Arylboron compounds, their preparation methods and applications, and pharmaceutical compositions

Abstract

An arylboron compound, its preparation method, applications, and pharmaceutical compositions are disclosed for tumor imaging. The compound of formula (I) exhibits high fluorescence quantum efficiency through intramolecular charge transfer. The compound of formula (I) synthesized in this invention can be linked to different antibodies via Q3 at certain concentrations, allowing for precise targeting of corresponding tumors based on the antibody. This type of boron drug formulation can be used in boron neutron capture therapy to kill tumor cells. It exhibits better killing effects; the compound of formula (I) targets tumor cells through antigen-antibody interaction. After the boron-10-containing drug accumulates at the tumor site, neutron radiation triggers a nuclear reaction releasing alpha particles and... 7 Lithium particles kill cells; the range of these two particles is approximately 10 μm. High-energy-density heavy ions disrupt the DNA double helix structure in tumor cells, causing irreparable cell death. Simultaneously, the 10 μm distance avoids damage to normal cells and tissues.

Description

Technical Field

[0001] This invention relates to the field of biomaterials technology, specifically to arylborane compounds, their preparation methods and applications, and pharmaceutical compositions. Background Technology

[0002] Common malignant tumors include colorectal cancer, thyroid cancer, liver cancer, stomach cancer, and breast cancer. The lifetime cancer rate is approximately 28.9%, meaning about one in three to four people will develop cancer. Currently, traditional treatments such as surgery, chemotherapy, and radiotherapy play a cornerstone role in prevention and treatment. However, these methods cannot effectively eradicate the lesions. Modern medicine is continuously optimizing treatment plans through multidisciplinary collaboration and precision medicine strategies, bringing more hope to patients.

[0003] Boron neutron capture therapy (BNCT) is a binary targeted radiotherapy technique in the field of nuclear medicine. After a boron-10-containing drug accumulates at the tumor site, neutron irradiation triggers a nuclear reaction that releases alpha and lithium particles to kill cells. This technique has a treatment range of approximately 10 μm, precisely destroying cancer cell DNA without affecting normal tissue cells. Currently, some boron preparations are used for head and neck cancer, melanoma, and breast cancer. With the continuous improvement of neutron source technology, more specific targeted molecular drugs will emerge, making BNCT a promising first-line treatment for malignant tumors. Summary of the Invention

[0004] To address the technical deficiencies of existing technologies, this invention provides an arylboron compound, its preparation method and application, and a pharmaceutical composition thereof.

[0005] The technical solution adopted in this invention is: an arylboron compound and its racemic, stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt, as shown in Formula I:

[0006]

[0007] Q1 and Q2 may be the same or different, and are selected independently from each other. , , , One or more of them; Q3 is selected from , , , One of them; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R14 R 15 R 16 They are either the same or different, and are independently selected from H, F, Cl, Br, I, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-C(O)NH-, C 1-6 Alkyl-C(O)O-, C 6-14 Aryl, 3-12 membered heterocyclic group, C 6-14 aryl-NH-, 5-14-membered heteroaryl-NH-, 3-12-membered heterocyclic-O-, C 6-14 One or more of aryl-O- and 5-14 heteroaryl-O-; Y1 is selected from O and S; Y2 is selected from N, O and S. n, m, z are 0, 1, 2, 3.

[0008] The Q3 mentioned is selected from , , , Or one of H.

[0009] The R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 It is one or more of F, Cl, Br, I, H, CH3, and CH2CH3.

[0010] The R mentioned 13 R 14 R 15 R 16 It is one or more of F, Cl, Br, I, H, CH3, CH2CH3, OCH3, N(CH3)2, and NHCH3.

[0011] Term "C" 1-6 "Alkyl" means a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers.

[0012] Term "C" 6-14 "Aryl" should preferably be understood to refer to a monocyclic, bicyclic, or tricyclic hydrocarbon ring having 6-14 carbon atoms and exhibiting monovalent aromaticity or partial aromaticity. 6-14 "Aryl" should be understood to preferably represent a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring ("C") having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. 6-14 Aryl), particularly a ring with 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl; or a ring with 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl; or a ring with 10 carbon atoms (“C9 aryl”). 10 Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or rings with 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups, or rings with 14 carbon atoms (“C”). 14 Aryl), for example, anthracene.

