WO2023143611A1 - Méthode de traitement du cancer - Google Patents

Méthode de traitement du cancer Download PDF

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WO2023143611A1
WO2023143611A1 PCT/CN2023/073851 CN2023073851W WO2023143611A1 WO 2023143611 A1 WO2023143611 A1 WO 2023143611A1 CN 2023073851 W CN2023073851 W CN 2023073851W WO 2023143611 A1 WO2023143611 A1 WO 2023143611A1
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cancer
tumor
cell
control group
group
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PCT/CN2023/073851
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Chinese (zh)
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侯睿
臧广喜
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兰泰克生物技术公司
侯睿
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Priority to CN202380019288.4A priority Critical patent/CN118678959A/zh
Publication of WO2023143611A1 publication Critical patent/WO2023143611A1/fr

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This article relates to the field of medicine, in particular to the use of a compound of formula I or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates in the preparation of drugs for the treatment of cancer, and the treatment of cancer method.
  • KDR2-2 is a small molecule compound, chemical name 2-(2-aminopyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)quinoline-5-carboxamide, structure As shown in formula I
  • the synthesis method of compound KDR2-2 can refer to International Patent Publication WO2014/166386A1.
  • International patent publication WO2021213512A1 discloses that the compound inhibits the abnormal proliferation of new blood vessels by inhibiting the activity of VEGFR2/KDR and PDGFR ⁇ , and can be used to treat the occurrence of new blood vessels in the eye.
  • the permeable blood-brain barrier formed between the blood and the brain effectively prevents more than 98% of small molecule drugs and almost 100% of large molecule drugs from exerting their therapeutic effects in the brain. Due to the effect of the blood-brain barrier, absolutely most of the drugs cannot reach the focal part of the nerve center, thereby failing to reach an effective therapeutic concentration and unable to exert the therapeutic effect of the drug.
  • the transport of small molecules across the BBB mainly consists of passive diffusion, efflux, and carrier-mediated endocytosis.
  • the passive diffusion and efflux of drugs are mainly affected by the physicochemical properties of the molecules.
  • Common strategies to improve the blood-brain barrier permeability of drug molecules and reduce the efflux rate include: increasing the lipophilicity of compounds, reducing hydrogen bond donors, deleting or replacing negatively charged atoms to reduce tPSA, removing basic groups to reduce pKa, And the introduction of constrained conformation to improve molecular rigidity is one of the important factors to improve the above effect.
  • Glioma refers to the tumor originating from the glial cells of the brain and is the most common primary intracranial tumor.
  • the World Health Organization (WHO) classification of central nervous system tumors divides glioma into grades I-IV. Grades I and II are low-grade gliomas, and grades III and IV are high-grade gliomas.
  • glioma The treatment of glioma is mainly based on surgical resection, combined with radiotherapy, chemotherapy and other comprehensive treatment methods. Surgery can relieve clinical symptoms, prolong survival, and obtain enough tumor samples for clear pathological diagnosis and molecular genetic testing.
  • the principle of surgical treatment is to safely remove tumors in the largest range, and new technologies such as conventional neuronavigation, functional neuronavigation, intraoperative neurophysiological monitoring, and intraoperative MRI real-time images can help achieve safe tumor removal in the largest range.
  • Radiotherapy can kill or inhibit tumor cells and prolong the survival period of patients.
  • Conventional fractionated external beam radiation is the standard treatment for glioma radiotherapy.
  • Postoperative radiotherapy combined with temozolomide (TMZ) and adjuvant chemotherapy for glioblastoma (GBM) has become an Standard treatment regimen for adults with newly diagnosed GBM.
  • the treatment of glioma requires the cooperation of multiple disciplines such as neurosurgery, neuroimaging, radiotherapy, neuro-oncology, pathology and neurorehabilitation.
  • individualized comprehensive treatment is adopted to optimize and standardize the treatment plan.
  • prolong the progression-free survival (PFS) and overall survival (OS) of patients as much as possible, and improve the quality of life.
