Use of naphthalenamide compounds in the treatment of meningiomas

Abstract

The present invention provides a use of naphthalene amide compound (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating meningioma, and a corresponding treatment method, wherein the structure of compound (I) is shown below: Compound (I) has excellent inhibitory effect on meningioma, can effectively treat meningioma, and has good safety and tolerability. [Formula 1] JPEG2026507706000014.jpg39169

Description

Detailed Description of the Invention

[0001] [Technical field] The present application belongs to the pharmaceutical field, and specifically relates to the application of naphthalene amide compounds or pharmaceutically acceptable salts thereof in the manufacture of drugs for the treatment of meningiomas.

[0002] [Background technology] Meningiomas are the most common intracranial primary tumors, accounting for approximately two-fifths of all cases. Meningiomas are divided into intracranial and ectopic meningiomas based on their location of origin. Intracranial meningiomas are composed of arachnoid cells within the skull, while ectopic meningiomas arise in tissues not covered by the meninges, primarily from arachnoid tissue remaining during the fetal stage. The annual incidence of meningiomas is approximately 7.6 per 100,000. Patients are relatively young at the time of initial diagnosis, with 77.7% of patients aged 20-44 years.

[0003] Based on the growth site, meningiomas may be divided into convex meningiomas, parafalx meningiomas, olfactory sulcus meningiomas, tubercle sellae meningiomas, sphenoid crest meningiomas, parasagittal sinus meningiomas, middle skull base meningiomas, petroclival meningiomas, foramen magnum meningiomas, etc. Based on the clinicopathological characteristics of meningiomas, the World Health Organization (WHO) divides meningiomas into three grades: benign meningiomas (WHO grade I), atypical meningiomas (WHO grade II), and malignant meningiomas (WHO grade III). Benign meningiomas (WHO grade I) account for approximately 65% ​​to 80% of all meningiomas and are divided into nine subtypes: 1. Meningothelial, 2. Fibroblastic, 3. Transitional, 4. Psammomatous, 5. Angiomatous, 6. Microcystic, 7. Secretory, 8. Lymphoplasmacyte-rich, and 9. Metaplastic. Most meningiomas grow slowly and are unlikely to recur after surgery. Atypical meningiomas (WHO grade II) account for approximately 20% to 35% of cases and are divided into three subtypes: 1. Atypical, 2. Clear cell, and 3. Chordoid. Malignant meningiomas (WHO grade III) account for approximately 3% of cases and are divided into three subtypes: 1. Rhabdoid, 2. Papillary, and 3. Anaplastic. WHO grades II to III are high-grade meningiomas, characterized by high invasiveness, poor differentiation, and a tendency to recur and metastasize.

[0004] Meningiomas can be accompanied by neurofibromatosis and can present with complications such as visual acuity, visual field, olfactory, or hearing impairment, as well as limb movement disorders. Vision loss correlates with the primary tumor site, and symptoms occurring in the optic nerve canal are often early and severe. Optic disc edema develops early, progressing over a long period to secondary optic nerve atrophy tubular meningiomas. Visual field narrowing occurs early, and if the tumor occurs in the orbital apex, a scotoma may appear in the visual field.

[0005] The overall 10-year survival rate for meningiomas is 57.1%. Patients with WHO grade II meningiomas have a 5-year recurrence rate of approximately 50%, with a 10-year survival rate of 53% after recurrence. Patients with WHO grade III meningiomas have a 5-year recurrence rate of approximately 90%, with a 10-year survival rate of 0% after recurrence.

[0006] Meningiomas are usually diagnosed with brain MRI, and patients are stratified based on the presence or absence of symptoms and tumor size. Treatment recommendations are usually based on tumor grade.

[0007] Patients with asymptomatic small tumors (≤3 cm) can undergo regular observation. In other situations, surgical resection is recommended whenever possible. If the patient is not eligible for surgery, radiation therapy can be selected. Patients with grade I meningiomas can undergo only regular observation (conservative treatment) after surgery, and if symptomatic, postoperative radiation therapy can be considered. For patients with grade II meningiomas that cannot be completely resected, postoperative radiation therapy is recommended. Certain patients (e.g., those not suitable for radiation therapy) can undergo regular observation. Patients with grade II meningiomas that are completely resected by surgery can be considered for postoperative radiation therapy. Patients with grade III meningiomas that are completely resected by surgery should receive adjuvant radiation therapy to enhance local control.

[0008] Systemic treatment is usually considered for meningiomas that recur after surgery and / or radiation therapy or are not suitable for surgery or radiation therapy, but no universally accepted standard of care exists. This therapeutic area lacks large-scale randomized trials. ORRs for systemic treatment of meningiomas are typically very low. In a review by the Response Assessment in Neuro-Oncology (RANO) Working Group on the Outcomes of Drug Treatment in Meningiomas, 37 of 42 publications reported radiological response data. Among 555 patients included in these 37 reports, the best radiological response reports were 1 CR (0.2%), 10 PR (1.8%), 13 MR (2.3%), and 343 SD (62%). The combined response rate of CR+PR+MR was 4.3%, indicating that little tumor shrinkage was observed. In this therapeutic area, PFS-6 (6-month PFS rate) or ORR is often used as a clinical trial endpoint. The RANO Working Group evaluated historical data from clinical trials of drug treatment for meningiomas. The weighted PFS6 for WHO grade I meningiomas is 29% (95% CI: 20.3%-37.7%). For WHO grade II / III meningiomas, the weighted mean PFS6 is 26% (95% CI: 19.3%-32.7%). Furthermore, in some small clinical trials, over 20% and even 60% of patients experience grade 3 or higher toxicity or discontinue treatment due to drug toxicity.

[0009] Therefore, in order to solve the problem of the lack of drugs currently available in clinical practice, there is an urgent need to develop safe and effective drugs for treating meningiomas.

