[go: up one dir, main page]

WO2024088275A1 - Utilisation d'un composé naphtylamide dans le traitement de tumeurs résistantes aux médicaments - Google Patents

Utilisation d'un composé naphtylamide dans le traitement de tumeurs résistantes aux médicaments Download PDF

Info

Publication number
WO2024088275A1
WO2024088275A1 PCT/CN2023/126296 CN2023126296W WO2024088275A1 WO 2024088275 A1 WO2024088275 A1 WO 2024088275A1 CN 2023126296 W CN2023126296 W CN 2023126296W WO 2024088275 A1 WO2024088275 A1 WO 2024088275A1
Authority
WO
WIPO (PCT)
Prior art keywords
drug
resistant
egfr
tumor
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2023/126296
Other languages
English (en)
Chinese (zh)
Inventor
谢华
段文虎
丁健
詹正生
耿美玉
杨汉煜
吕永聪
冯芳
赵倩
张阳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Materia Medica of CAS
Original Assignee
Shanghai Institute of Materia Medica of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Materia Medica of CAS filed Critical Shanghai Institute of Materia Medica of CAS
Publication of WO2024088275A1 publication Critical patent/WO2024088275A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the field of medicine, and specifically relates to the application of a naphthamide compound in preparing a medicine for treating drug-resistant tumors.
  • Gliomas are tumors that occur in the neuroectoderm, including astrocytomas, glioblastomas, medulloblastomas, ependymomas, and choroid papilloma, etc., and gliomas are divided into brain gliomas and spinal cord gliomas according to the site of onset. Glioblastoma is the most common malignant primary brain tumor, accounting for about 57% of all gliomas and 48% of all primary malignant central nervous system tumors.
  • Temozolomide is an imidazole tetrazine-derived alkylating agent. TMZ is rapidly hydrolyzed to 5-(3-methyltriazine-1-yl)imidazole-4-carboxamide (MTIC) at physiological pH, which then affects DNA replication through methylation at the O 6 and N 7 sites of guanine in deoxyribonucleic acid (DNA), thereby exerting a cytotoxic effect. Due to its oral administration and easy penetration of the blood-brain barrier, TMZ was approved by the FDA in 2005 and 2009 for the treatment of patients with astrocytoma and glioblastoma, respectively. It is also the only oral chemotherapy drug for the first-line treatment of glioma.
  • MTIC 5-(3-methyltriazine-1-yl)imidazole-4-carboxamide
  • TMZ-treated patients do not respond to TMZ, which is mainly caused by the overexpression of O 6 -methylguanine methyltransferase (MGMT) and the lack of DNA repair pathways in GBM cells.
  • MGMT can repair the methylation of guanine O 6 caused by TMZ, making tumor cells insensitive to TMZ.
  • the expression of MGMT is mainly affected by the methylation level of its promoter region. The higher the methylation level, the lower the MGMT expression, and the more sensitive it is to TMZ.
  • the MGMT methylation positivity rate in glioma patients is about 40%, and it is even lower in the most malignant glioblastoma. This means that without considering secondary resistance to TMZ treatment, at least half of glioma patients are resistant to TMZ.
  • the clinical recommendation is to use methylation-specific PCR (polymerase chain reaction) combined with immunohistochemistry to determine the expression of MGMT.
  • methylation-specific PCR polymerase chain reaction
  • immunohistochemistry to determine the expression of MGMT.
  • Non-small cell lung cancer (NSCLC), as the main histological type of the disease, accounts for more than 80% of lung cancer patients, with a 5-year survival rate of less than 15%.
  • High expression or abnormal activation of epidermal growth factor receptor (EGFR) is an important target that promotes the deterioration and development of NSCLC.
  • EGFR inhibitors In recent years, with the in-depth study of the pathogenesis of lung cancer, molecular targeted therapy represented by EGFR inhibitors has made breakthrough progress. So far, three generations of EGFR inhibitors have been approved for marketing, bringing huge clinical benefits to patients with EGFR mutant NSCLC, but EGFR inhibitors develop acquired resistance within about one year of use, which greatly limits the clinical application of the drug. Therefore, the development of strategies that can inhibit EGFR inhibitor resistance has become a hot topic in current NSCLC research.
  • the reported EGFR inhibitor resistance mechanisms can be divided into two categories: the first category is EGFR-dependent resistance mechanisms, which are mainly caused by changes in EGFR itself, such as EGFR T790M mutation, which is the main cause of resistance to first-generation EGFR inhibitors (accounting for about 60% of all resistant patients), or EGFR C797S/G , EGFR L798I , EGFR L792H and other point mutations and EGFR T790M loss mediating resistance to third-generation EGFR inhibitors. There is no treatment for tumors with EGFR C797S mutation.
