CN117919234A - Application of naphthalamide compound in treatment of drug-resistant tumor - Google Patents

Application of naphthalamide compound in treatment of drug-resistant tumor Download PDF

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CN117919234A
CN117919234A CN202311380825.6A CN202311380825A CN117919234A CN 117919234 A CN117919234 A CN 117919234A CN 202311380825 A CN202311380825 A CN 202311380825A CN 117919234 A CN117919234 A CN 117919234A
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egfr
resistant
tumor
compound
lung cancer
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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
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Shanghai Runshi Pharmaceutical Technology Co ltd
Shanghai Institute of Materia Medica of CAS
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Shanghai Runshi Pharmaceutical Technology Co ltd
Shanghai Institute of Materia Medica of CAS
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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
    • A61K31/41—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

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  • Organic Chemistry (AREA)
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Abstract

The invention relates to an application of a naphthalamide compound in treating drug-resistant tumors. In particular, the invention discloses the use of a compound (I) or a pharmaceutically acceptable salt thereof for preparing a medicament for treating drug-resistant tumors, in particular temozolomide-resistant tumors and EGFR inhibitor-resistant tumors. The invention also discloses a compound (I) or pharmaceutically acceptable salt thereof, which can be combined with an EGFR third-generation inhibitor ASK120067 to reverse EGFR inhibitor drug resistance.

Description

Application of naphthalamide compound in treatment of drug-resistant tumor
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of a naphthalamide compound in preparation of a medicine for treating drug-resistant tumors.
Background
Malignant tumor is a serious disease threatening human health, although tumor treatment has made a long-term progress in surgery, radiotherapy, chemotherapy, etc., the survival period of cancer is actually improved, however, drug resistance of tumor to drugs is still a serious problem in the field of tumor therapeutics.
Gliomas (also known as gliomas) are tumors occurring in the neuroectoderm, including astrocytomas, glioblastomas, medulloblastomas, ependymomas, and choroidal slave papillomas, and are classified as brain gliomas and spinal gliomas according to the site of disease. Glioblastomas are the most common malignant primary brain tumor, accounting for about 57% of all gliomas, and 48% of all primary malignant central nervous system tumors. Despite recent advances in the treatment of glioblastoma, including surgery, radiation, chemotherapy, and supportive care, the median survival in patients is only 10-12 months, the overall prognosis is still poor, long-term survival is low, and recurrence rates are near 100%.
Temozolomide (TMZ) is an imidazole tetrazine-derived alkylating agent, which rapidly hydrolyzes to 5- (3-methyltriazin-1-yl) imidazole-4-carboxamide (MTIC) at physiological pH, which in turn affects DNA replication by methylation at the O 6 and N 7 sites of deoxyribonucleic acid (DNA) guanine, thereby exerting a cytotoxic effect. TMZ was approved by the FDA in 2005 and 2009 for treatment of astrocytoma and glioblastoma patients, respectively, as the only oral chemotherapeutic for the current first line treatment of gliomas, due to its ability to be orally administered and to readily cross the blood brain barrier. However, at least 50% of the patients treated with TMZ were found to be refractory to TMZ, which is mainly caused by over-expression of O 6 -methylguanine methyltransferase (MGMT) and the lack of DNA repair pathways in GBM cells. MGMT can repair TMZ-induced methylation at guanine O 6, rendering tumor cells insensitive to TMZ. Whereas the expression of MGMT is mainly affected by the methylation level of its promoter region, the higher the methylation level, the lower the expression level of MGMT, and the more sensitive to TMZ. MGMT methylation positive rate was about 40% in glioma patients and lower in glioblastoma, where malignancy was highest. This means that at least half of glioma patients are resistant to TMZ without regard to the secondary resistance of TMZ treatment.
Currently, it is clinically recommended to use methylation-specific PCR (polymerase chain reaction) in combination with immunohistochemical methods to determine MGMT expression levels. According to the glioma diagnosis and treatment standard (2018 edition), for the non-methylation and methylation situation of the MGMT promoter region, only treatment means with very limited benefits such as synchronous radiotherapy and auxiliary TMZ chemotherapy can be selected. Furthermore, several drugs targeting MGMT are under clinical investigation, for example the development of inhibitors of MGMT (O 6 -BG, 6-BTG), however, these drugs have been slow to develop and systemic toxicity due to non-specific targeting normal cells is not negligible. In summary, glioma patients, particularly MGMT highly expressed patients, are in urgent need of effective therapeutic drugs or treatment regimens.