[0013] Term "5" "14-membered heteroaryl" should be understood as containing 5 14 ring atoms, or 5 12 ring atoms, or 5 10 ring atoms, or 5 Monocyclic, bicyclic, and tricyclic systems with six ring atoms, wherein at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms (e.g., N, O, S, Se, etc.), wherein each ring system contains 5 A seven-atom ring, with one or more bonding sites connected to the rest of the molecule. The heteroaryl group is optionally substituted with one or more substituents described in this invention. In some embodiments, 5 The 10-atom heteroaryl group comprises 1, 2, 3, or 4 heteroatoms independently selected from O, S, Se, and N. In other embodiments, 5 A heteroaryl group consisting of six atoms contains one, two, three, or four independent heteroatoms selected from O, S, Se, and N. Monocyclic examples of heteroaryl groups include, but are not limited to, thiophene, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazole, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and thiazolyl. 4H Pyrazolyl and their benzo[derivatives], such as benzofuranyl, benzothiophenyl, benzooxazolyl, benzoisooxazolyl, benzoimidazoyl, benzotriazolyl, indazole, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo[derivatives], such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or acrylonitrileyl, inazinyl, purineyl, etc., and their benzo[derivatives]; or terpineyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphridinyl, pteridinyl, carbazoyl, acridineyl, phenazinyl, phenothiazinyl, phenothiazinyl, etc.

[0014] Term "3" "12-membered heterocyclic group" refers to a monocyclic, bicyclic, or tricyclic system in which one or more atoms on the ring are independently and optionally replaced by heteroatoms. The ring can be fully saturated or contain one or more unsaturated atoms, but is not aromatic. It has one or more linkage sites attached to other molecules, preferably "3". "8-membered heterocyclic group". One or more hydrogen atoms on the ring may be independently unsubstituted or substituted by one or more substituents described in this invention. In some embodiments, the "heterocyclic group" is 3 A single ring composed of 7 atoms, or 7 A double ring composed of 10 atoms contains 1 5, 1 preferred Three heteroatoms selected from N, O, S, and Se. Specifically, the heterocyclic group may include, but is not limited to: four-membered rings, such as azirrobutyl or oxobutyl; five-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolyl, or pyrrololinyl; or six-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl, or trithiaalkyl; or seven-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group may be benzofused. The heterocyclic group may be bicyclic, for example, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopentano[c]pyrrole. 2(1H) The base ring, or a 5,6-membered bicyclic ring, such as hexahydropyrrolo[1,2] a] Pyrazine 2(1H) Basic ring. A nitrogen-containing ring can be partially unsaturated, meaning it can contain one or more double bonds, such as, but not limited to, 2,5-dioxane. Dihydrogen 1H Pyrrole, 4H [1,3,4]thiadiazinyl, 4,5 Dihydrooxazolyl or 4H [1,4]thiazinyl, or it can be benzofused, for example, but not limited to, dihydroisoquinolinyl, 1,3 Benzoxazolyl, 1,3 Benzodioxanepentenyl.

[0015] Unless otherwise stated, heterocyclic and heteroaryl groups include all their possible isomers, such as their positional isomers. Therefore, for some illustrative, non-limiting examples, pyridyl or pyridylene groups include pyridine. 2 pyridine 2 pyridine 3 pyridine 3 pyridine 4 pyridine and pyridine 4 Thiophene or thiophene groups, including thiophene. 2 basalt, thiophene 2 basalt, thiophene 3 methyl and thiophene 3 base.

[0016] The arylborane compounds described above have the following structures:

[0017] A method for preparing the aforementioned arylboron compound, wherein the reaction formula is as follows: ; Step a is as follows: reacting compound (VI) with boron trifluoride diethyl ether (BF3·Et2O) solution to obtain compound (V); Step b is: to mix compound (V) with... The reaction yields compound (IV); Step c is: reacting compound (IV) with Q1 and Q2 to obtain compound (III); Step d is: reacting compound (III) under alkaline conditions to obtain compound (II); Step e is as follows: when Q3 is absent, the compound shown in formula (I) is obtained; when Q3 is present, compound (II) is further reacted with... The reaction yields the compound shown in formula (I); In compound (VI-I), Ln, L1, L2, and L3 are selected from F, Cl, Br, and I; Q1 and Q2 may be the same or different and are independently selected from each other. , , , One or more of them; Q3 is selected from , , , One of them; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 They are either the same or different, and are independently selected from H, F, Cl, Br, I, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-C(O)NH-, C 1-6 Alkyl-C(O)O-, C 6-14 Aryl, 3-12 membered heterocyclic group, C 6-14 aryl-NH-, 5-14-membered heteroaryl-NH-, 3-12-membered heterocyclic-O-, C 6-14 One or more of aryl-O- and 5-14 heteroaryl-O-; Y1 is selected from O and S; Y2 is selected from N, O and S. n, m, z are 0, 1, 2, 3.