  • doctors need to closely follow up and observe patients, conduct regular imaging review, and take into account patients' daily life, social and family activities, nutritional support, pain control, rehabilitation treatment and psychological regulation, etc. .
  • the degree of surgical resection is closely related to the prognosis of the disease.
  • total tumor resection or subtotal resection is better than partial resection or biopsy.
  • Total resection or subtotal resection can not only prolong the survival time of patients, but also reduce the probability of glioma progression.
  • a retrospective study of 1097 patients with low-grade glioma found that the median survival time was 10.5 years and 14 years for patients with less than 50% resection and 50%-99% resection, and patients with total resection, Median survival was over 15 years.
  • glioma infiltrates the surrounding normal brain tissue, and it is difficult to find a clear resection boundary during surgery. In practice, it is difficult to find a balance between completely resecting the tumor and retaining more healthy tissue.
  • KDR2-2 has a high inhibitory efficiency for VEGFR2 receptors and can penetrate the blood-brain barrier.
  • isotope variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof in the preparation of a medicament for treating cancer.
  • the present application also provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound represented by formula I or its isotope variant, tautomer, pharmaceutically acceptable salt, solvate or Hydrate.
  • the present application also provides the compound represented by formula I or its isotope variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate for use in treating cancer.
  • the cancer is colon cancer, glioma, liver cancer, intrahepatic/extrahepatic cholangiocarcinoma, gallbladder cancer, biliary tract cancer, kidney cancer/renal cell carcinoma, gastric/gastroesophageal junction adenocarcinoma , gastrointestinal stromal tumor (GIST), solid tumors, colorectal cancer, small cell/non-small cell lung cancer, locally advanced or metastatic differentiated thyroid cancer/medullary thyroid carcinoma (MTC), diffuse large B-cell lymphoma, Head, neck, and thoracic tumors, primary malignant tumors of bone, malignant melanoma, pancreatic neuroendocrine tumors, urothelial carcinoma, gastrinoma, cytoma, insulinoma, or cervical cancer.
  • GIST gastrointestinal stromal tumor
  • MTC metastatic differentiated thyroid cancer/medullary thyroid carcinoma
  • the cancer is colon cancer or glioma.
  • the compound or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof inhibits tumor cell migration and growth.
  • the compound or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof is administered parenterally, orally or ophthalmically.
  • the compound or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof is administered by injection or orally.
  • Fig. 1 shows in embodiment 1, each group cell scratch pattern (100 *) at different times, wherein K is blank control group; 5 is 39ng/mL KDR2-2 group; 4 is 165ng/mL KDR2-2 group; 3 is 625ng/mL KDR2-2 group; 2 is 2500ng/mL KDR2-2 group; 1 is 10000ng/mL KDR2-2 group;
  • Figure 2 shows the average tumor volume for Example 2.
  • a p ⁇ 0.05, aa p ⁇ 0.01, aaa p ⁇ 0.001 compared with the solvent control group in the same period, b p ⁇ 0.05, bb p ⁇ 0.01, bbb p ⁇ 0.001; compared with the positive control group in the same period , c p ⁇ 0.05, cc p ⁇ 0.01, ccc p ⁇ 0.001; compared with the low dose group of the test product in the same period, d p ⁇ 0.05, dd p ⁇ 0.01, ddd p ⁇ 0.001.
  • Figure 3 shows the mean relative tumor volumes for Example 2.
  • a p ⁇ 0.05, aa p ⁇ 0.01, aaa p ⁇ 0.001 compared with the solvent control group in the same period, b p ⁇ 0.05, bb p ⁇ 0.01, bbb p ⁇ 0.001; compared with the positive control group in the same period , c p ⁇ 0.05, cc p ⁇ 0.01, ccc p ⁇ 0.001; compared with the low dose group of the test product in the same period, d p ⁇ 0.05, dd p ⁇ 0.01, ddd p ⁇ 0.001.
  • FIG. 4 shows the average tumor weight of Example 2.