Lung cancer is currently the leading cause of cancer death worldwide, with Non-SMALL CELL lung cancer (NSCLC) being the major histological type of the disease, accounting for over 80% of lung cancer patients, with 5-year survival rates below 15%. High expression or aberrant activation of the epidermal growth factor receptor (EPIDERMAL GROWTH FACTOR RECEPTOR, EGFR) is an important target for promoting the progression of NSCLC progression. In recent years, with intensive research on lung cancer pathogenesis, molecular targeted therapies typified by EGFR inhibitors have been advanced in breakthrough. To date, three generations of EGFR inhibitors have been marketed in batches, which brings great clinical benefit to EGFR mutant NSCLC patients, but EGFR inhibitors have acquired drug resistance within about one year of administration, which greatly limits the clinical application of the drugs. The development of strategies capable of inhibiting EGFR inhibitor resistance has therefore become a hotspot in current NSCLC research.
The reported mechanisms of EGFR inhibitor resistance fall into two main categories: the first type is EGFR-dependent drug resistance mechanism, mainly EGFR itself changes, for example EGFR T790M mutation which occupies main reasons in EGFR generation inhibitor drug resistance (accounting for about 60% of all drug resistant patients), or EGFR C797S/G、EGFRL798I、EGFRL792H and other various point mutations and EGFR T790M loss mediate EGFR generation inhibitor drug resistance, wherein tumors with EGFR C797S mutation have no therapeutic drug. The second category is EGFR independent drug resistance mechanisms including MET and HER2 amplification, FGFR1 amplification, PIK3CA mutation, minicell transformation, RAS-MAPK pathway activation and KRAS mutation and amplification, and the like. At present, four-generation EGFR inhibitors targeting EGFR C797S are in an early clinical research stage, and no medicine is marketed yet; in addition, aiming at the independent drug-resistant route of EGFR, the drug-resistant mechanism is complex due to the high heterogeneity of tumors, and the research on the drug-resistant mechanism is lacking, so that the research on overcoming the drug-resistant mechanism is slow in progress and can not meet the clinical requirements. In summary, overcoming the problem of EGFR inhibitor resistance remains a serious challenge, and there is a need to seek new therapeutic strategies.
The compound (I) is disclosed in CN104860885A for the first time, the structural formula is shown as the following formula (I),
The compound (I) is a VEGFR/CSF1R double-target inhibitor with excellent activity, and can inhibit the proliferation of tumor cells and promote tumor immunity to play an anti-tumor role.
Disclosure of Invention
The invention aims at providing an application of a naphthalamide compound in treating drug-resistant tumors.
In a first aspect of the invention there is provided the use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a drug resistant tumour;
the compound (I) has the following structure:
In another preferred embodiment, the resistant tumor is selected from the group consisting of: glioma, lung cancer.
In another preferred embodiment, the resistant tumor is selected from the group consisting of: temozolomide resistant tumors and EGFR inhibitor resistant tumors.
In another preferred embodiment, the drug resistant tumor is a tumor with high expression of O 6 -methylguanine methyltransferase.
In another preferred embodiment, the drug resistant tumor is a glioma with high expression of O 6 -methylguanine methyltransferase.
In another preferred embodiment, the temozolomide resistant tumor is a temozolomide resistant glioma.
In another preferred embodiment, the temozolomide resistant tumor is a glioma with high expression of O 6 -methylguanine methyltransferase.
In another preferred embodiment, the glioma is selected from the group consisting of: glioblastoma, astrocytoma, medulloblastoma.
In another preferred embodiment, the temozolomide resistant tumor is a temozolomide resistant medulloblastoma.
In another preferred embodiment, the EGFR inhibitor resistant tumor is EGFR inhibitor resistant lung cancer.
In another preferred embodiment, the lung cancer is selected from the group consisting of: small cell lung cancer, non-small cell lung cancer, and lung adenocarcinoma.
In another preferred embodiment, the EGFR inhibitor resistant tumor is EGFR inhibitor resistant non-small cell lung cancer.
In another preferred embodiment, the EGFR inhibitor resistant tumor is an EGFR mutant tumor.
In another preferred embodiment, the EGFR mutation is selected from the group consisting of: EGFR T790M mutations and EGFR C797S mutations.
In another preferred embodiment, the EGFR inhibitor resistant lung cancer is EGFR T790M mutated lung cancer or EGFR C797S mutated lung cancer.
In another preferred embodiment, the EGFR inhibitor resistant lung cancer is EGFR T790M mutated non-small cell lung cancer or EGFR C797S mutated non-small cell lung cancer.
In another preferred embodiment, the EGFR inhibitor resistant tumor is an EGFR independent EGFR inhibitor resistant tumor.