[0018] The reaction in step a is carried out under conditions of an organic solvent or an organic base. The preferred organic solvents are n-hexane, diethyl ether, and methyl tert-butyl ether; the organic base may be selected from at least one of n-butyllithium, tert-butyllithium, methyllithium, and phenyllithium. In step a, the molar ratio of compound (VI) to boron trifluoride ether (BF3·Et2O) is 1:(2-10), preferably 1:4.

[0019] In step a, the reaction temperature is -80 to 0°C, and the reaction time is 10 to 48 hours, preferably -78°C, and more preferably 24 hours.

[0020] In step b, the reaction is carried out in the presence of a solvent, which can be an organic solvent, preferably tetrahydrofuran, toluene, or 1,4-dioxane. The reaction in step b is carried out under a palladium catalyst, which is at least two of tetra(triphenylphosphine)palladium, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, and Lindra reagent.

[0021] In step b, the reaction is carried out under alkaline conditions, preferably at least one of sodium tert-butoxide, potassium carbonate, sodium carbonate, and cesium carbonate; In step b, compound (V) and The molar ratio is 1:(1-2), preferably 1:1.

[0022] In step b, the molar ratio of compound (V) to palladium catalyst is 1:(1-2), preferably 1:1.5.

[0023] In step b, the reaction temperature is 60-120℃, for example 100℃, and the reaction time is 6-24h, for example 12h.

[0024] In step c, the reaction is carried out in the presence of a solvent, which can be an organic solvent, preferably tetrahydrofuran, 1,4-dioxane, or toluene; In step c, the reaction is carried out in the presence of an inorganic base, which may be selected from at least one of potassium carbonate, sodium carbonate, and cesium carbonate. In step c, the reaction is carried out under a catalyst, which is at least two of tetra(triphenylphosphine)palladium, tris(dibenzylacetone)dipalladium, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, and 2-dicyclohexylphosphine-2,6'-diisopropoxy-1,1'-biphenyl. The molar ratio of compound (IV) to the catalyst is 1:(0.1-0.5), preferably 1:0.18.

[0025] In step c, the molar ratio of compound (IV) to Q1 and Q2 heteroalicylic rings is 1:(1-4), preferably 1:2.

[0026] In step c, the molar ratio of compound IV to the inorganic base is 1:(2-10), preferably 1:4.5; In step c, the reaction temperature is 60-120℃, for example 100℃, and the reaction time is 6-24h, for example 12h.

[0027] In step d, the reaction is carried out in the presence of a solvent, which can be an organic solvent, preferably at least two of 1,4-dioxane, tetrahydrofuran, and water. In step d, the reaction is carried out under an inorganic base, preferably at least one of sodium tert-butoxide, potassium carbonate, lithium hydroxide, and cesium carbonate; In step d, compound (III) reacts with an inorganic base in a molar ratio of 1:(1-10), preferably 1:8; In step d, the reaction temperature is 0-60℃, for example 30℃, and the reaction time is 3-12h, for example 6h.

[0028] In step e, the reaction is carried out in the presence of a solvent, which can be an organic solvent, preferably dichloromethane or N,N-dimethylformamide; In step e, the reaction is carried out in the presence of an organic base, which may be triethylamine or diisopropylethylamine. The reaction in step e is carried out in the presence of a condensing agent, which is one of dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, diisopropylcarbodiimide, or 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.

[0029] In step e, the reaction temperature is 0-50℃, for example 25℃, and the reaction time is 6-20h, for example 10h.