  • a p ⁇ 0.05, aa p ⁇ 0.01, aaa p ⁇ 0.001 compared with the solvent control group in the same period, b p ⁇ 0.05, bb p ⁇ 0.01, bbb p ⁇ 0.001; compared with the positive control group in the same period , c p ⁇ 0.05, cc p ⁇ 0.01, ccc p ⁇ 0.001; compared with the low dose group of the test product in the same period, d p ⁇ 0.05, dd p ⁇ 0.01, ddd p ⁇ 0.001.
  • FIG. 5 shows the average body weight of Example 2.
  • a p ⁇ 0.05, aa p ⁇ 0.01, aaa p ⁇ 0.001 compared with the solvent control group in the same period, b p ⁇ 0.05, bb p ⁇ 0.01, bbb p ⁇ 0.001; compared with the positive control group in the same period , c p ⁇ 0.05, cc p ⁇ 0.01, ccc p ⁇ 0.001; compared with the low dose group of the test product in the same period, d p ⁇ 0.05, dd p ⁇ 0.01, ddd p ⁇ 0.001.
  • Fig. 6 shows MRI images of mouse brains treated with KDR2-2.
  • Figure 7 shows the lesion volume in mice treated with KDR2-2.
  • Figure 8 shows the body weight of mice treated with KDR2-2.
  • Fig. 9 shows that after treatment with KDR2-2, the hair of mice turns white.
  • isotope variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof in the preparation of a medicament for treating cancer.
  • the present application also provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound represented by formula I or its isotope variant, tautomer, pharmaceutically acceptable salt, solvate or Hydrate.
  • the present application also provides the compound represented by formula I or its isotope variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate for use in treating cancer.
  • the cancer is colon cancer, glioma, liver cancer, intrahepatic/extrahepatic cholangiocarcinoma, gallbladder cancer, biliary tract cancer, kidney cancer/renal cell carcinoma, gastric/gastroesophageal junction adenocarcinoma , gastrointestinal stromal tumor (GIST), solid tumors, colorectal cancer, small cell/non-small cell lung cancer, locally advanced or metastatic differentiated thyroid cancer/medullary thyroid carcinoma (MTC), diffuse large B-cell lymphoma, Head, neck, and thoracic tumors, primary malignant tumors of bone, malignant melanoma, pancreatic neuroendocrine tumors, urothelial carcinoma, gastrinoma, cytoma, insulinoma, or cervical cancer.
  • GIST gastrointestinal stromal tumor
  • MTC metastatic differentiated thyroid cancer/medullary thyroid carcinoma
  • the cancer is colon cancer or glioma.
  • the compound or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof inhibits tumor cell migration and growth.
  • the compound or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof is administered parenterally, orally or ophthalmically.
  • the compound or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate thereof is administered by injection or orally.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula I or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate.
  • the pharmaceutical composition includes a pharmacologically effective amount of the compound of formula I or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates and pharmaceutically acceptable auxiliary materials.
  • excipients are known to those skilled in the art, for example, physiological saline, gelatin, gum arabic, lactose, microcrystalline cellulose, starch, modified starch, cellulose, modified cellulose, sodium glycolate , calcium hydrogen phosphate, magnesium stearate, talc, colloidal silicon dioxide, etc.
  • these compositions may further contain: stabilizers, wetting agents, emulsifiers, sweeteners, flavoring agents, buffering agents and the like.
  • the pharmaceutical composition provided by the application comprising the compound of formula I or its isotope variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate can be formulated as Solid or liquid form for oral administration, such as tablet, pill, oral liquid, etc.; or, sterile solution, suspension or emulsion form, etc. for parenteral administration.
  • the pharmaceutical composition provided by the application comprising the compound of formula I or its isotopic variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate is formulated as an ophthalmic preparation form.
  • the compound of formula I of the present application or its isotope variant, tautomer, pharmaceutically acceptable salt, solvate or hydrate or its pharmaceutical composition can be used as a single pharmaceutical active ingredient to be administered, or may be administered in combination with other anticancer drugs.