  • the second category is EGFR-independent resistance mechanisms, including MET and HER2 amplification, FGFR1 amplification, PIK3CA mutation, small cell transformation, RAS-MAPK pathway activation and KRAS mutation and amplification.
  • EGFR-independent resistance mechanisms including MET and HER2 amplification, FGFR1 amplification, PIK3CA mutation, small cell transformation, RAS-MAPK pathway activation and KRAS mutation and amplification.
  • Compound (I) is a VEGFR/CSF1R dual-target inhibitor with excellent activity, which can inhibit tumor cell angiogenesis and promote tumor immunity to exert anti-tumor effects.
  • the purpose of the present invention is to provide a use of a naphthamide compound in treating drug-resistant tumors.
  • the first aspect of the present invention provides a use of a compound (I) or a pharmaceutically acceptable salt thereof for preparing a drug for treating drug-resistant tumors;
  • the compound (I) has the following structure:
  • the drug-resistant tumor is selected from the following group: glioma and lung cancer.
  • the drug-resistant tumor is selected from the following group: temozolomide-resistant tumor, EGFR inhibitor-resistant tumor.
  • the drug-resistant tumor is a tumor with high expression of O 6 -methylguanine methyltransferase.
  • the drug-resistant tumor is a glioma with high expression of O 6 -methylguanine methyltransferase.
  • the temozolomide-resistant tumor is a temozolomide-resistant glioma.
  • the temozolomide-resistant tumor is a glioma with high expression of O 6 -methylguanine methyltransferase.
  • the glioma is selected from the group consisting of glioblastoma, astrocytoma, and medulloblastoma.
  • the temozolomide-resistant tumor is temozolomide-resistant medulloblastoma.
  • the EGFR inhibitor-resistant tumor is EGFR inhibitor-resistant lung cancer.
  • the lung cancer is selected from the group consisting of small cell lung cancer, non-small cell lung cancer, and lung adenocarcinoma.
  • the EGFR inhibitor-resistant tumor is a non-small cell tumor resistant to EGFR inhibitors.
  • Cell lung cancer is a non-small cell tumor resistant to EGFR inhibitors.
  • the EGFR inhibitor-resistant tumor is an EGFR mutation tumor.
  • the EGFR mutation is selected from the following group: EGFR T790M mutation and EGFR C797S mutation.
  • the EGFR inhibitor-resistant lung cancer is lung cancer with EGFR T790M mutation or lung cancer with EGFR C797S mutation.
  • the EGFR inhibitor-resistant lung cancer is non-small cell lung cancer with EGFR T790M mutation or non-small cell lung cancer with EGFR C797S mutation.
  • the EGFR inhibitor-resistant tumor is an EGFR-independent EGFR inhibitor-resistant tumor.
  • the EGFR-independent EGFR inhibitor-resistant tumor is a tumor caused by a mechanism selected from the following group: MET and HER2 amplification, FGFR1 amplification, PIK3CA mutation, small cell transformation, RAS-MAPK pathway activation, KRAS mutation and amplification.
  • the EGFR-independent EGFR inhibitor-resistant tumor is EGFR-independent EGFR inhibitor-resistant lung cancer.
  • the EGFR-independent EGFR inhibitor-resistant lung cancer is EGFR-independent EGFR inhibitor-resistant non-small cell lung cancer.
  • the EGFR inhibitor is selected from the following group: ASK120067 (Limertinib), osimertinib (AZD9291) or a salt thereof, ametinib or a salt thereof, vometinib or a salt thereof,
  • the EGFR inhibitor is ASK120067 (Limertinib), osimertinib (AZD9291) and salts thereof.
  • the second aspect of the present invention provides a pharmaceutical composition for treating drug-resistant tumors, the pharmaceutical composition comprising a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier;
  • the compound (I) has the following structure:
  • the drug-resistant tumor is as described above.
  • the pharmaceutical composition is an oral preparation.
  • a pharmaceutical combination comprising a first pharmaceutically active ingredient and a second pharmaceutically active ingredient in therapeutically effective amounts
  • the first active pharmaceutical ingredient is compound (I) or a pharmaceutically acceptable salt thereof;
  • the compound (I) has the following structure:
  • the second active ingredient of the drug is an anti-tumor drug selected from the following group: temozolomide and EGFR inhibitor.
  • the tumor is selected from the following group: temozolomide-resistant tumors and EGFR inhibitor-resistant tumors.
  • the temozolomide-resistant tumor is as described above.
