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WO2020177678A1 - Utilisation d'un inhibiteur de tyrosine kinase multi-cible en association avec un inhibiteur d'egfr dans la préparation d'un médicament pour le traitement d'une tumeur - Google Patents

Utilisation d'un inhibiteur de tyrosine kinase multi-cible en association avec un inhibiteur d'egfr dans la préparation d'un médicament pour le traitement d'une tumeur Download PDF

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WO2020177678A1
WO2020177678A1 PCT/CN2020/077520 CN2020077520W WO2020177678A1 WO 2020177678 A1 WO2020177678 A1 WO 2020177678A1 CN 2020077520 W CN2020077520 W CN 2020077520W WO 2020177678 A1 WO2020177678 A1 WO 2020177678A1
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tumor
cancer
egfr
day
tyrosine kinase
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Chinese (zh)
Inventor
任文明
唐蜜
杨昌永
廖成
张连山
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Jiangsu Hengrui Medicine Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
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Priority to CN202080009321.1A priority Critical patent/CN113301895B/zh
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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the application relates to the use of a combination of a multi-target tyrosine kinase inhibitor and a human epidermal growth factor receptor inhibitor (EGFRi) in the preparation of drugs for treating tumors, and belongs to the field of pharmacy.
  • EGFRi human epidermal growth factor receptor inhibitor
  • lung cancer has become the leading cause of cancer deaths. In China, lung cancer ranks first in terms of cancer incidence and mortality. Although several generations of newer generations of cytotoxic drugs and targeted therapies have been introduced in the past 20 years, patients with advanced lung cancer, especially those without known driver mutation genes, still have a poor survival prognosis, and advanced or metastatic lung cancer is still a kind of There are a large number of fatal diseases with unmet medical needs.
  • Non-small cell lung cancer accounts for about 85% of all lung cancers, and about 75% of NSCLC patients are already in the advanced stage when they are discovered, and the 5-year survival rate is very low. For patients with advanced or metastatic NSCLC, there is still a great clinical need to choose an appropriate systemic treatment.
  • NSCLC can be divided into squamous cell carcinoma and non-squamous cell carcinoma.
  • Non-squamous cell carcinomas include adenocarcinoma, large cell carcinoma and other subtypes of cell carcinoma. Patients with non-squamous cell carcinoma were further classified according to the presence or absence of driver mutation genes (EGFR mutation or ALK gene rearrangement).
  • EGFR Epidermal Growth Factor Receptor
  • EGF epidermal growth factor
  • EGFR can form homodimers on the cell membrane, or form heterodimers with other receptors in the family (such as erbB2, erbB3, or erbB4).
  • the formation of these dimers can cause the phosphorylation of key tyrosine residues in EGFR cells, thereby activating multiple downstream signaling pathways in the cells. These intracellular signaling pathways play an important role in cell proliferation, survival and anti-apoptosis.
  • the dysregulation of EGFR signaling pathways can promote malignant transformation of cells, and play an important role in tumor cell proliferation, invasion, metastasis, and angiogenesis.
  • Overexpression of EGFR has been reported in many human malignant diseases, including bladder cancer, brain tumors, head and neck cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, prostate cancer, and kidney cancer. In many cases, the overexpression of EGFR is related to the poor prognosis of patients.
  • the anti-tumor mechanism of TKIs may be achieved through the following ways: inhibiting the damage and repair of tumor cells, blocking cell division in G1 phase, inducing and maintaining cell apoptosis, and anti-angiogenesis.
  • Overexpression of EGFR often indicates poor prognosis, fast metastasis, resistance to chemotherapy drugs, hormone resistance, and shorter survival time.
  • the FDA has approved the marketing of a variety of multi-target TKIs, such as sorafenib, vandetanib and Sunitinib (Sutent, SU-11248). Among them, Sunitinib was approved for marketing in January 2006 to treat GIST. And advanced kidney cancer.
  • WO2007085188 discloses a compound similar to Sunitinib, as shown in the following formula (I), which may be better applied to the treatment of the above-mentioned tumors.