  • the "effective amount” or “effective dose” refers to an amount sufficient to affect beneficial or desired symptoms of the disease, its complications, or intermediate pathological indicators in the course of disease development.
  • a compound of Formula I or an isotopic variant, tautomer, pharmaceutically acceptable salt, solvate, or Hydrate or its pharmaceutical composition.
  • the compound of formula I or its isotopic variants, tautomers, pharmaceutically acceptable salts, solvates or hydrates can be dosed at 0.24-640 mg/day administered to human subjects.
  • KDR2-2 is a small molecular compound, chemical name 2-(2-aminopyrimidin-4-yloxy)-N-(3-(trifluoromethyl)phenyl ) quinoline-5-carboxamide, structure as shown in formula I
  • the cell scratch test was used to study whether KDR2-2 has an inhibitory effect on the activity and movement of tumor cells.
  • DMSO Dimethylsulfoxide
  • Pen Strep Glutamine (100 ⁇ ), Lot No.: 2051357, gibco;
  • trypsin-EDTA (trypsin), Lot No.: 1967360, gibco.
  • microporous membrane 0.22 ⁇ m microporous membrane, R6SA39060, Millipore;
  • Centrifuge tubes (5mL, 10mL, 50mL), OTHBR, HX;
  • Pipette gun (100-1000 ⁇ L, 10-100 ⁇ L), Eppendorf;
  • Blank control group 1% DMSO
  • different concentrations of KDR2-2 administration groups (10000ng/mL, 2500ng/mL, 625ng/mL, 156ng/mL, 39ng/mL).
  • Cell number (number of cells in 4 squares/4 ⁇ 10 4 ⁇ dilution factor) cells/mL;
  • the scratch width ratios of HT-29 cells in each group at different time points are shown in Table 1, and the scratch diagrams of cells in each group at different time points are shown in Figure 1 (100 ⁇ ).
  • Example 2 Efficacy evaluation of KDR2-2 on HT-29 human colon cancer tumor model
  • a colon cancer model was established by inoculating HT-29 cells subcutaneously, and then intervened with KDR2-2 to study whether KDR2-2 can inhibit the growth of colon cancer.
  • KDR2-2 suspension (specification: 0.4mL: 0.4mg; 1mL: 20mg), as the test product.
  • KDR2-2 suspension contains 0.10% (w/v) KDR2-2, 0.40% (w/v) hypromellose (HPMC E4M), 4.50% (w/v) Polyethylene glycol 15-hydroxystearate ( HS 15), 0.21% (w/v) sodium dihydrogen phosphate dihydrate (NaH 2 PO 4 2H 2 O), 1.60% (w/v) disodium hydrogen phosphate dodecahydrate (Na 2 HPO 4 12H 2 O), 0.30% (w/v) sodium chloride, 0.10% (w/v) anhydrous sodium thiosulfate, make up the volume with water for injection.
  • HPMC E4M hypromellose
  • the specification is 1mL: 20mg of KDR2-2 suspension containing 2% (w/v) KDR2-2, 0.40% (w/v) hypromellose (HPMC E4M), 4.50% (w/v) 15- Polyethylene glycol hydroxystearate ( HS 15), 0.21% (w/v) sodium dihydrogen phosphate dihydrate (NaH 2 PO 4 2H 2 O), 1.60% (w/v) disodium hydrogen phosphate dodecahydrate (Na 2 HPO 4 12H 2 O), 0.30% (w/v) sodium chloride, 0.10% (w/v) anhydrous sodium thiosulfate, make up the volume with water for injection.
  • 10mg/mL KDR2-2 suspension Take an appropriate amount of 20mg/mL KDR2-2 suspension and add an equal volume of blank excipients to dilute to obtain the target concentration solution.
  • mitomycin For mitomycin, use 1 mL sodium chloride injection to dissolve mitomycin lyophilized powder into a 10 mg/mL solution (stock solution). Take an appropriate amount of the stock solution and dilute it 200 times with sodium chloride injection to obtain a 0.05 mg/mL mitomycin solution.