  • the EGFR inhibitor-resistant tumor is as described above.
  • the EGFR inhibitor is selected from the following group: ASK120067 (Limertinib), osimertinib (AZD9291) or a salt thereof, ametinib or a salt thereof, and vometinib or a salt thereof.
  • the EGFR inhibitor is ASK120067 (Limertinib).
  • the mass ratio of the first pharmaceutically active ingredient to the second pharmaceutically active ingredient is 1-4, preferably 1-3, and preferably 2.
  • the fourth aspect of the present invention provides a use of compound (I) or a pharmaceutically acceptable salt thereof for preparing a drug for enhancing the efficacy of an anti-tumor drug;
  • the compound (I) has the following structure:
  • the anti-tumor drug is selected from the following group: temozolomide and EGFR inhibitor.
  • the tumor is selected from the following group: temozolomide-resistant tumors and EGFR inhibitor-resistant tumors.
  • the temozolomide-resistant tumor is as described above.
  • the EGFR inhibitor-resistant tumor is as described above.
  • the EGFR inhibitor is as described above.
  • the fifth aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the drug combination described in the third aspect of the present invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is an oral preparation.
  • the pharmaceutical composition is used to treat drug-resistant tumors.
  • the drug-resistant tumor is as described above.
  • the sixth aspect of the present invention provides a use of the drug combination described in the third aspect of the present invention for preparing a drug for treating drug-resistant tumors.
  • the drug-resistant tumor is as described above.
  • the patient with the drug-resistant tumor is a human.
  • the seventh aspect of the present invention provides a method for treating drug-resistant tumors, comprising the steps of:
  • the compound (I) has the following structure:
  • the drug-resistant tumor is as described above.
  • the anti-tumor drug is selected from the following group: temozolomide and EGFR inhibitors.
  • the EGFR inhibitor is as described above.
  • the method further comprises the following steps before step 1):
  • a genetic testing method is used to determine the patient's MGMT gene expression and/or EGFR gene mutation.
  • the patient is a patient with overexpression of MGMT gene.
  • the patient is a patient with EGFR gene mutation.
  • the patient is a patient with EGFR T790M mutation or a patient with EGFR C797S mutation.
  • the eighth aspect of the present invention provides a method for treating drug-resistant tumors, comprising the steps of:
  • the drug-resistant tumor is as described above.
  • the anti-tumor drug is selected from the following group: temozolomide and EGFR inhibitors.
  • the EGFR inhibitor is as described above.
  • the method further comprises the following steps before step 1):
  • a genetic testing method is used to determine the patient's MGMT gene expression and/or EGFR gene mutation.
  • the patient is a patient with overexpression of MGMT gene.
  • the patient is a patient with EGFR gene mutation.
  • the patient is a patient with EGFR T790M mutation or a patient with EGFR C797S mutation.
  • compound (I) has excellent inhibitory activity against drug-resistant tumors, can significantly inhibit the growth of drug-resistant tumors, especially temozolomide-resistant tumors and EGFR inhibitor-resistant tumors, and is expected to be developed as a drug against drug-resistant tumors.
  • the inventor completed the present invention.
  • pharmaceutically acceptable salt refers to a salt formed between a compound of the present invention and an acid or base that is suitable for use as a drug.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be mixed with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • compositions of the present invention are no particular limitation on the administration of the pharmaceutical composition of the present invention.
  • Representative administration methods include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and topical administration.
  • the drug of the present invention can be prepared into various clinically acceptable dosage forms, including oral dosage forms, injection dosage forms, local administration dosage forms or external dosage forms, etc.
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared with coatings and shells, such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in a certain part of the digestive tract. Examples of embedding compositions used are polymeric substances and waxes. If desired, the active compound can also be in microencapsulated form with one or more of the above-mentioned excipients.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).