In another preferred embodiment, the EGFR-independent EGFR inhibitor resistant tumor is a tumor caused by a mechanism selected from the group consisting of: MET and HER2 amplification, FGFR1 amplification, PIK3CA mutation, minicell transformation, RAS-MAPK pathway activation, KRAS mutation and amplification.
In another preferred embodiment, the EGFR-independent EGFR inhibitor resistant tumor is EGFR-independent EGFR inhibitor resistant lung cancer.
In another preferred embodiment, the EGFR-independent EGFR inhibitor resistant lung cancer is EGFR-independent EGFR inhibitor resistant non-small cell lung cancer.
In another preferred embodiment, the EGFR inhibitor is selected from the group consisting of: ASK120067 (Limertinib), octreotide (AZD 9291) or a salt thereof, ametinib or a salt thereof, vomittinib or a salt thereof,
In another preferred embodiment, the EGFR inhibitor is ASK120067 (Limertinib), octenib (AZD 9291), and salts thereof.
In a second aspect of the present invention, there is provided a pharmaceutical composition for the treatment of drug resistant tumors, 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:
In another preferred embodiment, the resistant tumor is as described above.
In another preferred embodiment, the pharmaceutical composition is an oral formulation.
In a third aspect of the invention, there is provided a pharmaceutical combination comprising a therapeutically effective amount of a first pharmaceutically active ingredient and a second pharmaceutically active ingredient;
The first pharmaceutical active ingredient is compound (I) or a pharmaceutically acceptable salt thereof;
the compound (I) has the following structure:
the second pharmaceutical active ingredient is an anti-tumor drug selected from the group consisting of: temozolomide and EGFR inhibitors.
In another preferred embodiment, the tumor is selected from the group consisting of: temozolomide resistant tumors and EGFR inhibitor resistant tumors.
In another preferred embodiment, the temozolomide resistant tumor is as described above.
In another preferred embodiment, the EGFR inhibitor resistant tumor is as described above.
In another preferred embodiment, the EGFR inhibitor is selected from the group consisting of: ASK120067 (Limertinib), octreotide (AZD 9291) or a salt thereof, ametinib or a salt thereof, and vomittinib or a salt thereof.
In another preferred embodiment, the EGFR inhibitor is ASK120067 (Limertinib).
In another preferred embodiment, the mass ratio of the first pharmaceutically active ingredient to the second pharmaceutically active ingredient is 1-4, preferably 1-3, preferably 2.
In a fourth aspect of the present invention, there is provided the use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for enhancing the efficacy of an anti-tumour agent;
the compound (I) has the following structure:
The antitumor drug is selected from the group consisting of: temozolomide and EGFR inhibitors.
In another preferred embodiment, the tumor is selected from the group consisting of: temozolomide resistant tumors and EGFR inhibitor resistant tumors.
In another preferred embodiment, the temozolomide resistant tumor is as described above.
In another preferred embodiment, the EGFR inhibitor resistant tumor is as described above.
In another preferred embodiment, the EGFR inhibitor is as described above.
In a fifth aspect of the invention there is provided a pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutical combination according to the third aspect of the invention and a pharmaceutically acceptable carrier.
In another preferred embodiment, the pharmaceutical composition is an oral formulation.
In another preferred embodiment, the pharmaceutical composition is for the treatment of drug resistant tumors.
In another preferred embodiment, the resistant tumor is as described above.
In a sixth aspect of the invention there is provided the use of a pharmaceutical combination according to the third aspect of the invention for the manufacture of a medicament for the treatment of a resistant tumour.
In another preferred embodiment, the resistant tumor is as described above.
In another preferred embodiment, the patient with the drug resistant tumor is a human.
In a seventh aspect of the invention, there is provided a method of treating a drug resistant tumor comprising the steps of:
1) Administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof to a patient suffering from a drug resistant tumor or a patient not susceptible to an anti-tumor drug;
the compound (I) has the following structure:
In another preferred embodiment, the resistant tumor is as described above.
In another preferred embodiment, the antineoplastic agent is selected from the group consisting of: temozolomide and EGFR inhibitors.
In another preferred embodiment, the EGFR inhibitor is as described above.
In another preferred embodiment, the method further comprises the following steps before step 1):
determining the patient's MGMT gene expression profile and/or EGFR gene mutation profile using a gene detection method.
In another preferred embodiment, the patient is a patient with over-expression of the MGMT gene.
In another preferred embodiment, the patient is a patient with EGFR gene mutation.
In another preferred embodiment, the patient is a patient with EGFR T790M mutation or a patient with EGFR C797S mutation.