[0010] Compound (I) was first disclosed in CN104860885A, and its structural formula is shown in the following formula (I):

[0011] [ka]

[0012] Compound (I) is a VEGFR / CSF1R dual-target inhibitor with excellent activity, but its therapeutic effect on meningioma has not yet been studied.

[0013] [Summary of the Invention] After extensive and in-depth research, the present inventors unexpectedly discovered that compound (I) has excellent inhibitory activity against meningioma cells. Preliminary clinical studies have shown that compound (I) can effectively treat meningioma and has good safety and tolerability, and it is expected to be developed as an anti-meningioma drug.

[0014] In a first aspect of the present application, there is provided a use of compound (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating meningioma, wherein said compound (I) has the following structure:

[0015] [ka]

[0016] In a second aspect of the present application, there is provided a pharmaceutical composition for treating meningioma, the pharmaceutical composition comprising a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein Compound (I) has the following structure:

[0017] [ka]

[0018] In a third aspect of the present application, there is provided a method of treating meningioma in an individual, the method comprising: The method comprises administering to an individual suffering from meningioma 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, wherein Compound (I) has the following structure:

[0019] [ka]

[0020] In a fourth aspect, the present application provides compound (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof, for treating meningioma, wherein compound (I) has the following structure:

[0021] [ka]

[0022] In some embodiments of the present application, the meningiomas described in the first to fourth aspects include, but are not limited to, the following WHO grade I meningiomas, WHO grade II meningiomas, and WHO grade III meningiomas, which are classified based on clinicopathological features.

[0023] In some embodiments, the WHO Grade I meningioma is a benign meningioma, including, but not limited to, meningothelial meningioma, fibrous meningioma, transitional meningioma, psammomatous meningioma, hemangiomatous meningioma, microcystic meningioma, secretory meningioma, lymphocyte-plasmacytoma-rich meningioma, and metaplastic meningioma. In specific embodiments, the meningioma is one or more of meningothelial meningioma, fibrous meningioma, transitional meningioma, psammomatous meningioma, hemangiomatous meningioma, microcystic meningioma, secretory meningioma, lymphocyte-plasmacytoma-rich meningioma, and metaplastic meningioma.

[0024] In some embodiments, the WHO Grade II meningioma is an atypical meningioma, including, but not limited to, atypical meningioma, clear cell meningioma, and chordoma meningioma. In specific embodiments, the meningioma is one or more of atypical meningioma, clear cell meningioma, and chordoma meningioma.

[0025] In some embodiments, the WHO Grade III meningioma is a malignant meningioma, including, but not limited to, rhabdoid meningioma, papillary meningioma, and anaplastic meningioma. In specific embodiments, the meningioma is one or more of rhabdoid meningioma, papillary meningioma, and anaplastic meningioma.

[0026] In some embodiments of the present application, the meningiomas according to the first to fourth aspects include intracranial meningiomas and ectopic meningiomas, which are classified based on the site of occurrence as follows.

[0027] In some embodiments of the present application, the meningiomas described in the first to fourth aspects include, but are not limited to, the following types classified based on the site of growth: convex meningioma, falx cerebri parameningioma, olfactory sulcus meningioma, tubercle sellae meningioma, sphenoid crest meningioma, parasagittal sinus meningioma, middle skull base meningioma, petroclival meningioma, and foramen magnum meningioma.

[0028] In some embodiments of the present application, the meningioma described in the first to fourth aspects is a meningioma that has failed treatment with other therapeutic means or has recurred (also called recurrent or refractory meningioma).

[0029] In some embodiments, the other therapeutic procedures include, but are not limited to, surgery, radiation therapy, and anti-tumor drug therapy.

[0030] In some embodiments, the anti-tumor drug includes, but is not limited to, chemotherapeutic drugs, targeted therapy drugs, immunotherapy drugs, etc., such as camrelizumab, bevacizumab, sunitinib, everolimus, etoposide, temozolomide, sirolimus, honokiol, etc. In a specific embodiment, the anti-tumor drug is one or more selected from camrelizumab, bevacizumab, sunitinib, everolimus, etoposide, temozolomide, sirolimus, and honokiol.

[0031] In some embodiments of the present application, the pharmaceutical compositions according to the second to fourth aspects are prepared into a clinically acceptable pharmaceutical dosage form, for example, an oral formulation, preferably an oral solution.

[0032] In some embodiments of the present application, the therapeutically effective amount according to the third aspect is a daily dose of Compound (I) of 5 mg to 30 mg, preferably 10 mg to 25 mg, more preferably 10 mg to 20 mg or 15 to 25 mg. In specific embodiments, the daily dose of Compound (I) is 10 mg, 15 mg, 20 mg, or 25 mg.

[0033] In some embodiments of the present application, compound (I) according to any one of the first to fourth aspects is administered in a single dose once a day, or in multiple doses within a day, or at intervals. In a preferred embodiment, compound (I) is administered in a single dose once a day. In some embodiments of the present application, compound (I) according to any one of the first to fourth aspects is administered in a 21-day continuous administration cycle, and optionally, administration can be repeated for multiple cycles.

[0034] In some embodiments of the present application, the individual described in the third aspect above refers to a mammal, including, but not limited to, a primate, a cow, a horse, a pig, a sheep, a goat, a dog, a cat, and a rodent such as a rat or a mouse. In a preferred embodiment, the individual is a human.

[0035] It should be understood that within the scope of the present application, any combination of the above technical features of the present application and the technical features specifically described below (e.g., in the Examples) can be used to form new or preferred technical solutions, and a detailed description thereof will be omitted here due to space limitations.

[0036] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed with a compound of the present application and an acid or base, which is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts.