  • mice SPF grade BALB/c nude mice, 5-6 weeks old, weighing 15-18g. Purchased from Guangdong Medical Experimental Animal Center; production license number: SCXK (Guangdong) 2018-0002; animal quality certificate number: No.44007200077964.
  • Each animal is identified by a tail tag and a cage card.
  • the marking method of the cage card during the environmental adaptation period indicate the experiment number, animal strain, cage number, number of animals, time of entry, animal number, etc.
  • Marking method of the cage card after grouping Indicate the experiment number, animal species, treatment factors, number of animals, cage number, start and end time of the experiment, animal number, etc. on the cage card.
  • mice were acclimated to the environment for 6 days before modeling.
  • the main inspection contents of the adaptation period whether it is consistent with the quality indicators required at the time of order; general status; whether the body weight reaches the weight range required by the experiment; the adaptation period inspection is qualified, and subcutaneous inoculation is carried out to make models.
  • Stocking density 5 animals/cage during the environmental adaptation period, 5 animals/cage for the formal experiment.
  • Cell number (number of cells in 4 squares/4 ⁇ 10 4 ⁇ dilution factor) cells/mL;
  • the HT-29 human colon cancer cell line was cultured and passaged routinely, after three passages in vitro. Centrifuge to obtain cells according to the above operation, resuspend the cells in the basal medium, absorb 10 ⁇ L of cells and dilute them 10 times, and calculate the cell concentration. Adjust the cell concentration to 1 ⁇ 10 7 cells/mL.
  • Group design model group, solvent control group, positive control group, KDR2-2 high and low dose group subcutaneous injection (10mg/kg, 100mg/kg), KDR2-2 high and low dose group intragastric administration (10mg/kg, 100mg/kg) .
  • Grouping method select tumor-forming animals for experiments, and randomly group them according to tumor volume
  • mice that did not meet the experimental requirements were euthanized.
  • Dosing frequency 1 time/day
  • the day of the first administration is defined as the first day of the experiment (day1, D1)
  • Observation time observe once a day after tumor inoculation, and the observation frequency can be appropriately increased according to the actual situation;
  • Routine observation content tumor growth, body weight, appearance and signs of mice, general behavioral activities, mental state, respiratory state, feces properties, genitalia, death, etc.;
  • Measurement time measure once before the first administration, and measure twice a week during the administration period
  • Measuring animals all surviving experimental mice.
  • Tumor size was measured twice a week
  • Measuring method measure the long diameter (a) and short diameter (b) of the transplanted tumor with a vernier caliper;
  • Dissected Animals All planned dissected animals.
  • Tumor weight detection The animals were sacrificed on the second day after the last administration, and the complete tumor body was carefully removed, weighed and recorded with an electronic balance.
  • Tumor fixation After the tumor was weighed, a portion of the tumor was selected and fixed in 10 times the volume of neutral formaldehyde.
  • V tumor volume
  • a and b represent the length and width respectively.
  • V 0 is the tumor volume measured on the day of group administration (ie, the first day)
  • V t is the tumor volume at each measurement.
  • Evaluation criteria for curative effect T/C(%)>40% is invalid; T/C(%) ⁇ 40%, and P ⁇ 0.05 compared with the model group by variance analysis is effective.
  • the tumor inhibition rate can be calculated by tumor weight or tumor volume.
  • the animals were euthanized, and the tumor pieces were dissected to weigh the tumor weight of each group;
  • Tumor growth inhibition rate% (average tumor weight of the control group-average tumor weight of the treatment group)/average tumor weight of the control group ⁇ 100%;
  • Tumor growth inhibition rate % (calculated by tumor volume):
  • T and C are the tumor volumes of the treatment group and the control group at the end of the experiment, respectively; T0 and C0 are the tumor volumes of the treatment group and the control group at the beginning of the experiment, respectively.