In an eighth aspect of the invention, there is provided a method of treating a drug resistant tumor comprising the steps of:
1) A therapeutically effective amount of a combination of the agents of the third aspect of the invention is administered to a patient suffering from a resistant tumor or a patient not susceptible to an anti-tumor agent.
In another preferred embodiment, the resistant tumor is as described above.
In another preferred embodiment, the antineoplastic agent is selected from the group consisting of: temozolomide and EGFR inhibitors.
In another preferred embodiment, the EGFR inhibitor is as described above.
In another preferred embodiment, the method further comprises the following steps before step 1):
determining the patient's MGMT gene expression profile and/or EGFR gene mutation profile using a gene detection method.
In another preferred embodiment, the patient is a patient with over-expression of the MGMT gene.
In another preferred embodiment, the patient is a patient with EGFR gene mutation.
In another preferred embodiment, the patient is a patient with EGFR T790M mutation or a patient with EGFR C797S mutation.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Through long-term and intensive researches, the inventor surprisingly discovers that the compound (I) has excellent inhibitory activity on drug-resistant tumors, can obviously inhibit the growth of drug-resistant tumors, especially temozolomide drug-resistant tumors and EGFR inhibitor drug-resistant tumors, and is hopeful to be developed into drugs of drug-resistant tumors. On this basis, the inventors completed the present invention.
As used herein, the term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention with acids or bases that are suitable for use as medicaments. Pharmaceutically acceptable salts include inorganic and organic salts.
"Pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds.
The mode of administration of the pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to: oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and topical administration.
Correspondingly, the medicine of the 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, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
Dosage forms of the compounds of the present invention for topical administration 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 which may be required if necessary.
The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., antineoplastic agents).
The methods of treatment of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
The therapeutically effective amount as used herein refers to the amount of the active compound that is pharmaceutically effective, i.e., an amount sufficient to significantly improve the condition without causing serious side effects. For a person weighing 60kg, the daily dosage is usually 0.01 to 2000mg, preferably 1 to 500mg. The preparation can be administered once a day in a single dose, can be administered in multiple times per day, or can be used at intervals. The particular dosage and frequency of administration should take into account factors such as the route of administration, the health of the patient, etc., which can be determined by a skilled practitioner according to routine skill.
The invention also provides methods of using the pharmaceutical compositions, i.e., administering a therapeutically effective amount of a compound (I) of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention, to a mammal (e.g., a human) in need of treatment. In some embodiments, the method of using the pharmaceutical composition further comprises the step of genetic testing to determine MGMT methylation status and/or EGFR gene mutation in a mammal (e.g., a human) in need of treatment, prior to administering a therapeutically effective amount of compound (I) of the present invention, or a pharmaceutically acceptable salt thereof, to the mammal (e.g., human) in need of treatment. The methylation status of MGMT in a mammal (e.g., human) can be detected using MGMT gene methylation detection reagents (e.g., manufacturer-specific gene technology, national standard 20193400101). The most common methods currently used for detecting EGFR gene mutations include direct sequencing and amplification block mutation systems (ARMS-PCR). DNA direct sequencing is the most direct and basic method for detecting gene mutation at present, and known and unknown gene mutation in tumor tissue samples can be detected by reading DNA base sequences. The ARMS-PCR method utilizes a designed specific primer to carry out PCR accurate amplification on the mutation sequence, and simultaneously adopts real-time fluorescent PCR quantitative analysis, so that EGFR gene mutation in a biopsy small sample and a blood sample can be detected with high sensitivity. EGFR gene mutations in mammals (e.g., humans) can be detected using EGFR gene mutation detection kits (e.g., human EGFR gene mutation detection kit, manufactured by Ed organism, national mechanical standard 20143402001).
Compared with the prior art, the invention has the following main advantages:
(1) The compound (I) has excellent inhibitory activity on drug-resistant tumors, can obviously inhibit the growth of drug-resistant tumors, especially temozolomide drug-resistant tumors and EGFR inhibitor drug-resistant tumors, and is hopeful to be developed into drugs for drug-resistant tumors;
(2) In EGFR independent EGFR third-generation inhibitor resistant tumors, the compound (I) and EGFR third-generation inhibitor are combined effectively, so that the growth of the tumors can be obviously inhibited, and the EGFR third-generation inhibitor resistance is overcome;
(3) The preparation method of the compound (I) is simple;
(4) The compound (I) is effective on EGFR T790M mutation and EGFR C797S mutation and EGFR independent third-generation inhibitor resistant tumors.
Detailed Description
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
Experimental material sources or formulations:
compound (I): prepared with reference to CN104860885A example 21.