[0037] "Pharmaceutically acceptable carrier" refers to a carrier that does not interfere with the biological activity of an active ingredient, and includes those commonly used in the pharmaceutical field, such as one or more compatible solid or liquid fillers or gel substances that are suitable for use in mammals, particularly humans, and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that each component of the composition can be mixed with the compound of the present application and with each other without significantly reducing the efficacy of the compound.

[0038] The method of administration of the pharmaceutical composition of the present application is not particularly limited. In some embodiments, representative administration methods include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous) and topical administration.

[0039] Accordingly, the drug of the present application can be prepared into various clinically acceptable dosage forms. In some embodiments, the dosage forms include oral dosage forms, injection dosage forms, topical dosage forms, external dosage forms, etc., preferably oral dosage forms, such as solid dosage forms or oral liquids, more preferably oral solutions.

[0040] Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared using coating and shell materials, such as enteric coatings and other materials known in the art. They can also contain opacifying agents, and in this composition, the release of the active compound can be delayed in a certain part of the digestive tract. If necessary, the active compound can also be formed into a microencapsulated form with one or more of the above-mentioned excipients.

[0041] The oral liquid dosage form may include a solution, syrup, emulsion, suspension, etc., preferably an emulsion, more preferably a self-emulsifying formulation. The self-emulsifying adjuvant includes an oil phase, an emulsifier, a co-emulsifier, and may further include an antioxidant. The oil phase may include medium-chain triglycerides (MCT), monocaprylin, dicaprylin, glyceryl monooleate, glyceryl monolinoleate, corn oil, castor oil, sesame oil, peanut oil, olive oil, etc. The emulsifiers include polyoxyethylene (40) hydrogenated castor oil (RH40), polyoxyethylene (35) castor oil (Cremophor EL), vitamin E succinic acid polyethylene glycol ester (TPGS 1000), 15-hydroxystearic acid polyethylene glycol ester (HS15), linoleoyl polyoxyethylene (6) glyceride, linoleoyl polyoxyethylene (6) glyceride, caprylocaproyl macrogolglyceride (Labrasol ALF), etc. The co-emulsifiers are selected from polyethylene glycol (PEG), diethylene glycol monoethyl ether (Transcutol HP), propylene glycol, glycerol, etc. The antioxidants are selected from dibutylhydroxytoluene, butylhydroxyanisole, vitamin E, and propyl gallate. The self-emulsifying formulations can also be prepared into capsules or tablets. Examples of oral solutions are described in the specific embodiments section of this application.

[0042] Compositions for parenteral injection can include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.

[0043] Dosage forms of the compounds of the present application for topical administration include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier (including any preservatives, buffers, or propellants as may be required).

[0044] The compounds of the present application can be administered alone or in combination with other pharmaceutically acceptable anti-tumor drugs (e.g., chemotherapeutic drugs, targeted therapy drugs, immunotherapy drugs), or other therapeutic means (e.g., radiation therapy, surgery).

[0045] The therapeutically effective dose described herein refers to a dose considered pharmaceutically effective, i.e., an amount of active compound that can significantly improve symptoms without causing serious side effects. The specific dose and administration frequency should take into account factors such as the route of administration and the patient's health status, all of which can be determined by a skilled physician based on their usual skills. In the initial human dose-escalation study (Phase I study), the most sensitive animal species is selected based on preclinical toxicity studies to estimate the maximum recommended starting dose for clinical trials. The starting dose is calculated based on the calculation method recommended in the "Technical Guidelines for Nonclinical Research of Antitumor Drugs" and other guidelines. In some embodiments, in Phase I clinical trials of Compound (I), to ensure the safety of subjects, the starting dose of Compound (I) in Phase I clinical trials is designed to be 5 mg, taking into account the feasibility of clinical trials and formulation specifications. Based on the results of long-term animal toxicity studies, the maximum tolerated dose in humans, converted to a human weight of 60 kg, is 200 mg. The Phase 1 clinical trial of Compound (I) will investigate the safety, tolerability, and therapeutic efficacy of a continuous administration regimen with a daily dose of 5 mg to 200 mg. In some embodiments, for a human weighing 60 kg, the daily dose of Compound (I) is preferably 5 to 30 mg, more preferably 10 to 25 mg, even more preferably 10 to 20 mg or 15 to 25 mg, and even more preferably 10 mg, 15 mg, 20 mg, or 25 mg. Compound (I) may be administered as a single dose once daily, or in multiple divided doses within a day, or at intervals. Preferably, Compound (I) is administered as a single dose once daily. Preferably, the administration cycle is 21 days of continuous administration, and optionally, multiple cycles of administration may be repeated.

[0046] In the specification and claims of this application, the terms "comprise," "include," and "contain" refer to "including, but not limited to," and are not intended to exclude other parts, additives, compositions, or steps.

[0047] In some embodiments, compound (I) of the present application has an excellent inhibitory effect on meningioma. In a specific embodiment, compound (I) of the present application can significantly inhibit the activity, proliferation, migration, or invasion of meningioma cells, such as meningioma cell lines IOMM-Lee cells and CH157-MN cells. In another specific embodiment, compound (I) of the present application has a significant promoting effect on apoptosis of meningioma cells, such as meningioma cell lines IOMM-Lee cells and CH157-MN cells.

[0048] In some embodiments, preliminary clinical studies have shown that Compound (I) of the present application can effectively treat meningiomas. In some embodiments, preliminary clinical studies have shown that Compound (I) of the present application has good safety and tolerability.

[0049] Therefore, compared with the prior art, the present application has one or more of the following major advantages:

[0050] (1) The above compound (I) has excellent inhibitory activity against meningioma, and can significantly inhibit the activity, proliferation, migration, and invasion of meningioma cells, such as meningioma cell lines IOMM-Lee cells and CH157-MN cells, and has a significant promoting effect on apoptosis of meningioma cells.