  • the treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.
  • the therapeutically effective amount of the present invention refers to the effective dosage considered in medicine, that is, the amount of active compound is sufficient to significantly improve the condition without causing serious side effects.
  • the daily dosage is usually 0.01 to 2000 mg, preferably 1 to 500 mg. It can be administered as a single dose once a day, can be administered multiple times a day, or can be used at intervals.
  • the specific dosage and frequency of administration should take into account factors such as the route of administration and the patient's health status, which can be determined by a skilled physician based on routine skills.
  • the present invention also provides a method for using the pharmaceutical composition, that is, applying a therapeutically effective amount of the compound of the present invention (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention to a mammal (such as a human) in need of treatment.
  • the method for using the pharmaceutical composition before applying a therapeutically effective amount of the compound of the present invention (I) or a pharmaceutically acceptable salt thereof to a mammal (such as a human) in need of treatment, also includes a step of genetic testing to determine the MGMT methylation status and/or EGFR gene mutation of the mammal (such as a human) in need of treatment.
  • the MGMT methylation status of mammals can be detected using a mgmt gene methylation detection reagent (such as a manufacturer of gene technology, national medical device registration number 20193400101).
  • a mgmt gene methylation detection reagent such as a manufacturer of gene technology, national medical device registration number 20193400101.
  • the most commonly used methods for detecting EGFR gene mutations include direct sequencing and amplification retardation mutation system (ARMS-PCR).
  • Direct DNA sequencing is currently the most direct and basic method for detecting gene mutations, and known and unknown gene mutations in tumor tissue samples can be detected by reading DNA base sequences.
  • the ARMS-PCR method uses designed specific primers to accurately amplify the mutant sequence by PCR, and uses real-time fluorescence PCR quantitative analysis to highly sensitively detect the EGFR gene in small biopsy samples and blood specimens.
  • EGFR gene mutations in mammals can be detected using an EGFR gene mutation detection kit (such as: Human EGFR Gene Mutation Detection
  • the present invention has the following main advantages:
  • the compound (I) has excellent inhibitory activity against drug-resistant tumors and can significantly inhibit the growth of drug-resistant tumors, especially temozolomide-resistant tumors and EGFR inhibitor-resistant tumors, and is expected to be developed as a drug against drug-resistant tumors;
  • the compound (I) is effective against EGFR T790M mutation, EGFR C797S mutation and EGFR-independent third-generation inhibitor-resistant tumors.
  • control compounds, reagents and raw materials used in the experiments were purchased commercially or prepared by us.
  • test compound (I) preparation was prepared according to the following prescription as shown in Table A:
  • Blank preparation same formulation as Table A, except that it does not contain compound (I)
  • the latent solvent was evaporated and removed during the preparation process, and the obtained test substance and blank preparation did not contain the latent solvent.
  • the preparation containing compound (I) or the blank preparation was diluted with water to the desired concentration or volume.
  • TMZ Prepare the required dose with 0.5% sodium carboxymethylcellulose solution.
  • ASK120067 and AZD9291 Prepare the required dose with water for injection containing 1% Tween 80.
  • D283 and NCI-H1975 were purchased from ATCC (American Type Culture Collection).
  • PC-9-OR and 67R were constructed by the Shanghai Institute of Materia Medica, Chinese Academy of Sciences using conventional methods. For details, see the methods in the literature (Cancer Science 2022; 113: 709–720 and Molecular Cancer 2020; 19: 90) to obtain cells.
  • Example 1 Inhibitory effect of compound (I) on the growth of human medulloblastoma D283 transplanted tumors in nude mice 1.
  • mice Female, age: 4-6 weeks.
  • Human brain medulloblastoma D283 cell line (TMZ-resistant tumor cells, MGMT high expression) was inoculated subcutaneously in the right axilla of nude mice, with a cell inoculation amount of 5 ⁇ 10 6 /mouse. After the tumor grew to an average volume of about 120 mm 3 , the animals were randomly divided into 3 groups.