The control compounds, reagents used in the experiments, and raw materials were all purchased commercially or were self-formulated.
In vivo test compound (I) formulations are prepared as follows:
Table A
Raw and auxiliary materials Dosage of
Compound (I) 60mg
Medium chain triglycerides 1ml
Polyoxyethylene 40 hydrogenated castor oil 1.5ml
Diethylene glycol monoethyl ether 2.5ml
Oleic acid 1ml
Ethanol: ethyl acetate (1:1) as a latent solvent 15～20ml
Blank formulation: the formulation is as in Table A, except that it does not contain compound (I)
The latent solvent is removed by evaporation in the preparation process, and the obtained test object and blank preparation do not contain the latent solvent.
The preparation or blank preparation containing compound (I) is diluted with water to a desired concentration or desired volume immediately before use.
TMZ: the solution is prepared to the required dosage by using 0.5% sodium carboxymethyl cellulose solution.
ASK120067 and AZD9291: the water for injection containing 1% Tween 80 was used after being formulated into the desired dosage.
Cell strain source and obtaining: d283 and NCI-H1975 were purchased from ATCC (American type culture Collection). PC-9-OR and 67R were constructed by methods conventional in Shanghai pharmaceutical research institute of China academy of sciences, see in particular literature (CANCER SCIENCE 2022;113:709-720 and Molecular Cancer 2020; 19:90) to obtain cells.
Example 1: compound (I) has effect of inhibiting the growth of human brain medulloblastoma D283 nude mice transplantation tumor
1. Experimental method
BALB/c nude mice, females, age: 4-6 weeks of age. Human brain medulloblastoma D283 cell line (TMZ resistant tumor cells, MGMT high expression) was inoculated under the right armpit of nude mice, the cell inoculum size was 5X 10 6/mouse, and animals were randomly divided into 3 groups after tumor growth to an average volume of about 120mm 3. The compound (I) 10mg/kg group was orally administered twice daily for 21 days continuously, and the solvent control group was administered with the same volume of the blank formulation as the compound (I) 10mg/kg group was orally administered twice daily for 21 days continuously. The control drug TMZ 3mg/kg group was orally administered once daily for 21 consecutive days. Throughout the experiment, the diameter of the transplanted tumor was measured 3 times per week while weighing the mice. The calculation formula of Tumor Volume (TV) is: tv=1/2×a×b 2, where a and b represent length and width, respectively. The relative tumor volume (relative tumor volume, RTV) is calculated from the measured results, the calculation formula being: rtv=v t/V0. Where V 0 is the tumor volume measured at the time of divided administration (i.e., d 0), and V t is the tumor volume at each measurement. The evaluation indexes of the antitumor activity are as follows: relative tumor proliferation rate T/C (%), the calculation formula is as follows: T/C (%) = (T RTV/CRTV)×100％,TRTV: RTV in treatment group (compound (I) group or TMZ group) and C RTV: RTV in solvent control group.
2. Experimental results
The results are shown in Table 1. The control drug TMZ 3mg/kg group is orally administered once a day, and has no inhibition effect on the growth of subcutaneous transplantation tumor of the human brain medulloblastoma D283 nude mice after 21 days of continuous administration, and the T/C percentage obtained on the 21 st day is 104.1%, so that the human brain medulloblastoma D283 cell strain is proved to be a TMZ drug resistant cell strain. The test compound (I) is orally administered at a dosage of 10mg/kg twice a day for three consecutive weeks to significantly inhibit the growth of subcutaneous transplantation tumor of human brain medulloblastoma D283 nude mice, and the T/C percentage obtained on day 21 is 18.9%. In the experiment, each group of mice was in good condition. The results show that the compound (I) can obviously inhibit the growth of human brain medulloblastoma D283, and has outstanding curative effect on TMZ drug-resistant tumors.
TABLE 1 therapeutic Effect of Compound (I) on human brain medulloblastoma D283 nude mice transplantation tumor
Note that: experimental data were analyzed using t-test, p <0.05, p <0.01, p <0.001.