[0051] (2) Preliminary clinical studies have shown that compound (I) can effectively treat meningioma and has good safety and tolerability, and it is expected to be developed as an anti-meningioma drug.

[0052] [Brief description of the drawing] [Figure 1] The inhibitory effect of compound (I) on the activity of human meningeal chief cells.

[0053] [Figure 2] The inhibitory effect of compound (I) on the proliferation of human meningioma cells.

[0054] [Figure 3] The inhibitory effect of compound (I) on the migration of human meningioma cells is shown. Figures 3-1 and 3-2 show the inhibitory effect of compound (I) on the migration of human meningioma cells IOMM-Lee, and Figure 3-3 shows the inhibitory effect of compound (I) on the migration of human meningioma cells CH157-MN. In Figures 3-2 and 3-3, Panel A shows the crystal violet stained human meningioma cells, and Panel B shows the t-test analysis (*** indicates P<0.001 compared to the blank control group).

[0055] [Figure 4] The inhibitory effect of compound (I) on the invasion of human meningioma cells is shown. Figures 4-1 and 4-2 show the inhibitory effect of compound (I) on the invasion of human meningioma cells IOMM-Lee, and Figure 4-3 shows the inhibitory effect of compound (I) on the invasion of human meningioma cells CH157-MN. In Figures 4-1, 4-2, and 4-3, Figure A shows the crystal violet staining of human meningioma cells, and Figure B shows the t-test analysis (*** indicates P<0.001 compared to the blank control group).

[0056] [Figure 5] The promoting effect of compound (I) on apoptosis in human meningioma cells. Figures 5-1 and 5-2 show the promoting effect of compound (I) on apoptosis in human meningioma cells IOMM-Lee. Figure 5-3 shows the promoting effect of compound (I) on apoptosis in human meningioma cells CH157-MN. In Figures 5-1, 5-2, and 5-3, Figure A is a flow cytometry chart, and Figure B is a t-test analysis chart (*** indicates P<0.001 compared to the blank control group).

[0057] [Mode for Carrying Out the Invention] The present application will be further described below in conjunction with specific examples. It should be understood that these examples are merely for the purpose of illustrating the present application and do not limit the scope of the present application. In the following examples, experimental methods for which specific conditions are not specified generally follow conventional conditions or conditions suggested by the manufacturer. Unless otherwise defined, all technical and scientific terms used in the specification have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described can all be applied to the methods of the present application. The preferred implementation methods and materials shown in the specification are provided for illustrative purposes only.

[0058] Source or preparation of experimental materials: Compound (I) is self-produced by Shanghai Runshi Pharmaceutical Technology Co., Ltd.

[0059] Positive control compounds, reagents and raw materials used in the experiments are all commercially purchased or self-prepared.

[0060] In the method for preparing the test compound (I) for in vitro experiments, after weighing, the compound is dissolved in DMSO to 10 mM, and immediately before use, diluted with PBS to a desired concentration.

[0061] The test compound (I) for the clinical trial is prepared according to the following formulation:

[0062] [Table 1]

[0063] Manufacturing method: Based on the above formulation, polyoxyethylene (40) hydrogenated castor oil is pre-dissolved in warm water at about 60°C until it becomes liquid, and then medium-chain triglyceride, polyoxyethylene (40) hydrogenated castor oil, polyethylene glycol 400, and dibutylhydroxytoluene are added to a preparation tank and stirred uniformly at 40-70°C. Compound (I) is added, and the mixture is heated and stirred until the raw materials are completely dissolved, and then dispensed into oral solution bottles according to the specifications.

[0064] Example 1: The effect of Compound (I) on the cell activity of human meningioma cell lines was measured by trypan blue viable cell counting. 1. Experimental Method Human meningioma cell line IOMM-Lee cells (purchased from ATCC) were cultured in DMED medium containing 10% FBS and 100 U / mL of penicillin-streptomycin double antibody in an incubator at 37°C and 5% CO2. 2 × 10 cells in the logarithmic growth phase were cultured. 5 The cells were uniformly inoculated into a 6-well plate at a density of 100 cells / mL and cultured for 24 hours. Afterwards, the cells were divided into a blank control group and groups treated with different concentrations of Compound (I), namely, 0.4 μM, 0.8 μM, 1.6 μM, 2 μM, 10 μM, 20 μM, 60 μM, and 120 μM. Each group consisted of 3 to 4 duplicate wells.

[0065] After culturing each group of cells for 24 hours, the cells were digested with 0.25% trypsin. 50 μL of the cell suspension and 50 μL of 0.4% trypan blue solution were mixed to a final concentration of 0.2%. 10 μL of each suspension was then added to a counting plate. The cells (total and dead cells) were counted under a microscope and statistically analyzed.

[0066] 2. Experimental Results The experimental results showed that, compared with the blank control group, after 24 hours of treatment with different concentrations of compound (I), all had an inhibitory effect on the cell activity of IOMM-Lee, and the cell activity tended to decrease with increasing concentrations of compound (I). The results are shown in Table 1 and Figure 1. These results indicate that compound (I) can inhibit the cell activity of meningioma cells IOMM-Lee.

[0067] [Table 2]

[0068] NOTE: Cellular activity = (total cell number - dead cell number) / total cell number × 100%.