  • tumor inhibition rate ie tumor growth inhibition rate
  • P ⁇ 0.05 tumor inhibition rate
  • Model control group on D0 (15 days after inoculation and modeling, group administration began), D7 (7 days after group administration), D14, and D20, the tumor volumes were 181.21 ⁇ 67.42mm 3 , 498.14 ⁇ 136.65mm 3 , 796.39 ⁇ 121.96mm mm 3 and 1161.48 ⁇ 168.3mm 3 .
  • Vehicle control group on D0, D7, D14 and D20, the tumor volumes were 172.7 ⁇ 57.27mm 3 , 625.95 ⁇ 222.89mm 3 , 1202.55 ⁇ 509.6mm 3 and 1387.18 ⁇ 506.07mm 3 , compared with the same period model at D7, D14 and D20 There was no statistical difference between the groups (p>0.05).
  • the tumor volumes were 180.67 ⁇ 52.45mm 3 , 299.38 ⁇ 110.7mm 3 , 302.72 ⁇ 130.68mm 3 and 250.29 ⁇ 83.45mm 3 .
  • intraperitoneal injection of mitomycin and KDR2-2 suspension can inhibit the tumor volume of HT-29.
  • 5mg/kg mitomycin can significantly inhibit or even reduce the tumor volume.
  • the inhibitory effect of KDR2-2 suspension on tumor volume can be seen in a certain dose-response relationship.
  • the low dose of 10mg/kg KDR2-2 suspension The inhibitory effect is slightly weak, and the high dose of 100mg/kg KDR2-2 suspension has a very strong inhibitory effect.
  • n indicates the number of animals included in the statistical analysis.
  • RTV Relative tumor volume
  • Solvent control group On D7, D14 and D20, the RTVs were 3.73 ⁇ 0.97, 6.91 ⁇ 1.24 and 8.19 ⁇ 1.79, respectively, and there was no statistical difference compared with the model control group during the same period (p>0.05).
  • the RTVs were 2.44 ⁇ 0.40, 3.86 ⁇ 1.15 and 5.4 ⁇ 2.46, respectively.
  • D7 there was no statistical difference compared with the model control group and the same period (p>0.05), and compared with the solvent control group and the positive control group during the same period, the RTV was reduced and there was a significant statistical difference (p ⁇ 0.05, p ⁇ 0.05) ;
  • p>0.05, p>0.05 There was no statistical difference (p>0.05, p>0.05) compared with the model control group and the solvent control group at the same period on D14, and the RTV was reduced compared with the positive control group and there was a significant statistical difference (p ⁇ 0.05) ;
  • D20 There was no statistical difference in D20 compared with the model control group, solvent control group and positive control group (p>0.05).
  • the RTVs were 1.64 ⁇ 0.19, 1.63 ⁇ 0.3 and 1.32 ⁇ 0.33, respectively.
  • the RTV all decreased and had significant statistical differences (p ⁇ 0.01, p ⁇ 0.01, p ⁇ 0.01, p ⁇ 0.01, p ⁇ 0.001)
  • the RTV all decreased and had significant statistical differences (p ⁇ 0.001, p ⁇ 0.001, p ⁇ 0.01)
  • RTV average relative tumor volume
  • n indicates the number of animals included in the statistical analysis.
  • Solvent control group at D7, D14 and D20, T/C were 127.88%, 142.87% and 105.33%, respectively.
  • the low dose group of the test product on D7, D14 and D20, T/C were 83.20%, 80.17% and 69.42% respectively.
  • T/C were 56.73%, 34.03% and 16.98% respectively.
  • T/C (%) > 40% is invalid; T/C (%) ⁇ 40%, and compare p ⁇ 0.05 to be effective curative effect evaluation standard with model group through analysis of variance, positive control drug mitomycin ( 5mg/kg) and high-dose test product KDR2-2 suspension (100mg/kg) all reach effective evaluation standard, show that mitomycin and KDR2-2 suspension all can effectively inhibit HT-29 tumor under this condition proliferation.
  • the average tumor weight of the model control group was 0.82 ⁇ 0.23g.
  • the average tumor weight of the solvent control group was 0.92 ⁇ 0.25g, which was not significantly different from that of the model control group (p>0.05).