Example 2: compound (I) has inhibitory effect on human non-small cell lung cancer NCI-H1975 (EGFR T790M mutation) mouse transplantation tumor growth
1. Experimental method
NOD-SCID mice, females, age: 4-6 weeks of age. The NOD-SCID mice were inoculated subcutaneously in the right armpit with the non-small cell lung carcinoma NCI-H1975 cell line (EGFR T790M mutation) at a cell inoculum size of 5X 10 6/unit, and animals were randomly grouped after tumor growth to an average volume of about 135mm 3. The compound (I) was divided into 10mg/kg and 5mg/kg groups, and orally administered twice daily for 14 days, and the solvent control group was administered with a blank formulation of the same volume as the 10mg/kg compound (I) administration group, orally administered twice daily for 14 days. Throughout the experiment, the diameter of the transplanted tumor was measured 3 times per week while weighing the mice. The calculation formula of Tumor Volume (TV) is: tv=1/2×a×b 2, where a and b represent length and width, respectively. The relative tumor volume (relative tumor volume, RTV) is calculated from the measured results, the calculation formula being: rtv=v t/V0. Where V 0 is the tumor volume measured at the time of divided administration (i.e., d 0), and V t is the tumor volume at each measurement. The evaluation indexes of the antitumor activity are as follows: relative tumor proliferation rate T/C (%), the calculation formula is as follows: T/C (%) = (T RTV/CRTV)×100％,TRTV: RTV in the treatment group (compound (I) two groups) and C RTV: RTV in the solvent control group.
2. Experimental results
The experimental results are shown in table 2. The test compounds (I) in the groups of 10mg/kg and 5mg/kg significantly retarded the growth of the tumor, and the inhibition effect increased with increasing dose, and the T/C percentages obtained on day 14 were 9.3% and 10.5%, respectively. Tumors carried by mice of groups 10mg/kg and 5mg/kg of compound (I) were almost completely arrested during the two cycles of experimental treatment. Mice slightly lost weight during the experiment but had good overall performance. The results show that the compound (I) can obviously inhibit the growth of the NCI-H1975 (EGFR T790M mutation) mouse transplanted tumor, and has obvious curative effect on EGFR T790M mutant tumor.
TABLE 2 therapeutic Effect of Compound (I) on non-Small cell lung cancer NCI-H1975 mice transplantations
Remarks: experimental data were analyzed using t-test, p <0.05, p <0.01, p <0.001.
Example 3: compound (I) has effect of inhibiting growth of transplanted tumor of human non-small cell lung cancer mice containing EGFR C797S mutation
1. Experimental method
BALB/c nude mice, females, age: 4-6 weeks of age. Human non-small cell lung cancer cell line PC-9-OR containing EGFR C797S mutation (cell line containing EGFR C797S mutation constructed on PC-9 cell line of Shanghai pharmaceutical institute of China institute of science, construction method see document CANCER SCIENCE 2022; 113:709-720.) was inoculated under the right armpit skin of nude mice, cell inoculum size was 5×10 6/animal was randomly divided into 4 groups after tumor growth was carried out to an average volume of about 100mm 3. The compound (I) was divided into 10mg/kg and 5mg/kg groups, and orally administered twice daily for 49 days continuously, and the solvent control group was administered with a blank formulation of the same volume as the 10mg/kg compound (I) administration group, orally administered twice daily for 49 days continuously. The control drug AZD9291 (third generation EGFR inhibitor) was orally administered once daily for 49 days in a 10mg/kg group. Throughout the experiment, the diameter of the transplanted tumor was measured 3 times per week while weighing the mice. The calculation formula of Tumor Volume (TV) is: tv=1/2×a×b 2, where a and b represent length and width, respectively. The relative tumor volume (relative tumor volume, RTV) is calculated from the measured results, the calculation formula being: rtv=v t/V0. Where V 0 is the tumor volume measured at the time of divided administration (i.e., d 0), and V t is the tumor volume at each measurement. The evaluation indexes of the antitumor activity are as follows: relative tumor proliferation rate T/C (%), the calculation formula is as follows: T/C (%) = (T RTV/CRTV)×100％,TRTV: RTV in the treatment group (compound (I) group or AZD9291 group) and C RTV: RTV in the solvent control group.
2. Experimental results
The experimental results are shown in table 3. AZD9291 hardly inhibits the growth of PC-9-OR tumors, and T/C is more than 90%. Compound (I) significantly retarded tumor growth at doses of 10mg/kg and 5mg/kg, respectively, and the inhibition effect increased with increasing dose, resulting in T/C percentages of 13.0% and 21.6% on day 49, respectively. Mice were in good condition during the experiment. The results show that the compound (I) can obviously inhibit the growth of mouse transplanted tumor of human non-small cell lung cancer PC-9-OR (containing EGFR C797S mutation), and has obvious curative effect on EGFR C797S mutant tumor.
TABLE 3 Experimental therapeutic Effect of Compound (I) on human non-small cell lung cancer cell line PC-9-OR mouse transplantation tumor containing EGFR C797S mutation
Remarks: experimental data were analyzed using t-test, p <0.05, p <0.01, p <0.001.