[0069] Example 2: EdU was used to measure the effect of Compound (I) on the proliferation of human meningioma cell lines 1. Experimental Method The logarithmic growth phase IOMM-Lee single cell suspension obtained in Example 1 was cultured at 3 × 10 5 The cells were seeded into a 6-well plate at a cell density of 1000 / mL and cultured overnight, after which they were divided into a blank control group and a compound (I)-treated group (1 μM concentration, 24 h treatment). Each group was then cultured with EdU (10 μM) for 2 hours, the medium was discarded, and the cells were washed with PBS (in this experiment, PBS was used for all washing processes). The cells were fixed with 4% paraformaldehyde, the fixative was discarded, and the cells were washed. The cells were then passed through 0.3% Triton X100, the effluent was discarded, and the cells were washed. The prepared click reaction solution (Click reaction solution, commercially available C0081 BeyoClick) was then added. TM Add EdU-647 cell proliferation assay reagent kit and incubate at room temperature for 30 minutes, avoiding light, then discard the reaction solution and wash. Cell nuclei were stained with Hoechst fluorescent dye 33342 (Hoechst 33342). Add 1 mL of 1x Hoechst 33342 solution to each well and incubate at room temperature for 10 minutes, avoiding light, then remove the 1x Hoechst 33342 solution and wash three times. Fluorescence detection and recording were then performed.

[0070] 2. Experimental Results The results are shown in Figure 2. In the fluorescence detection image, the blue fluorescent channel represents the staining of cell nuclei by Hochest33342, and the red fluorescent channel represents the staining of proliferating cell nuclei by EdU. Merging the two channels results in a magenta color, clearly indicating the proportion of proliferating cells to the total cell population. The experimental results show that the number of EdU-labeled (proliferating) cells in IOMM-Lee meningioma cells treated with compound (I) was significantly reduced compared to the blank control group. These results indicate that compound (I) can inhibit cell proliferation in IOMM-Lee meningioma cells.

[0071] Example 3: Cell scratch experiment to examine the effect of Compound (I) on migration of human meningioma cell line 1. Experimental Method (1) IOMM-Lee single cell suspension in logarithmic growth phase was cultured at 6 × 10 5 Cells were seeded into 6-well plates at a density of 1000 cells / well and cultured for 24 hours, ensuring that cell growth covered the entire Petri dish. A 10 μL sterile pipette tip was used to create a vertical cell scratch on the Petri dish, and the original culture medium was discarded. The cells were then washed three times with PBS to remove detached cells. The cells were then cultured in serum-free DMEM medium and divided into a blank control group and groups treated with different concentrations of Compound (I), 0.5 μM, 1 μM, and 2 μM, respectively. At 0 and 24 hours, the cells were observed under bright field microscopy and recorded.

[0072] (2) Refer to the experimental method (1), except that the concentrations of Compound (I) in the treatment groups were 2 μM, 5 μM, and 10 μM, respectively, and the human meningioma cell lines used were IOMM-Lee or CH157-MN.

[0073] 2. Experimental Results The experimental results showed that after 24 hours of treatment of IOMM-Lee or CH157-MN cells with different concentrations of Compound (I), the cell scratch healing in the Compound (I)-treated group was significantly lower than that in the blank control group, and the cell scratch healing gradually decreased with increasing Compound (I) concentration, as shown in Figure 3 (Figures 3-1, 3-2, and 3-3). The above results indicate that Compound (I) has a significant inhibitory effect on the cell migration of IOMM-Lee and CH157-MN meningioma cells, and the effect is dose-dependent.

[0074] Example 4: The effect of Compound (I) on cell invasion of human meningioma cell lines was examined using a Transwell chamber. 1. Experimental Method (1) Coat the upper chamber of a pre-cooled Transwell cell with 50 μL of Matrigel. The Matrigel-coated cell is then cultured in a 37°C incubator for 6–8 hours to polymerize the Matrigel into a gel. 100 μL of serum-free medium is added to each well, and the well is then left in the incubator for 1 hour to allow hydration of the basement membrane. The liquid in the upper chamber is removed, and a single IOMM-Lee cell suspension in the logarithmic growth phase is cultured in serum-free DMEM medium at a cell density of 2 × 10 5 The cell concentration was adjusted to 100 cells / mL, and 200 μL of the cell suspension was added to a Transwell chamber. The subculture medium was DMEM medium containing 20% ​​FBS, and different concentrations of compound (I) were added to the chamber: 0 μM, 0.5 μM, 1 μM, and 2 μM. After 24 hours of incubation, the cells were removed from the chamber with a cotton swab and fixed with 4% paraformaldehyde for 20 minutes. They were then washed three times with PBS and stained with crystal violet for 30 minutes. The cells were then observed under a microscope and statistically analyzed.

[0075] (2) Refer to the experimental method (1), except that the concentrations of Compound (I) in the treatment groups were 2 μM, 5 μM, and 10 μM, respectively, and the human meningioma cell lines used were IOMM-Lee or CH157-MN.

[0076] 2. Experimental Results The experimental results showed that after treating IOMM-Lee cells or CH157-MN cells with different concentrations of Compound (I) for 24 hours, the invasion rate significantly decreased with increasing concentrations of Compound (I), as shown in Figure 4 (Figures 4-1, 4-2, and 4-3).The above results indicate that Compound (I) has a significant inhibitory effect on the invasion of IOMM-Lee and CH157-MN meningioma cells, and the inhibitory effect is dose-dependent.

[0077] Example 5: Effect of Compound (I) on apoptosis in human meningioma cell lines 1. Experimental Method (1) IOMM-Lee single cell suspension in logarithmic growth phase was cultured at 5 × 10 5The cells were seeded into a 6-well plate at a cell density of 1000 cells / mL and cultured overnight. Then, the cells were divided into a blank control group and groups treated with different concentrations of compound (I). The concentrations of compound (I) were 1 μM, 5 μM, and 10 μM, respectively. Three to four duplicate wells were set up in each well, and the cells were treated with different concentrations of compound (I) for 24 hours. After that, the blank control group and the compound (I) treatment group were each (1 to 10) × 10 5 Collect the cells, wash them with PBS, and centrifuge them. Resuspend the cells in 500 μL of 1× Binding Buffer. Add 5 μL of Annexin V-FITC and 10 μL of PI to each tube. Gently vortex to mix evenly, then incubate at room temperature for 5 minutes in the dark before performing flow cytometry analysis.