  • the chemical name of the compound is 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indole-3-ylidene-methyl)- 3-Methyl-1,5,6,7-tetrahydro-pyrrole [3,2-c]pyridin-4-one, which is known to inhibit tumor proliferation and angiogenesis, and can selectively inhibit vascular endothelial growth factor
  • VEGF vascular endothelial growth factor
  • the kinase activity of (VEGF) receptors can be used clinically for the treatment of renal cancer, gastrointestinal stromal tumors, colorectal cancer and pancreatic neuroendocrine tumors.
  • WO2016054987A discloses a 4-substituted-(2-(N-(5-allylamido)phenyl)amino)pyrimidine derivative represented by the structure of formula (II), which has the ability to inhibit L858R EGFR mutant, T790M The activity of EGFR mutants and exon 19 deletion activation mutants can be used to treat diseases mediated by EGFR mutant activity alone or in part.
  • WO2017161937 discloses the mesylate of the EGFR inhibitor represented by formula (II),
  • WO2006120557A discloses a method for treating patients with non-small cell lung cancer, including giving With the patient’s daily 25-50 mg of sunitinib malate and about 250 mg of gefitinib or 150 mg of erlotinib per day, but there is no specific experimental data in the instructions of the application, so the combined effect is impossible Know.
  • the application provides a use of a combination of a multi-target tyrosine kinase inhibitor and an EGFR inhibitor in the preparation of drugs for treating tumors.
  • the tumor described in this application can be selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, stomach cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, and glia Tumor, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, Leukemia, thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, cholangiocarcinoma or choriocarcinoma, preferably non-small cell lung cancer.
  • the use of the multi-target tyrosine kinase inhibitor and EGFR inhibitor described in the present application in the preparation of drugs for preventing or treating tumors and the tumors are preferably tumors with EGFR mutations.
  • the EGFR-mutant tumor described in the present application is preferably non-small cell lung cancer, and the preferred EGFR mutant is selected from L858R EGFR mutant and/or T790M EGFR mutant and/or EGFR exon 20 insertion and/or EGFR exon Sub 19 is missing.
  • the non-small cell lung cancer described in this application is selected from squamous cell carcinoma and non-squamous cell carcinoma, preferably non-phosphorous cell carcinoma, wherein the non-phosphorous cell carcinoma can be adenocarcinoma, large cell carcinoma And other subtypes of cell carcinoma.
  • the multi-target tyrosine kinase inhibitor has an inhibitory effect on VEGFR kinase.
  • the multi-target tyrosine kinase inhibitors described in this application can be selected from sunitinib, axitinib, sorafenib, nintedanib, cabozantinib S-malate, lenvatinib mesylate, regorafenib, ponatinib, MP-0250, pazopanib, anlotinib, ningetinib, rebastinib, PF -06753512, tivozanib, telatinib, AL-2846, vorolanib, BMS-817378, lucitanib hydrochloride, ODM-203, sitravatinib, fenretinide, surufatinib, vandetanib, ENMD-2076, AMC-303, brivanib alaninate, cediranib, BI-836880, dovitinib , Muparfostat sodium,
  • the EGFR inhibitor described in this application can be selected from osimertinib, gefitinib, erlotinib, olmutinib, icotinib, pyrotinib, brigatinib, dacomitinib, afatinib, neratinib, lapatinib, ABT-414, varlitinib, HLX-07, theliatinib, epitinib succinate, S- 222611, poziotinib, AST-2818, GNS-1480, mavelertinib, AP-32788, AZD-3759, clawinib, Sym-013, allitinib tosylate, tarloxotinib bromide, poziotinib, CK-101, QL-1203, JNJ-61186372, SKLB- 1028, TAS-121, Hemay-020, Hemay-02
  • the pharmaceutically acceptable salt of the drug described in the application can be hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate, and valerate. , Glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate, Malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate or lauryl sulfonate, etc.
  • the pharmaceutically acceptable salt of the compound represented by formula (I) is malate.
  • the pharmaceutically acceptable salt of the compound represented by formula (II) is methanesulfonate.
  • the pharmaceutically acceptable salt of the compound represented by formula (I) is malate, and the pharmaceutically acceptable salt of the compound represented by formula (II) is methanesulfonate.