Example 4: compound (I) sensitization EGFR third-generation inhibitor ASK120067 anti-tumor drug effect
1. Experimental method
NOD-SCID mice, females, age: 4-6 weeks of age. Under aseptic conditions, EGFR three-generation inhibitor ASK120067 drug-resistant non-small cell lung Cancer cell strain 67R (drug-resistant cell strain of EGFR three-generation inhibitor ASK120067 constructed on the basis of NCI-H1975 by Shanghai pharmaceutical institute of China academy of sciences, which is EGFR independent drug-resistant cell, is constructed by a method of literature Molecular Cancer 2020; 19:90) is injected under the right armpit of NOD-SCID mice. BALB/c mice were subcutaneously transplanted with vernier calipers to measure the diameter of the transplanted tumor, and animals were randomly grouped after the tumor had grown to an average volume of about 110mm 3. Compound (I) (5 mg/kg alone or in combination) was orally administered twice daily for 28 consecutive days; ASK120067 (5 mg/kg for single and combination) was orally administered once daily for 28 consecutive days. The solvent control group was given a blank formulation of the same volume as that of the 5mg/kg compound (I) administration group, orally administered twice daily for 28 consecutive days. Throughout the experiment, the diameter of the transplanted tumor was measured 2 times per week while weighing the mice. The calculation formula of the tumor volume is: tv=1/2×a×b 2, where a and b represent length and width, respectively. The relative tumor volume (relative tumor volume, RTV) is calculated from the measured results, the calculation formula being: rtv=v t/V0. Where V 0 is the tumor volume measured at the time of divided administration (i.e., d 0), and V t is the tumor volume at each measurement. The evaluation indexes of the antitumor activity are as follows: relative tumor proliferation rate T/C (%), the calculation formula is as follows: T/C (%) = (T RTV/CRTV)×100％,TRTV: RTV in the treatment group (compound (I) alone, ASK120067 alone, compound (I) and ASK120067 in combination), C RTV: RTV in the solvent control group, combination index (Combination Ratio =expected-FTV/Observed-FTV), expected-ftv= (FTV of drug a) × (FTV of drug B), FTV (fractional tumor volume, tumor volume fraction) =final tumor volume in the experimental group/final tumor volume in the control group, observed-ftv=final tumor volume in the combination/final tumor volume in the control group when the combination index is greater than 1, the two drugs were considered to have a synergistic effect, and less than 1, there was no synergistic effect.
2. Experimental results
Compound (I) has partial inhibitory activity (T/c=43.8%) against the in vivo growth of 67R tumors at a single dose of 5 mg/kg; ASK120067 (5 mg/kg) alone also had some inhibitory effect on tumor growth (T/c=32.3%) but the tumor continued to grow slowly. The combination of compound (I) was administered at a dose of 5mg/kg twice daily on the basis of ASK120067, tumor growth was significantly inhibited, and tumor volume was not substantially increased. The combined T/C at the end of the experiment was 8.5%. The combination index is 1.69, which shows that the combination compound (I) can enhance the tumor inhibiting effect of ASK120067 in a 67R drug-resistant tumor model. The results show that in an EGFR inhibitor drug resistance model independent of EGFR, the compound (I) and the EGFR inhibitor are combined effectively, so that the growth of tumors can be obviously inhibited, and the EGFR inhibitor drug resistance is reversed.
TABLE 4 Experimental therapeutic effects of Compound (I) in combination with ASK120067 on ASK120067 resistant non-small cell lung cancer 67R mice transplantation tumor
Remarks: experimental data were analyzed using t-test, p <0.05, p <0.01, p <0.001.
TABLE 5 Combined index calculation
In vivo studies showed that:
(1) The compound (I) can have remarkable in-vivo inhibition activity on the growth of human brain medulloblastoma D283 nude mice transplantation tumor (TMZ drug-resistant tumor model). The test compound (I) is orally administered at a dose of 10mg/kg twice daily for three consecutive weeks to significantly inhibit the growth of subcutaneous transplantation tumor of human brain medulloblastoma D283 nude mice, and the T/C obtained on day 21 is 18.9%. The results show that the compound (I) can obviously inhibit the growth of TMZ drug-resistant tumors and has obvious effect on the TMZ drug-resistant tumors.
(2) The compound (I) has remarkable in-vivo inhibition activity on the growth of human non-small cell lung cancer NCI-H1975 mouse transplantation tumor (EGFR T790M mutation). NCI-H1975 tumors carried by mice of groups 10mg/kg and 5mg/kg of compound (I) were almost completely arrested during the two cycles of experimental treatment. Mice slightly lost weight during the experiment but had good overall performance. The above results demonstrate that compound (I) is capable of significantly inhibiting EGFR T790M mutant tumor growth.