[0078] (2) Refer to the experimental method (1), except that the concentrations of Compound (I) in the treatment groups were 2 μM, 5 μM, and 10 μM, respectively, and the human meningioma cell lines used were IOMM-Lee or CH157-MN.

[0079] 2. Experimental Results The experimental results showed that after 24 hours of treatment of IOMM-Lee or CH157-MN cells with different concentrations of compound (I), the total apoptosis rate increased with increasing compound (I) concentration, with a significant increase in late apoptosis, as shown in Figure 5 (Figures 5-1, 5-2, and 5-3). The above results indicate that compound (I) has a significant promoting effect on apoptosis of IOMM-Lee and CH157-MN meningioma cells.

[0080] Example 6: Typical clinical cases Compound (I) is currently undergoing phase I clinical trials to evaluate its initial therapeutic effects on meningioma patients.

[0081] Drug: Compound (I) oral solution, 10-25 mg / day, administered once a day.

[0082] Subject dosing regimen: Single-dose period: After enrollment, a single dose will be administered followed by a 3-day observation period. Multiple-dose period: 21 consecutive days of administration. If no serious adverse events occur, subsequent treatment cycles can be initiated, each 21-day cycle, until disease progression (PD) or intolerable toxicity occurs.

[0083] Tumor evaluation will be based on the "RANO Meningioma Evaluation Criteria" (Huang, Raymond Y et al. Proposed response assessment and endpoints for meningioma clinical trials: report from the Response Assessment in Neuro-Oncology Working Group. Neuro-oncology vol. 21,1 (2019): 26-36. doi:10.1093 / neuonc / noy137). Target lesions with enhanced tumor activity will be selected based on the criteria, and accurate measurements will be performed. Changes in measurements will be compared to confirm the effectiveness of tumor treatment in the target lesions. All tumor lesions not selected as target lesions will be recorded as non-target lesions. These non-target lesions will be observed at each tumor evaluation, and their changes will be explained and compared. Improvement or worsening of the patient's clinical symptoms and changes in the use of steroid hormones for symptomatic treatment of neurological symptoms will also serve as evaluation indicators for tumor evaluation. Tumor assessments will be performed during the baseline period before the first administration, and once every 6 weeks during the administration period, until disease progression (PD) or the initiation of new anti-tumor treatment.

[0084] A total of 34 meningioma patients with postoperative residual disease, recurrence, or disease progression were treated with Compound (I), and the majority of patients experienced tumor regression and stable or improved clinical symptoms after administration. As of January 16, 2023, tumor evaluations had been completed for five patients, with two achieving PR, one achieving MR, and two achieving SD. As of February 2, 2024, tumor evaluations had been completed for 32 patients, with four achieving PR, six achieving MR, and 18 achieving SD. The objective response rate, assessed according to the RANO-Meningioma Criteria, was 29.41%, and the disease control rate was 82.4%. Twenty-six patients experienced tumor regression after administration, accounting for 76.5% of all patients. Adverse events occurring after administration of Compound (I) and correlated with it are mostly mild and moderate, with adverse events occurring with an incidence of more than 20% being hypertension, decreased platelet count, increased blood lactate dehydrogenase, sinus bradycardia, proteinuria, increased aspartate aminotransferase, increased alanine aminotransferase, hypokalemia, hyperlipidemia, decreased neutrophil count, decreased white blood cell count, diarrhea, and anemia.

[0085] Typical case 1: A patient, female, 59 years old, disease diagnosis: anaplastic meningioma, pathological classification: anaplastic (malignant) meningioma (CNS WHO grade III) invading brain tissue.

[0086] On July 12, 2015, the patient underwent right middle cranial meningioma resection. Subsequently, radiotherapy, chemotherapy, and targeted therapy were not performed, and the patient was followed up regularly. From November to December 2020, enhanced head MRI showed tumor progression. On January 18, 2021, meningioma resection was performed. During the operation, the tumor matrix was confirmed to be attached to the middle cranial base, measuring 4 × 4 × 4.5 cm. On July 4, 2022, the patient participated in a clinical trial of injectable honokiol liposome (HK), with the final treatment time scheduled for July 31, 2022. On August 9, 2022, the patient's clinical symptoms worsened, and he was withdrawn from the study group based on comprehensive evaluation.

[0087] On August 16, 2022, he will participate in a Phase I clinical trial of Compound (I). On August 31, 2022, he will begin taking Compound (I) oral solution at a dose of 15 mg once daily.

[0088] Evaluation of tumor treatment efficacy: After enrollment, a single dose was administered. After three days of observation, if no adverse events occurred, multiple doses were administered until two cycles were completed. The subject's head pain was significantly alleviated. Head MRI showed that the tumor had clearly shrunk (C2 target lesions shrank by 56%), non-target lesions were not cured or progressed, hormones were no longer used, the clinical condition was stable or improved, and the overall treatment effect was evaluated as PR. No adverse events were reported during the treatment period.

[0089] Typical case 2: A patient, female, 46 years old, disease diagnosis: meningioma (fibrous type), pathological classification: meningioma (fibrous type), WHO grade I.

[0090] On May 4, 2017, the patient underwent surgical treatment. He underwent a second surgery in June 2020, followed by gamma knife treatment in August 2020 and March 2021. On March 22, 2022, he underwent intravenous camrelizumab treatment, which he was unable to tolerate, leading to progressive visual loss and gradual blindness.

[0091] On November 7, 2022, the patient will participate in a Phase I clinical trial of Compound (I). On November 16, 2022, the patient will begin taking Compound (I) oral solution at a dose of 15 mg once daily. Baseline physical examination: the patient is bilaterally blind and has only light perception.