  • the dose of the multi-target tyrosine kinase inhibitor is selected from 0.1-1000 mg, and the frequency of administration can be once a day, twice a day or three times a day; the dose of EGFR inhibitor The range is selected from 1-1000 mg, and the frequency of administration can be once a day, twice a day or three times a day.
  • the dose of the multi-target tyrosine kinase inhibitor is selected from 0.1-500 mg, and the frequency of administration can be once a day, twice a day or three times a day, preferably once a day
  • the dose range of EGFR inhibitors is selected from 1-500mg, specifically 1mg, 2.5mg, 5mg, 7.5mg, 10mg, 12.5mg, 15mg, 17.5mg, 20mg, 22.5mg, 25mg, 27.5mg, 30mg, 32.5mg , 35mg, 37.5mg, 40mg, 42.5mg, 45mg, 47.5mg, 50mg, 52.5mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 120mg, 130mg, 140mg , 150mg, 160mg, 170m
  • the dose of the multi-target tyrosine kinase inhibitor is selected from 0.1-100 mg, specifically 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8mg, 0.9mg, 1.0mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg , 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45m
  • the dose of the multi-target tyrosine kinase inhibitor is selected from 1-25 mg, specifically 15 mg, 20 mg, or 25 mg, and the frequency of administration may be once a day, twice a day, or a day Three times, preferably once a day, the dose range of the EGFR inhibitor is selected from 1-500 mg, specifically 55 mg, 110 mg, 220 mg or 260 mg, preferably once a day.
  • the dose of the multi-target tyrosine kinase inhibitor can be 15mg, 20mg or 25mg, the frequency of administration is once a day, and the dose of the EGFR inhibitor can be 55mg, 110mg, 220mg or 260mg. The frequency of administration is once a day.
  • the dose of the multi-target tyrosine kinase inhibitor is 15 mg, and the frequency of administration is once a day.
  • the dose of EGFR inhibitor can be 55 mg, 110 mg, 220 mg or 260 mg, and the frequency of administration is Once a day.
  • the dose of the multi-target tyrosine kinase inhibitor is 20 mg, and the frequency of administration is once a day.
  • the dose of EGFR inhibitor can be 55 mg, 110 mg, 220 mg or 260 mg, and the frequency of administration is one. Once a day.
  • the dose of the multi-target tyrosine kinase inhibitor is 25 mg, and the frequency of administration is once a day.
  • the dose of EGFR inhibitor can be 55 mg, 110 mg, 220 mg or 260 mg, and the frequency of administration is one. Once a day.
  • the dose of the multi-target tyrosine kinase inhibitor can be 15 mg, 20 mg or 25 mg, the frequency of administration is once a day, the dose of EGFR inhibitor is 55 mg, and the frequency of administration is once a day .
  • the dose of the multi-target tyrosine kinase inhibitor can be 15 mg, 20 mg or 25 mg, the frequency of administration is once a day, the dose of EGFR inhibitor is 110 mg, and the frequency of administration is once a day .
  • the dose of the multi-target tyrosine kinase inhibitor can be 15 mg, 20 mg or 25 mg, the frequency of administration is once a day, the dose of EGFR inhibitor is 220 mg, and the frequency of administration is once a day .
  • the dose of the multi-target tyrosine kinase inhibitor can be 15 mg, 20 mg or 25 mg, the frequency of administration is once a day, the dose of EGFR inhibitor is 260 mg, and the frequency of administration is once a day .
  • the multi-target tyrosine kinase inhibitor is administered according to body weight, the dosage is selected from 0.1 to 10.0 mg/kg, and the frequency of administration may be once a day or twice a day. Once or three times a day; the dose range of EGFR inhibitor is selected from 1-1000 mg, and the frequency of administration can be once a day, twice a day or three times a day.