  • the average tumor weight of the positive control group was 0.47 ⁇ 0.05g, which was smaller than that of the model control group and the solvent control group with significant statistical difference (p ⁇ 0.05, p ⁇ 0.01).
  • the average tumor weight of the low-dose group of the test product was 0.63 ⁇ 0.16g, which had no statistical difference compared with the model control group and the positive control group (p>0.05), and decreased compared with the solvent control group and had statistically significant There were no statistical differences (p ⁇ 0.05).
  • the average tumor weight of the high-dose group of the test product was 0.18 ⁇ 0.05g, which was significantly reduced compared with the model control group, the solvent control group, the positive control group and the low-dose group of the test product (p ⁇ 0.001 , p ⁇ 0.001, p ⁇ 0.05, p ⁇ 0.001).
  • n indicates the number of animals included in the statistical analysis.
  • Solvent control group the tumor inhibition rate was -5.33% (calculated by tumor volume) and -11.65% (calculated by tumor weight).
  • tumor inhibition rate was 45.88% (calculated by tumor volume) and 43.50% (calculated by tumor weight).
  • the low-dose group of the test product was 30.58% (calculated by tumor volume) and 23.99% (calculated by tumor weight).
  • the high-dose group of the test product was 83.02% (calculated by tumor volume) and 78.39% (calculated by tumor weight).
  • tumor inhibition rate i.e. tumor growth inhibition rate
  • p ⁇ 0.05 is an effective efficacy evaluation standard
  • positive control drug mitomycin 5mg/kg
  • high-dose test product KDR2-2 suspension 100mg/kg
  • Model control group on D0, D7, D14 and D20, the body weight was 21.96 ⁇ 1.45g, 22.48 ⁇ 1.58g, 21.44 ⁇ 2.25g and 21.08 ⁇ 3.15g.
  • Solvent control group on D0, D7, D14 and D20, the body weight was 23.02 ⁇ 0.99g, 22.94 ⁇ 0.88g, 22.9 ⁇ 0.94g and 22.42 ⁇ 0.87g, compared with the model control group at the same period on D0, D7, D14 and D20 There was no statistical difference (p>0.05).
  • Positive control group on D0, D7, D14 and D20, the body weight was 21.54 ⁇ 0.27g, 20.42 ⁇ 0.94g/18.52 ⁇ 0.97g and 17.7 ⁇ 1.41g.
  • the model control group and the solvent control group in the same period at D7 there was a significant statistical difference (p ⁇ 0.05, p ⁇ 0.01); at D14, compared with the model control group and the solvent control group in the same period, the And there is a significant statistical difference (p ⁇ 0.01, p ⁇ 0.001); compared with the model control group at the same time, there is a decrease and a significant statistical difference (p ⁇ 0.05) at D20, but the death of the animal makes the group There are only two individual data, so the statistical data is not very meaningful.
  • the low-dose group of the test product on D0, D7, D14 and D20, the body weight was 22.01 ⁇ 1.23g, 21.79 ⁇ 1.23g, 21.97 ⁇ 1.54g and 21.45 ⁇ 1.55g.
  • solvent control group and positive control group there was no statistical difference (p>0.05) at D7; there was no statistical difference compared with the same period model control group and solvent control group at D14 and D20 (p >0.05), compared with the positive control group in the same period, the body weight increased and there was a significant statistical difference (p ⁇ 0.001, p ⁇ 0.05).
  • the sample size of the positive control group was too small at D20, and the statistical significance was not significant.
  • the high-dose group of the test product on D0, D7, D14 and D20, the body weight was 22.29 ⁇ 1.11g, 20.21 ⁇ 1.18g, 17.29 ⁇ 1.17g and 15.03 ⁇ 0.46g.
  • the body weight all decreased and there was a significant statistical difference (p ⁇ 0.01, p ⁇ 0.001, p ⁇ 0.05) at D7, compared with the same period of positive control group There was no statistical difference (p>0.05); when D14 and D20, compared with the model control group, the solvent control group, and the low-dose group of the test product, the body weight all decreased and there was a significant statistical difference (p ⁇ 0.001, p ⁇ 0.001, p ⁇ 0.001), there was no statistical difference compared with the positive control group in the same period (p>0.05).