[0092] Evaluation of tumor treatment efficacy: After enrollment, a single dose was administered. After three days of observation, no adverse events occurred. Multiple doses were administered. At the end of two cycles, the subject returned to the hospital for a medical examination, regaining vision and regaining independence. A head MRI showed a clear reduction in tumor size (C2 target lesions reduced by 36%), no non-target lesions, no hormone therapy was used, and the clinical condition was stable or improved. The overall therapeutic effect was assessed as MR. The main adverse event during treatment was mild to moderate hypertension, which resolved after discontinuation of administration.

[0093] Typical case 3: A patient, female, 50 years old, disease diagnosis: meningioma.

[0094] In May 2018, a right parieto-occipital tumor resection was performed, and postoperative pathology revealed grade III anaplastic meningioma. Postoperative synchronous radiation therapy and chemotherapy were performed. In March 2021, a second surgery was performed due to tumor recurrence, and postoperative pathology revealed grade II atypical meningioma. Postoperative radiation therapy and chemotherapy were not performed. In September 2022, a third right parieto-occipital craniotomy was performed, and postoperative pathology revealed a diagnosis of malignant meningioma.

[0095] On October 17, 2022, he will participate in a Phase I clinical trial of Compound (I). On October 26, 2022, he will begin taking Compound (I) oral solution at a dose of 15 mg, administered orally once daily.

[0096] Evaluation of tumor treatment efficacy: Head MRI showed a clear tumor shrinkage (C2 target lesions shrank by 56%), no non-target lesions were found, hormone therapy was not used, clinical condition was stable or improved, and the overall treatment efficacy was evaluated as PR. The main adverse event during treatment was mild to moderate hypertension, which resolved after the use of antihypertensive medication.

[0097] Typical case 4: A patient, female, 55 years old, disease diagnosis: meningioma.

[0098] In May 2021, he was diagnosed with meningioma and underwent right frontal craniotomy and meningioma resection. In June 2022, he underwent a second surgery due to recurrence, and postoperative pathology revealed atypical meningioma, WHO grade II. He underwent gamma knife radiotherapy after surgery and will not undergo further treatment.

[0099] On May 5, 2023, he will participate in a Phase I clinical trial of Compound (I), and on May 11, 2023, he will begin taking Compound (I) oral solution at a dose of 20 mg, administered orally once daily.

[0100] Evaluation of tumor treatment efficacy: During the patient's screening period, an 18x12mm irregular circular enhancement lesion was found near the superior sagittal sinus in the right parietal lobe. After six cycles of treatment, a head MRI showed that the tumor had shrunk (the target lesion shrank by 61.47%), and non-target lesions in the right parietal lobe had stabilized. Hormones were no longer used, and the clinical condition remained stable or improved. The overall treatment efficacy was assessed as partial response. Subsequent evaluations of treatment efficacy showed that the target lesion continued to shrink. The patient is currently undergoing treatment for nine months. The main adverse events during treatment were mild proteinuria, decreased platelet count, decreased neutrophil count, decreased white blood cell count, and increased alanine aminotransferase, which resolved after symptomatic treatment.

[0101] Typical case 5: A patient, male, 45 years old, disease diagnosis: meningioma.

[0102] A left frontotemporal abnormality was discovered in 2017, and the first left frontotemporal space-occupying lesion resection was performed on September 14, 2017. Postoperative pathology: meningoepithelial meningioma, WHO grade I. Left temporal meningioma resection was performed in July 2019 due to recurrence, with postoperative pathology: atypical meningioma, WHO grade II. A third craniofacial joint radical surgery was performed in April 2020 due to recurrence, with postoperative pathology: atypical meningioma, WHO grade II. Postoperative synchronous radiation therapy and chemotherapy were performed, and a fourth brain lesion resection was performed on December 29, 2022, with postoperative pathology: papillary meningioma, WHO grade III. X-ray stereotactic radiosurgery (20GUy / 4fx) will be performed in August 2023.

[0103] On October 19, 2023, he will participate in a Phase I clinical trial of Compound (I), and on October 25, 2023, he will begin taking Compound (I) oral solution at a dose of 25 mg, administered orally once daily.

[0104] Evaluation of tumor treatment efficacy: During the patient's screening period, 60x32x27mm enhancing lesions were found in the parafalci bilateral frontal regions. After six cycles of treatment, occipital MRI showed that the tumor had shrunk (target lesions shrank by 36.73%), and non-target lesions were stable in the left temporal lobe and left orbit. Hormones were no longer used, and the clinical condition was stable or improved. The overall treatment efficacy was evaluated as MR. Subsequent evaluations of treatment efficacy showed that the target lesions continued to shrink. The main adverse events during treatment were mild hypertension, decreased platelet count, decreased neutrophil count, and increased alanine aminotransferase, which were remitted / recovered after symptomatic treatment.

[0105] The above preliminary clinical treatment data indicate that Compound (I) can effectively treat meningioma and has good safety and tolerability.