(3) The compound (I) has remarkable in-vivo inhibition activity on a PC-9-OR (EGFR C797S mutant cell-containing) human non-small cell lung cancer mouse transplantation tumor model. The 10mg/kg and 5mg/kg groups of compound (I) were able to dose-dependently inhibit PC-9-OR tumor growth in mice, with T/C percentages obtained at day 49 of 13.0% and 21.6%, respectively. The results show that the compound (I) can obviously inhibit EGFR C797S mutant tumor growth.
(4) The compound (I) sensitizes EGFR third-generation inhibitor ASK120067 to have anti-tumor drug effect. Compound (I) has partial inhibitory activity (T/c=43.8%) against the in vivo growth of 67R tumors (ASK 120067 resistance model) at a single dose of 5mg/kg; ASK120067 (5 mg/kg) alone also had some inhibitory effect on tumor growth (T/c=32.3%) but the tumor continued to grow slowly. The combination of compound (I) was administered at a dose of 5mg/kg twice daily on the basis of ASK120067, tumor growth was significantly inhibited, and tumor volume was not substantially increased. The combined T/C at the end of the experiment was 8.5%. The combination index is 1.69, which shows that the combination compound (I) can enhance the tumor inhibiting effect of ASK120067 in a 67R drug-resistant tumor model. The compound (I) and the EGFR third-generation inhibitor are combined to effectively inhibit the growth of tumors and overcome EGFR third-generation inhibitor resistance in EGFR independent EGFR third-generation inhibitor resistant tumors.
The experimental result shows that the compound (I) has excellent inhibitory activity on drug-resistant tumors, can obviously inhibit the growth of drug-resistant tumors, especially temozolomide drug-resistant tumors and EGFR inhibitor drug-resistant tumors, and is hopeful to be developed into drugs for drug-resistant tumors.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (10)

1. The use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a drug resistant tumour;
the compound (I) has the following structure:
2. the use of claim 1, wherein the resistant tumor is selected from the group consisting of: glioma, lung cancer;
preferably, the glioma is selected from the group consisting of: astrocytoma, glioblastoma, medulloblastoma;
preferably: the lung cancer is selected from the group consisting of: small cell lung cancer, non-small cell lung cancer, and lung adenocarcinoma.
3. The use of claim 2, wherein the resistant tumor is selected from the group consisting of: temozolomide resistant tumors or EGFR inhibitor resistant tumors, preferably the EGFR inhibitor is selected from the group consisting of: ASK120067 or a salt thereof, octreotide or a salt thereof, amotinib or a salt thereof, and vomittinib or a salt thereof.
4. The use according to claim 3, wherein the temozolomide resistant tumor is a temozolomide resistant glioma or a glioma with high expression of O 6 -methylguanine methyltransferase;
Preferably, the temozolomide resistant tumor is a temozolomide resistant medulloblastoma.
5. The use of claim 3, wherein the EGFR inhibitor resistant tumor is an EGFR inhibitor resistant lung cancer, or the EGFR inhibitor resistant tumor is an EGFR independent EGFR inhibitor resistant tumor;
Preferably, the EGFR inhibitor resistant lung cancer is EGFR inhibitor resistant non-small cell lung cancer.
6. The use of claim 5, wherein the EGFR inhibitor resistant lung cancer is EGFR T790M mutated lung cancer or EGFR C797S mutated lung cancer;
Preferably, the EGFR inhibitor resistant lung cancer is EGFR T790M mutated non-small cell lung cancer or EGFR C797S mutated non-small cell lung cancer.
7. A pharmaceutical combination comprising a therapeutically effective amount of a first pharmaceutically active ingredient and a second pharmaceutically active ingredient;
The first pharmaceutical active ingredient is compound (I) or a pharmaceutically acceptable salt thereof;
the compound (I) has the following structure:
the second pharmaceutical active ingredient is an anti-tumor drug selected from the group consisting of: temozolomide and EGFR inhibitors.
8. The use of a compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for enhancing the efficacy of an anti-tumour agent;
the compound (I) has the following structure:
The antitumor drug is selected from the group consisting of: temozolomide and EGFR inhibitors.
9. A pharmaceutical composition comprising a therapeutically effective amount of the pharmaceutical combination of claim 7 and a pharmaceutically acceptable carrier.
10. Use of a combination according to claim 7 for the preparation of a medicament for the treatment of a resistant tumour.
CN202311380825.6A 2022-10-25 2023-10-24 Application of naphthalamide compound in treatment of drug-resistant tumor Pending CN117919234A (en)

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