  • the compound (I) 10 mg/kg group was orally administered twice a day for 21 consecutive days, and the solvent control group was given an equal volume of blank preparation to the 10 mg/kg compound (I) administration group, orally administered twice a day for 21 consecutive days.
  • the control drug TMZ 3 mg/kg group was orally administered once a day for 21 consecutive days. During the entire experiment, the diameter of the transplanted tumor was measured 3 times a week, and the mouse body weight was weighed at the same time.
  • the relative tumor volume (RTV) was calculated based on the measurement results.
  • T/C (%) ( TRTV / CRTV ) x 100%, TRTV : RTV of the treatment group (compound (I) group or TMZ group); CRTV : RTV of the solvent control group.
  • the results are shown in Table 1.
  • the control drug TMZ 3 mg/kg group was orally administered once a day. After 21 consecutive days of administration, it had no inhibitory effect on the growth of human brain medulloblastoma D283 nude mouse subcutaneous transplanted tumors.
  • the T/C percentage obtained on the 21st day was 104.1%, proving that the human brain medulloblastoma D283 cell line is a TMZ-resistant cell line.
  • the test compound (I) was administered at a dose of 10 mg/kg, and was orally administered twice a day for three consecutive weeks. It can significantly inhibit the growth of human brain medulloblastoma D283 nude mouse subcutaneous transplanted tumors.
  • the T/C percentage obtained on the 21st day was 18.9%. In the experiment, all groups of mice were in good condition. The above results show that compound (I) can significantly inhibit the growth of human brain medulloblastoma D283 and show outstanding therapeutic effects on TMZ-resistant tumors.
  • Example 2 Inhibitory effect of compound (I) on the growth of human non-small cell lung cancer NCI-H1975 (EGFR T790M mutation) transplanted tumors in mice
  • Non-small cell lung cancer NCI-H1975 cell line (EGFR T790M mutation) was inoculated subcutaneously in the right axilla of NOD-SCID mice, with a cell inoculation amount of 5 ⁇ 10 6 /mouse. After the tumor grew to an average volume of about 135 mm 3 , the animals were randomly divided into groups. Compound (I) was divided into 10 mg/kg and 5 mg/kg groups, and was orally administered twice a day for 14 consecutive days. The solvent control group was given a blank preparation of the same volume as the 10 mg/kg compound (I) administration group, and was orally administered twice a day for 14 consecutive days.
  • V 0 is the tumor volume measured at the time of cage administration (i.e., d 0 )
  • V t is the tumor volume at each measurement.
  • T/C (%) ( TRTV / CRTV ) ⁇ 100%, TRTV : RTV of the treatment group (two groups of compound (I)); CRTV : RTV of the solvent control group.
  • the experimental results are shown in Table 2.
  • the test compound (I) 10 mg/kg and 5 mg/kg groups significantly delayed the growth of tumors, and the inhibitory effect increased with the increase in dose.
  • the T/C percentages obtained on the 14th day were 9.3% and 10.5%, respectively.
  • the growth of the tumors in the mice in the 10 mg/kg and 5 mg/kg groups of compound (I) was almost completely stagnant during the two-week experimental treatment.
  • the weight of the mice decreased slightly during the experiment, but the overall condition was good.
  • the above results show that compound (I) can significantly inhibit the growth of NCI-H1975 (EGFR T790M mutation) mouse transplanted tumors and has outstanding therapeutic effects on EGFR T790M mutation tumors.
  • Example 3 Inhibitory effect of compound (I) on the growth of human non-small cell lung cancer transplanted tumors in mice harboring EGFR C797S mutation
  • the human non-small cell lung cancer cell line PC-9-OR containing the EGFR C797S mutation (a cell line containing the EGFR C797S mutation constructed by the Shanghai Institute of Materia Medica, Chinese Academy of Sciences on the PC-9 cell line, the construction method is described in the literature Cancer Science 2022; 113: 709-720.) was inoculated subcutaneously in the right axilla of nude mice, with a cell inoculation amount of 5 ⁇ 10 6 /mouse, and the tumor was grown to an average volume. The animals were randomly divided into 4 groups after the diameter of the transplanted tumor was about 100 mm 3.
  • Compound (I) was divided into 10 mg/kg and 5 mg/kg groups, which were orally administered twice a day for 49 consecutive days.
  • the solvent control group was given a blank preparation of the same volume as the 10 mg/kg compound (I) administration group, which was orally administered twice a day for 49 consecutive days.
