
  • Cisplatin (DDP) experimental group The drug dose is 2-4 mg/kg, and about 100 ⁇ L of DDP solution is injected intraperitoneally every week according to body weight;
  • Paclitaxel (PTX) experimental group 12 mg/kg, approximately 100 ⁇ L of PTX solution is injected intraperitoneally according to body weight every week;
  • the length, short diameter and body weight of the transplanted tumors in nude mice were measured every 1 day, and the tumor growth curve and body weight change curve were drawn respectively.
  • attention should be paid to the growth status of the mice such as skin color and temperature, whether there is weight loss, etc.
  • the mice were sacrificed approximately 3 weeks after administration.
  • nude mice The important organs of nude mice were fixed with 4% paraformaldehyde and reserved for subsequent paraffin embedding, sectioning and HE staining.
  • the p-toluenesulfonate corresponding to the MNK/VEGFR2 small molecule inhibitor compound 12 was used to treat the xenograft tumor model of human DLBCL cell SU-DHL-6 and MCL cell JeKo-1.
  • mice After tumor grafting, the patients were randomly divided into 5 groups: blank group, solvent group, p-toluenesulfonate single drug group corresponding to compound 12, doxorubicin single drug group and combination group. Among them, the p-toluenesulfonate corresponding to Compound 12 was intragastrically administered at 25 mg/kg daily, and doxorubicin was administered through the tail vein at 3.3 mg/kg, once every 10 days, a total of 2 times.
  • mice were sacrificed, and the subcutaneous tumors were carefully peeled off, photographed, weighed, and analyzed statistically. At the same time, fresh eye blood and important organs were collected.
  • mouse lung cancer cells LL2 were injected subcutaneously. Inject 100 ⁇ L of cell suspension containing 1X10 6 LL2 into the right back of female C57 mice. One week after inoculation (tumor volume is about 50-100mm 3 ), the mice were randomly divided into 4 groups, with 6 mice in each group.
  • the p-toluenesulfonate corresponding to compound 12 is administered orally daily at a dose of 50 mg/kg.
  • Single PD-1 antibody PD-1 antibody was administered intraperitoneally twice a week starting from the 5th day after tumor grafting, with a dose of 200 ⁇ g/animal.
  • PD-1 isotype control ISO Administration started on the 5th day after tumor grafting, twice a week, intraperitoneally, with a dose of 200 ⁇ g/animal.
  • Combination therapy After the start of treatment, the p-toluenesulfonate corresponding to Compound 12 was administered orally every day, and the PD-1 antibody was injected intraperitoneally twice a week, 200 ⁇ g/animal.
  • Cell culture Perform routine cell culture in 5% CO 2 , 37°C, and MEM culture medium containing 10% fetal bovine serum; digest and passage with 0.25% trypsin; according to cell growth, passage 2 to 3 times a week, passage ratio is 1:3 to 1:6.
  • Animal model preparation Collect Hep G2 cells in the logarithmic growth phase, count the cells and resuspend them in medium containing 50% serum-free MEM and 50% Matrigel. Adjust the cell concentration to 2.5 ⁇ 10 7 cells/mL; use a pipette Pipette the cells to disperse them evenly and then put them into a 50-mL centrifuge tube. Place the centrifuge tube in an ice box; use a 1-mL syringe to absorb the cell suspension and inject it into the subcutaneous axilla of the front right limb of the nude mouse. Each animal is inoculated with 200L. (5 ⁇ 10 6 cells/mouse) to establish a Hep G2 nude mouse transplanted tumor model.
  • the animal status and tumor growth were regularly observed, and the tumor diameter was measured using an electronic vernier caliper.
  • the data was directly entered into an Excel spreadsheet to calculate the tumor volume.
  • the tumor volume reaches 100-300mm 3
  • the day of grouping was regarded as the first day of the experiment (D1).
  • the tumor diameter was measured twice a week, the tumor volume was calculated, and the animal body weight was weighed and recorded.
  • the animal grouping and dosing schedule are shown in Table 2. Dosing will begin on the day of grouping and end the experiment after 3 weeks (or the tumor volume in the solvent control group reaches more than 2000 mm 3 , whichever comes first). The dosing volume is 10 mL ⁇ kg. -1 . On the last day of the experiment, the body weight and tumor diameter were measured, and the animals were euthanized by CO 2 inhalation. The tumor pieces were removed, weighed, and photographed.
  • MDA-MB-231 cells were cultured in L-15 culture medium containing 10% fetal bovine serum; according to the cell growth conditions, 0.25% pancreatic Enzyme digestion and passage, 1 to 2 times a week, with a passage ratio of 1:3 to 1:10.
  • Animal model preparation Collect MDA-MB-231 cells in the logarithmic growth phase, count the cells and resuspend them in serum-free L-15 culture medium. Adjust the cell concentration to 3 ⁇ 10 7 cells/mL; use a pipette to pipette the cells. Disperse it evenly and put it into a 50-mL centrifuge tube. Place the centrifuge tube in an ice box; use a 1-mL syringe to absorb the cell suspension and inject it into the subcutaneous skin of the axilla of the front right limb of nude mice. Each animal is inoculated with 100L (3.0 ⁇ 10 6 cells/mouse) to establish MDA-MB-231 nude mouse transplanted tumor model.
  • the animal status and tumor growth were regularly observed, and the tumor diameter was measured using an electronic vernier caliper.
  • the data was directly entered into an Excel spreadsheet to calculate the tumor volume.
  • the tumor volume reaches 100-300mm 3
  • the day of grouping was regarded as the first day of the experiment (D1).
  • the tumor diameter was measured twice a week, the tumor volume was calculated, and the animal body weight was weighed and recorded.
  • the animal grouping and dosing schedule are shown in Table 3. Dosing will begin on the day of grouping and end the experiment after 3 weeks (or the tumor volume in the solvent control group reaches more than 2000 mm 3 , whichever comes first). The dosing volume is 10 mL ⁇ kg. -1 . On the last day of the experiment, the body weight and tumor diameter were measured, and the animals were euthanized by CO 2 inhalation. The tumor pieces were removed, weighed, and photographed.

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Abstract

La présente invention concerne l'utilisation d'un composé représenté par la formule (I) dans la préparation d'un médicament antitumoral. Le composé a un effet inhibiteur sur la protéine eIF4E et/ou la protéine VEGFR2 et a un bon effet inhibiteur sur diverses tumeurs solides ou non solides.
PCT/CN2023/107850 2022-07-19 2023-07-18 Utilisation de composé de pyrrolotriazine dans la préparation de médicament antitumoral Ceased WO2024017229A1 (fr)

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WO2025190364A1 (fr) * 2024-03-14 2025-09-18 山东轩竹医药科技有限公司 Inhibiteur de kif18a et son utilisation

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CN119745884A (zh) * 2025-03-05 2025-04-04 江苏长泰药业股份有限公司 一种用于治疗非小细胞肺癌的丙酮酸盐制剂及其制备方法
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