[0106] The full English abbreviations and Japanese names used in this application are as follows:

[0107] [Table 3]

[0108] Although the present application has described the present invention in the above specific embodiments, it should be understood that the present invention is not limited to the specific contents described in these specific embodiments. As will be apparent to those skilled in the art, various equivalent modifications may be made to the technical features included in the present invention without departing from the spirit of the invention described in the present application, and all such modifications should fall within the scope of the claims of the present invention. [Brief explanation of the drawings]

[0109] [Figure 1] 1 shows the inhibitory effect of compound (I) on the activity of human meningeal chief cells. [Figure 2] 1 shows the inhibitory effect of Compound (I) on the proliferation of human meningioma cells. [Figure 3]Figures 3-1 and 3-2 show the inhibitory effect of compound (I) on the migration of human meningioma cells, IOMM-Lee. Figure 3-3 shows the inhibitory effect of compound (I) on the migration of human meningioma cells, CH157-MN. In Figures 3-2 and 3-3, Figure A shows the crystal violet stained image of human meningioma cells, and Figure B shows the t-test analysis (*** indicates P<0.001 compared to the blank control group). [Figure 4] Figures 4-1 and 4-2 show the inhibitory effect of compound (I) on the invasion of human meningioma cells, IOMM-Lee. Figure 4-3 shows the inhibitory effect of compound (I) on the invasion of human meningioma cells, CH157-MN. In Figures 4-1, 4-2, and 4-3, Figure A shows the crystal violet stained human meningioma cells, and Figure B shows the t-test analysis (*** indicates P<0.001 compared to the blank control group). [Figure 5] Figures 5-1 and 5-2 show the promoting effect of compound (I) on apoptosis of human meningioma cells, IOMM-Lee, and Figure 5-3 shows the promoting effect of compound (I) on apoptosis of human meningioma cells, CH157-MN. In Figures 5-1, 5-2, and 5-3, Figure A is a flow cytometry chart, and Figure B is a t-test analysis chart (*** indicates P<0.001 compared to the blank control group).

Claims

1. 1. Use of compound (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating meningioma, wherein said compound (I) has the following structure: 【Chemistry 1】 use.

2. The meningiomas are classified based on clinicopathological features as follows: WHO grade I meningioma, WHO grade II meningioma, and WHO grade III meningioma.

2. The use according to claim 1.

3. The WHO grade I meningioma is a benign meningioma, preferably one or more types selected from meningothelial meningioma, fibrous meningioma, transitional meningioma, psammomatous meningioma, hemangioma, microcystic meningioma, secretory meningioma, lymphocyte-plasmocyte-rich meningioma, and metaplastic meningioma, and / or The WHO grade II meningioma is an atypical meningioma, preferably one or more selected from atypical meningioma, clear cell meningioma, and chordoma meningioma, and / or The WHO grade III meningioma is a malignant meningioma, preferably one or more types selected from rhabdoid meningioma, papillary meningioma, and anaplastic meningioma.

3. The use according to claim 2.

4. The meningioma is a meningioma that has failed or recurred after treatment with other therapeutic means, including surgery, radiation therapy, and anti-tumor drug therapy; 2. The use according to claim 1.

5. The anti-tumor drugs include chemotherapeutic drugs, targeted therapy drugs and immunotherapy drugs; 5. The use according to claim 4.

6. The antitumor drug is one or more selected from camrelizumab, bevacizumab, sunitinib, everolimus, etoposide, temozolomide, sirolimus, and honokiol; 6. The use according to claim 5.

7. A pharmaceutical composition for treating meningioma, comprising a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; Among them, the compound (I) has the following structure: 【Chemistry 2】 Pharmaceutical compositions.

8. The pharmaceutical composition is an oral formulation, preferably an oral solution. The pharmaceutical composition of claim 7.

9. 1. A method of treating meningioma in an individual, the method comprising:

9. A method for treating meningioma comprising administering to an individual suffering from meningioma a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7 or 8, Among them, the compound (I) has the following structure: 【Transformation 3】 method.

10. The therapeutically effective amount is The daily dose of compound (I) is 5 mg to 30 mg, preferably 10 mg to 25 mg, more preferably 10 mg to 20 mg or 15 mg to 25 mg, and even more preferably 10 mg, 15 mg, 20 mg, or 25 mg.

10. The method of claim 9.

11. Compound (I) may be administered in a single dose once a day, or in multiple doses or at intervals within a day, preferably in a single dose once a day. The method of claim 10.

12. The administration cycle of compound (I) is 21 days of continuous administration, and optionally, multiple cycles of administration can be repeated. The method of claim 10.

13. The meningioma comprises the following, classified based on clinicopathological features: WHO grade I meningioma, WHO grade II meningioma, WHO grade III meningioma, and optionally: The WHO grade I meningioma is a benign meningioma, preferably one or more types selected from meningothelial meningioma, fibrous meningioma, transitional meningioma, psammomatous meningioma, hemangioma, microcystic meningioma, secretory meningioma, lymphocyte-plasmocyte-rich meningioma, and metaplastic meningioma, and / or The WHO grade II meningioma is an atypical meningioma, preferably one or more selected from atypical meningioma, clear cell meningioma, and chordoma meningioma, and / or The WHO grade III meningioma is a malignant meningioma, preferably one or more types selected from rhabdoid meningioma, papillary meningioma, and anaplastic meningioma.

10. The method of claim 9.

14. A compound (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing said compound (I) or a pharmaceutically acceptable salt thereof, for treating meningioma, wherein said compound (I) has the following structure: 【Chemistry 4】 1. Compound (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound (I) or a pharmaceutically acceptable salt thereof, for treating meningioma.

15. The meningioma comprises the following, classified based on clinicopathological features: WHO grade I meningioma, WHO grade II meningioma, WHO grade III meningioma, and optionally: The WHO grade I meningioma is a benign meningioma, preferably one or more types selected from meningothelial meningioma, fibrous meningioma, transitional meningioma, psammomatous meningioma, hemangioma, microcystic meningioma, secretory meningioma, lymphocyte-plasmocyte-rich meningioma, and metaplastic meningioma, and / or The WHO grade II meningioma is an atypical meningioma, preferably one or more selected from atypical meningioma, clear cell meningioma, and chordoma meningioma, and / or The WHO grade III meningioma is a malignant meningioma, preferably one or more types selected from rhabdoid meningioma, papillary meningioma, and anaplastic meningioma.

15. Compound (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound (I) or a pharmaceutically acceptable salt thereof, for treating meningioma according to claim 14.

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