  • the dose of the multi-target tyrosine kinase inhibitor may be 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1.0mg/kg, 1.2mg/kg, 1.4mg/kg, 1.6mg/kg, 1.8mg/kg, 2.0mg/kg, 2.2mg/kg, 2.4mg/kg, 2.6mg/kg, 2.8mg/kg, 3.0mg/kg, 3.2mg/kg, 3.4mg/kg, 3.6mg/kg, 3.8mg/kg, 4.0mg/kg, 4.2mg/kg, 4.4mg/kg, 4.6mg/kg, 4.8mg/kg, 5.0mg/kg, 5.2mg/kg, 5.4mg/kg, 5.6mg/kg
  • the route of administration of the combination described in the present application can be selected from oral administration, parenteral administration, and transdermal administration.
  • the parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, intramuscular injection, preferably oral Administration.
  • the combination optionally further includes other components, and the other components include but are not limited to other drugs for treating tumors.
  • This application also provides a method for treating tumors, which comprises administering to a patient an effective amount of the above-mentioned multi-target tyrosine kinase inhibitor and an effective amount of the above-mentioned EGFR inhibitor.
  • the application also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned multi-target tyrosine kinase inhibitor and EGFR inhibitor, and one or more pharmaceutical carriers, excipients, and diluents.
  • the pharmaceutical composition can be made into any pharmaceutically acceptable dosage form. For example, it can be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injections and concentrated solutions for injections), suppositories, inhalants or sprays Agent.
  • composition comprising a multi-target tyrosine kinase inhibitor and an EGFR inhibitor described in this application can be administered alone or in combination with one or more therapeutic agents.
  • the application also provides a pharmaceutical kit, wherein the pharmaceutical composition comprising the multi-target tyrosine kinase inhibitor and the EGFR inhibitor described in the application is packaged.
  • the combined administration of a multi-target tyrosine kinase inhibitor and an EGFR inhibitor improves the therapeutic effect.
  • the “combination” mentioned in this application is a mode of administration, which refers to the administration of at least one dose of multi-target tyrosine kinase inhibitor and at least one dose of EGFR inhibitor within a certain period of time, wherein two All substances show pharmacological effects.
  • the time limit can be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week or within 24 hours.
  • Multi-target tyrosine kinase inhibitors and EGFR inhibitors can be administered simultaneously or sequentially. This period includes treatments in which the multi-target tyrosine kinase inhibitor and the EGFR inhibitor are administered by the same route of administration or different routes of administration.
  • a therapeutically effective amount of the drug can reduce the number of cancer cells; reduce the size of the tumor; inhibit (ie, slow down and preferably prevent) the infiltration of cancer cells into the surrounding organs; inhibit (ie, slow down to a certain extent) Preferably prevent) tumor metastasis; inhibit tumor growth to a certain extent; and/or reduce one or more symptoms related to the disease to a certain extent.
  • the drug can prevent the growth of and/or kill existing cancer cells, it can be cytostatic and/or cytotoxic.
  • in vivo efficacy can be measured by assessing survival duration, progression-free survival (PFS) duration, response rate (RR), response duration, and/or quality of life.
  • Figure 1 The efficacy of drug A and drug B alone or in combination on human lung cancer H1975 nude mice subcutaneously transplanted tumor;
  • Figure 3 The efficacy of drug A and drug B alone or in combination on human lung cancer PC-9 subcutaneous transplantation tumor in nude mice;
  • Figure 4 The effect of drug A and drug B alone or in combination on body weight of tumor-bearing nude mice.
  • Example 1 Evaluation of the compound malate of formula (I) (compound A), the compound methanesulfonate of formula (II) (drug B) alone or a combination of both for subcutaneous transplantation of human lung cancer H1975 nude mice Tumor efficacy
  • Drug A was prepared according to the method disclosed in WO2007085188;
  • Drug B was prepared according to the co-preparation method of WO2017161937; the drug formulations were all prepared and diluted with 0.1% Tween-80 + 0.5% CMC.
  • H1975 cells were purchased from American Type Culture Collection. Use a 10-cm petri dish for adherent culture. The culture conditions are RPMI 1640 medium with 10% fetal bovine serum, penicillin and streptomycin, and culture at 37°C in an incubator with 5% CO 2 air. Passage 2-3 times a week, when the cells are in the exponential growth phase, trypsin digestion, collect the cells, count, and inoculate.
  • BALB/c nude mice, 6-7 weeks, ⁇ purchased from Shanghai Lingchang Biotechnology Co., Ltd.