  • the control drug AZD9291 (third-generation EGFR inhibitor) 10 mg/kg group was orally administered once a day for 49 consecutive days.
  • the diameter of the transplanted tumor was measured 3 times a week, and the weight of the mice was weighed at the same time.
  • Example 4 Compound (I) enhances the anti-tumor efficacy of the third-generation EGFR inhibitor ASK120067
  • NOD-SCID mice female, age: 4-6 weeks.
  • the EGFR third-generation inhibitor ASK120067-resistant non-small cell lung cancer cell line 67R (a resistant cell line of the EGFR third-generation inhibitor ASK120067 constructed by the Shanghai Institute of Materia Medica, Chinese Academy of Sciences on the basis of NCI-H1975, whose EGFR itself has not mutated or deleted, is an EGFR-independent resistant cell, and the construction method is described in the literature Molecular Cancer 2020; 19:90) was injected subcutaneously into the right axilla of NOD-SCID mice.
  • the diameter of the subcutaneous transplanted tumor of BALB/c mice was measured with a vernier caliper, and the animals were randomly divided into groups after the tumor grew to an average volume of about 110 mm 3.
  • Compound (I) (5 mg/kg alone or in combination) was orally administered twice a day for 28 consecutive days; ASK120067 (5 mg/kg alone and in combination) was orally administered once a day for 28 consecutive days.
  • the solvent control group was given an equal volume of blank preparation without compound (I) as the 5 mg/kg compound (I) administration group, and the administration was orally administered twice a day for 28 consecutive days.
  • the diameter of the transplanted tumor was measured twice a week, and the mice were weighed at the same time.
  • T/C (%) ( TRTV / CRTV ) ⁇ 100%
  • TRTV RTV of treatment group (compound (I) alone group, ASK120067 alone group, compound (I) and ASK120067 combination group);
  • ASK120067 was combined with compound (I) at a dose of 5 mg/kg twice a day, tumor growth was significantly inhibited. The tumor volume did not increase substantially.
  • the T/C of the combination group was 8.5%.
  • the combination index was 1.69, indicating that the combination of compound (I) can enhance the tumor inhibition effect of ASK120067 in the 67R resistant tumor model.
  • the above results show that in the EGFR-independent EGFR inhibitor resistance model, the combination of compound (I) and EGFR inhibitor is effective, can significantly inhibit tumor growth, and reverse EGFR inhibitor resistance.
  • the compound (I) of the present invention can have significant in vivo inhibitory activity on the growth of human brain medulloblastoma D283 nude mouse transplanted tumor (TMZ-resistant tumor model).
  • the test compound (I) was administered at a dose of 10 mg/kg, orally twice a day, and for three consecutive weeks, it was able to significantly inhibit the growth of human brain medulloblastoma D283 nude mouse subcutaneous transplanted tumors, and the T/C obtained on the 21st day was 18.9%.
  • the above results show that compound (I) can significantly inhibit the growth of TMZ-resistant tumors and has a significant effect on TMZ-resistant tumors.
  • Compound (I) has significant in vivo inhibitory activity against PC-9-OR (containing EGFR C797S mutant cells) human non-small cell lung cancer mouse transplant tumor model.
  • the 10 mg/kg and 5 mg/kg groups of compound (I) can inhibit the growth of mouse PC-9-OR tumors in a dose-dependent manner, and the T/C percentages obtained on day 49 are 13.0% and 21.6%, respectively.
  • the above results show that compound (I) can significantly inhibit the growth of EGFR C797S mutant tumors.
  • Compound (I) enhances the anti-tumor efficacy of the third-generation EGFR inhibitor ASK120067.
  • compound (I) was combined with a dose of 5 mg/kg twice a day, and tumor growth was significantly inhibited, and the tumor volume basically did not increase.
  • the T/C of the combination group was 8.5%.
  • the combination drug index was 1.69, indicating that the combination of compound (I) can enhance the tumor inhibition effect of ASK120067 in the 67R resistant tumor model. This indicates that in EGFR-independent EGFR third-generation inhibitor-resistant tumors, the combination of compound (I) and EGFR third-generation inhibitors is effective and can significantly inhibit tumor growth and overcome EGFR third-generation inhibitor resistance.
  • the above experimental results show that the compound (I) has excellent inhibitory activity against drug-resistant tumors and can significantly inhibit the growth of drug-resistant tumors, especially temozolomide-resistant tumors and EGFR inhibitor-resistant tumors, and is expected to be developed as a drug against drug-resistant tumors.