  • the intraperitoneal injection of the positive control drug mitomycin and the high-dose test product 100mg/kg KDR2-2 suspension can significantly reduce the body weight of the animals.
  • the positive control group mitomycin 5 mg/kg
  • n indicates the number of animals included in the statistical analysis.
  • mice Adult male C57BL/6 mice (7-8 weeks) were purchased from the Experimental Animal Center of Sun Yat-sen University, and KDR2-2 was administered 2 weeks after gamma knife irradiation (to induce glioma formation). The doses of 10 and 80 mg/kg body weight were continuously administered for 4 weeks.
  • KDR2-2 suspension (specification: 0.4mL: 4.0mg, the preparation is the same as in Example 2).
  • the vehicle control without drug was placebo.
  • KDR2-2 test sample is the same as in Example 2.
  • KDR2-2-L represents the KDR2-2 low-dose group
  • KDR2-2-H represents the KDR2-2 high-dose group.
  • Number of animals 10 animals/group in the model group, 10 animals/group in the solvent control group, and 10 animals/group in each of the high and low dose groups.
  • Administration route intraperitoneal injection; administration frequency: 1 time/day
  • MRI detection detect the size of edema focus at 1w, 2w, 4w, and 6w after irradiation
  • Fig. 6 shows MRI images of mouse brains treated with KDR2-2.
  • Figure 7 shows the lesion volume in mice treated with KDR2-2.
  • Figure 8 shows the body weight of mice treated with KDR2-2.
  • Figure 9 demonstrates graying of mouse hair after treatment with KDR2-2.

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Abstract

La présente demande concerne une méthode de traitement du cancer, comprenant l'administration à un sujet en ayant besoin d'une quantité thérapeutiquement efficace d'un composé de formule I ou d'un variant isotopique, d'un tautomère, d'un sel de qualité pharmaceutique, d'un solvate ou d'un hydrate de celui-ci. La présente demande concerne en outre l'utilisation d'un composé de formule I ou d'un variant isotopique, d'un tautomère, d'un sel de qualité pharmaceutique, d'un solvate ou d'un hydrate de celui-ci pour le traitement du cancer. Le cancer est un cancer du côlon, un gliome cérébral, un cancer du foie, un cholangiocarcinome intra-hépatique/extra-hépatique, un cancer de la vésicule biliaire, un cancer du tractus biliaire, un cancer du rein/un carcinome des cellules rénales, un adénocarcinome de la jonction gastrique/gastro-œsophagienne, une tumeur stromale gastro-intestinale, une tumeur solide, un cancer colorectal, un cancer du poumon à petites cellules/non à petites cellules, un cancer de la thyroïde local à un stade avancé ou métastatique différencié/un cancer myéloïde de la thyroïde, un lymphome diffus à grandes cellules B, une tumeur de la tête et du cou et une tumeur thoracique, une tumeur osseuse maligne primaire, un mélanome malin, une tumeur neuroendocrine pancréatique, un carcinome urothélial, un gastrinome, une tumeur cellulaire, un insulinome ou un cancer du col de l'utérus.
PCT/CN2023/073851 2022-01-30 2023-01-30 Méthode de traitement du cancer WO2023143611A1 (fr)

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Citations (3)

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WO2014166386A1 (fr) * 2013-04-09 2014-10-16 广州康睿生物医药科技有限公司 Composé anti-angiogenèse, intermédiaire et son utilisation
WO2021213512A1 (fr) * 2020-04-24 2021-10-28 Guangzhou Kangrui Biological Pharmaceutical Technology Co., Ltd. Formulation pour le traitement d'affections ophtalmiques
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CN113747920A (zh) * 2019-04-26 2021-12-03 株式会社益力多本社 使用喹啉甲酰胺衍生物的免疫检查点抑制剂并用疗法
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