  • mice were subcutaneously inoculated with human lung cancer H1975 cells. After the tumor grew to 100-150 mm 3 , the animals were divided into groups according to the tumor volume (D0). Mice were administered intragastrically (ig), 1 day (QD; administration volume 10mL/kg; the solvent group was given the same volume of "solvent" (0.1% Tween-80 + 0.5% CMC); specific dosage and administration The drug protocol is shown in Table 1. The tumor volume was measured twice a week, the mice were weighed, and the data was recorded.
  • the experimental index is to investigate the effect of drugs on tumor growth, and the specific index is T/C% or tumor inhibition rate TGI (%).
  • V 1/2 ⁇ a ⁇ b 2 where a and b represent length and width respectively.
  • T/C(%) (T-T0)/(C-C0) ⁇ 100 where T and C are the tumor volume at the end of the experiment; T0 and C0 are the tumor volume at the beginning of the experiment.
  • TGI Tumor inhibition rate
  • TGI tumor inhibition rate
  • the tumor is smaller than the initial volume, that is, when T ⁇ T0 or C ⁇ C0, it is defined as partial tumor regression (PR); if the tumor disappears completely, it is defined as complete tumor regression (CR).
  • PR partial tumor regression
  • CR complete tumor regression
  • the end of the experiment was reached, or the tumor volume reached 1500 mm 3 , the animals were killed under CO 2 anesthesia, and then the tumors were dissected and taken and photographed.
  • Drug B (3, 5mg/kg, ig, QD ⁇ 17) dose-dependently inhibited the growth of human lung cancer H1975 (EGFRL858R/T790M) subcutaneously transplanted tumors in nude mice, and the tumor inhibition rates were 44% and 74%; drug A ( The inhibitory rate of 10mg/kg, ig, QD ⁇ 17) against H1975 subcutaneous xenograft tumor is 37%; drug B (3, 5mg/kg, ig, QD ⁇ 17) and drug A (10mg/kg, ig, QD ⁇ 17) The tumor inhibition rate increased to 85% and 98% respectively, which was significantly better than the single-agent efficacy (P ⁇ 0.05, compared with single-agent).
  • mice can tolerate the above drugs well, and there is no significant weight loss and other symptoms.
  • the results show that the combination of drug B and drug A has a synergistic effect on human lung cancer H1975 nude mice subcutaneously transplanted tumors.
  • Drug B 5mg/kg, ig, QD ⁇ 17
  • drug A 10mg/kg, ig, QD ⁇ 17
  • the combination of the two has a significant synergistic effect (P ⁇ 0.05, compared with the single drug)
  • tumor-bearing mice can tolerate the above drugs in combination.
  • Example 2 Evaluation of the compound represented by formula (I) malate (compound A), the compound represented by formula (II) methanesulfonate (drug B) alone or in combination on human lung cancer PC-9 nude mice Efficacy of subcutaneous transplantation tumor
  • Drug A was prepared according to the method disclosed in WO2007085188;
  • Drug B was prepared according to the co-preparation method of WO2017161937; the drug formulations were all prepared and diluted with 0.1% Tween-80 + 0.5% CMC.
  • PC-9 cells are adhered to the wall in a 10-cm petri dish.
  • the culture conditions are RPMI 1640 medium with 10% fetal bovine serum, penicillin and streptomycin, and culture in an incubator at 37°C and 5% CO 2 air. . Passage 2-3 times a week, when the cells are in the exponential growth phase, trypsin digestion, collect the cells, count, and inoculate.
  • BALB/c nude mice, 6-7 weeks, ⁇ purchased from Shanghai Lingchang Biotechnology Co., Ltd.
  • mice were subcutaneously inoculated with human lung cancer PC-9 cells. After the tumor grew to 100-150 mm 3 , the animals were divided into groups according to the tumor volume (D 0 ). Mice were administered intragastrically (ig), 1 day (QD; administration volume 10mL/kg; the solvent group was given the same volume of "solvent" (0.1% Tween-80 + 0.5% CMC); specific dosage and administration The drug protocol is shown in Table 3. The tumor volume was measured twice a week, the mice were weighed, and the data was recorded.