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une utilisation d'un composé naphtylamide dans le traitement de tumeurs résistantes aux médicaments. Plus particulièrement, la présente invention concerne l'utilisation d'un composé (I) ou d'un sel pharmaceutiquement acceptable de celui-ci dans la préparation d'un médicament pour le traitement de tumeurs résistantes aux médicaments, en particulier de tumeurs résistantes au témozolomide et de tumeurs résistantes à l'inhibiteur d'EGFR. La présente invention concerne également un composé (I) ou un sel pharmaceutiquement acceptable de celui-ci, qui, lorsqu'il est utilisé en association avec un inhibiteur d'EGFR de troisième génération ASK120067, peut contrecarrer la résistance à l'inhibiteur d'EGFR.
PCT/CN2023/126296 2022-10-25 2023-10-24 Utilisation d'un composé naphtylamide dans le traitement de tumeurs résistantes aux médicaments Ceased WO2024088275A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202211327146 2022-10-25
CN202211327146.8 2022-10-25

Publications (1)

Publication Number Publication Date
WO2024088275A1 true WO2024088275A1 (fr) 2024-05-02

Family

ID=90767424

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/126296 Ceased WO2024088275A1 (fr) 2022-10-25 2023-10-24 Utilisation d'un composé naphtylamide dans le traitement de tumeurs résistantes aux médicaments

Country Status (2)