  • the experimental index is to investigate the effect of drugs on tumor growth, and the specific index is T/C% or tumor inhibition rate TGI (%).
  • V 1/2 ⁇ a ⁇ b 2 , where a and b represent length and width respectively.
  • T/C(%) (T-T0)/(C-C0) ⁇ 100, where T and C are the tumor volume at the end of the experiment; T0 and C0 are the tumor volume at the beginning of the experiment.
  • TGI Tumor inhibition rate
  • TGI tumor inhibition rate
  • the tumor is smaller than the initial volume, that is, when T ⁇ T0 or C ⁇ C0, it is defined as partial tumor regression (PR); if the tumor disappears completely, it is defined as complete tumor regression (CR).
  • PR partial tumor regression
  • CR complete tumor regression
  • the end of the experiment was reached, or the tumor volume reached 1500 mm 3 , the animals were killed under CO 2 anesthesia, and then the tumors were dissected and taken and photographed.
  • drug A 10 mg/kg + drug B 1 mg/kg has a maximum weight change of -6.3% on day 11; drug A 10 mg/kg + drug B 3 mg/kg has a maximum weight change of -4.7% on day 11.
  • D0 Time of first administration; P value refers to the comparison with the solvent; **P ⁇ 0.01, compared with the drug A 10mg/kg group; ##P ⁇ 0.01, compared with the drug B 3mg/kg group; $$P ⁇ 0.01, compared with drug B 1mg/kg group.
  • Drug B (1, 3mg/kg, ig, QD ⁇ 20) dose-dependently inhibited the growth of human lung cancer PC-9 (EGFR ex19del) subcutaneously transplanted tumors in nude mice, with tumor inhibition rates of 27% and 59%, respectively;
  • Drug A (10mg/kg, ig, QD ⁇ 20) the tumor inhibition rate of PC-9 subcutaneous transplantation tumor is 59%;
  • drug B (1, 3mg/kg, ig, QD ⁇ 20) and drug A (10mg/kg, ig ,QD ⁇ 20)
  • the combined tumor inhibition rate increased to 74% and 96%, respectively, which was significantly stronger than the single drug efficacy (P ⁇ 0.01).
  • Drug B (1, 3 mg/kg, ig, QD ⁇ 20) and drug A (10 mg/kg, ig, QD ⁇ 20) inhibit the growth of human lung cancer PC-9 (EGFR ex19del) subcutaneously transplanted tumor in nude mice
  • PC-9 EGFR ex19del
  • the combination of the two has a significant synergistic effect (P ⁇ 0.01, compared with the single drug); the combined group caused a transient weight loss in mice, and other tumor-bearing mice could well tolerate the above drugs.

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Abstract

L'invention concerne une utilisation d'un inhibiteur de tyrosine kinase multi-cible en association avec un inhibiteur d'EGFR dans la préparation d'un médicament pour le traitement d'une tumeur. En particulier, l'inhibiteur de tyrosine kinase multi-cible décrit dans la présente invention est choisi parmi un composé représenté par la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci, et l'inhibiteur d'EGFR est choisi parmi un composé représenté par la formule (II) ou un stéréoisomère, un complexe ou un sel pharmaceutiquement acceptable de celui-ci. (I), (II)
PCT/CN2020/077520 2019-03-04 2020-03-03 Utilisation d'un inhibiteur de tyrosine kinase multi-cible en association avec un inhibiteur d'egfr dans la préparation d'un médicament pour le traitement d'une tumeur Ceased WO2020177678A1 (fr)

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CN202080009321.1A CN113301895B (zh) 2019-03-04 2020-03-03 多靶点酪氨酸激酶抑制剂与egfr抑制剂联合在制备治疗肿瘤的药物中的用途

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WO2024017403A1 (fr) * 2022-07-19 2024-01-25 中南大学湘雅二医院 Utilisation d'une pluralité de composés dans la préparation d'un médicament pour le traitement de néoplasmes myéloprolifératifs

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CN116889565A (zh) * 2022-04-07 2023-10-17 深圳微芯生物科技股份有限公司 西奥罗尼在抗胰腺癌中的用途
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