Country Link
CN (1) CN117919234A (fr)
WO (1) WO2024088275A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119095596A (zh) * 2023-03-03 2024-12-06 上海润石医药科技有限公司 一种萘酰胺类化合物治疗脑膜瘤的用途
CN118894823B (zh) * 2024-06-28 2025-09-19 重庆医科大学 作为vegfr抑制剂的萘酰胺类化合物及其应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100087499A1 (en) * 2007-01-30 2010-04-08 Schering Corporation Pharmaceutical compositions and methods of using temozolomide and multi-targeted kinase inhibitors
CN104860885A (zh) * 2014-02-24 2015-08-26 中国科学院上海药物研究所 萘酰胺类化合物、其制备方法和用途
US20180036304A1 (en) * 2015-03-06 2018-02-08 Beyondspring Pharmaceuticals, Inc. Method of treating cancer associated with a ras mutation
US20200246346A1 (en) * 2017-05-02 2020-08-06 Novartis Ag Combination therapy
CN115215847A (zh) * 2021-04-16 2022-10-21 中国科学院上海药物研究所 一类kras-sos1抑制剂、其制备方法及其应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100087499A1 (en) * 2007-01-30 2010-04-08 Schering Corporation Pharmaceutical compositions and methods of using temozolomide and multi-targeted kinase inhibitors
CN104860885A (zh) * 2014-02-24 2015-08-26 中国科学院上海药物研究所 萘酰胺类化合物、其制备方法和用途
US20180036304A1 (en) * 2015-03-06 2018-02-08 Beyondspring Pharmaceuticals, Inc. Method of treating cancer associated with a ras mutation
US20200246346A1 (en) * 2017-05-02 2020-08-06 Novartis Ag Combination therapy
CN115215847A (zh) * 2021-04-16 2022-10-21 中国科学院上海药物研究所 一类kras-sos1抑制剂、其制备方法及其应用

Also Published As

Publication number Publication date
CN117919234A (zh) 2024-04-26

Similar Documents

Publication Publication Date Title
CN109310684B (zh) 用于治疗癌症的notch和cdk4/6抑制剂的组合疗法
WO2024088273A1 (fr) Utilisation d'un composé naphtylamide dans le traitement de maladies associées à une mutation de kras
CN109310685B (zh) 用于治疗癌症的notch和pi3k/mtor抑制剂的组合疗法
US20230293526A1 (en) Method for treating cancer with a reverse transcriptase inhibitor
TW202521120A (zh) 藥物組合物及其應用
WO2024088275A1 (fr) Utilisation d'un composé naphtylamide dans le traitement de tumeurs résistantes aux médicaments
TW201839399A (zh) 癌症治療
CN110652514A (zh) 第三代egfr抑制剂的制药用途
JP7640033B2 (ja) ピリド［１，２－ａ］ピリミジノン類似体の使用
WO2011153495A1 (fr) Traitement anticancéreux avec des analogues de la wortmannine
CN118787649B (zh) 一种治疗非小细胞肺癌kras g12c突变的药物组合物及其应用
WO2021140478A1 (fr) Polythérapie pour le traitement du cancer
CN113840608A (zh) Cdk4/6抑制剂与vegfr抑制剂联合在制备治疗肿瘤的药物中的用途
WO2020192506A1 (fr) Chiauranib pour le traitement du cancer du poumon à petites cellules
TWI872311B (zh) 一種吡啶并[1,2-a]嘧啶酮類似物的應用
CN112203675A (zh) 用于改善虚弱和衰老的方法
CN115135326B (zh) 作为c-Met激酶抑制剂的化合物的联用药物组合物及其用途
TW202339754A (zh) 以他拉唑帕尼治療之作為預測性生物標記之基因雜合性缺失及其治療方法
CN115190800A (zh) 一种brd4抑制剂的用途
TWI843217B (zh) 一種藥物組合及其應用
WO2025199434A1 (fr) Méthodes de traitement du cancer du sein à l'aide d'un composé pyrazole
US20120309845A1 (en) Dosing regimens and methods for treating or preventing acute myeloid leukemia
WO2025049904A1 (fr) Inhibiteur d'egfr destiné à être utilisé dans le traitement du cancer du poumon positif pour une mutation de l'exon 20 de l'egfr
Zhu EP12. 01-68 Durable Response to High-Dose Aumolertinib 165mg After Local Progression in EGFR-Mutated Non-Small Cell Lung Cancer with Brain Metastases
CN121360215A (zh) 达托霉素在制备非小细胞肺癌egfr-tki耐药的逆转剂中的应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23881852

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 23881852

Country of ref document: EP

Kind code of ref document: A1