[0030] In steps a, b, c, d, and e, the organic solvent may be selected from at least one of the following: alcohols, such as methanol, ethanol, isopropanol, and n-butanol; ethers, such as ethyl propyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dimethyl ethylene glycol, biphenyl ether, propyl ether, isopropyl ether, isobutyl ether, isopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, and polyethers of ethylene oxide and propylene oxide; lipids. Aliphatic, cycloaliphatic, or aromatic hydrocarbons, such as pentane, hexane, heptane, octane, nonane, and hydrocarbons that may be substituted with fluorine or chlorine atoms, such as methylene chloride, dichloromethane, trichloromethane, carbon tetrachloride, fluorobenzene, chlorobenzene, or dichlorobenzene, cyclohexane, methylcyclohexane, petroleum ether, acetone, octane, benzene, toluene, bromobenzene, and xylene; esters such as ethyl acetate, butyl acetate, isobutyl acetate, and dimethyl carbonate, dibutyl carbonate, or ethylene carbonate.

[0031] The compound (IV) in the reaction is a commercially available compound. The compounds (V), (VI), (III), (II), and (I) obtained from the above reaction can be separated and purified by normal-phase silica gel column chromatography.

[0032] The present invention also provides the use of arylboron compounds, their racemates, stereoisomers, tautomers, isotope labels, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds in the preparation of antitumor drugs.

[0033] According to an embodiment of the present invention, the type of tumor can be various tumors such as lung cancer, colon cancer, breast cancer, cholangioma, melanoma, pancreatic cancer, and liver cancer.

[0034] The present invention also provides a pharmaceutical composition comprising at least one of an arylborane compound, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound thereof in a therapeutically effective amount.

[0035] According to embodiments of the present invention, the pharmaceutical composition further includes one or more pharmaceutically acceptable excipients.

[0036] According to embodiments of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0037] The present invention also provides the use of arylborane compounds in killing tumors, such as their use in in vivo boron neutron capture therapy for antitumor activity.

[0038] According to an embodiment of the present invention, the tumor may be breast cancer or lung cancer.

[0039] According to an embodiment of the present invention, all detections are performed in PBS buffer solution.

[0040] This invention also provides bright-field images of arylborane compounds in antitumor imaging.

[0041] The beneficial effects of this invention are as follows: This invention provides an arylboron compound, its preparation method, applications, and pharmaceutical compositions for tumor imaging. Through intramolecular charge transfer, the general formula (I) compound exhibits high fluorescence quantum efficiency. The formula (I) compound synthesized in this invention can be linked to different antibodies via Q3 at certain concentrations, allowing for precise targeting of corresponding tumors based on the antibody. This type of boron drug formulation can be used in boron neutron capture therapy to kill tumor cells. It has a better killing effect; the formula (I) compound targets tumor cells through antigen-antibody interaction. After the boron-10-containing drug accumulates at the tumor site, neutron radiation triggers a nuclear reaction that releases alpha particles and... 7 Lithium particles kill cells; the range of these two particles is approximately 10 μm. High-energy-density heavy ions disrupt the DNA double helix structure in tumor cells, causing irreparable cell death. Simultaneously, the 10 μm distance avoids damage to normal cells and tissues. Attached Figure Description

[0042] Figure 1 A diagram illustrating the therapeutic mechanism of the compound prepared in Example 9 against cancer cells; Figure 2 This is the synthesis route diagram for Example 9; Figure 3 This is the in vitro absorption spectrum of Example 9 in water.

[0043] Figure 4 This is a diagram showing the biosafety test results of Example 9 in HEK293 cells.

[0044] Figure 5 Example 9 shows the anti-tumor effect after neutron capture therapy. Detailed Implementation

[0045] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0046] Example 1 Preparation of compound (1) 5-Bromo-2-iodo-m-xylene (16 mmol, 5 g) was added to a flask, and anhydrous diethyl ether solution was added using a disposable syringe under nitrogen protection. The flask was cooled to -78 °C, and n-butyllithium (16.96 mmol, 6.8 mL) was slowly added dropwise. The reaction was then brought back to room temperature and maintained for 20 min. The flask was cooled to -78 °C again, and 0.63 mL of boron trifluoride diethyl ether solution (5 mmol, 0.63 mL) was added. After returning to room temperature, the reaction was allowed to proceed for 12 h. After the reaction was complete, the solvent was evaporated under vacuum, and then extracted three times with dichloromethane and saturated brine. The mixture was dried over anhydrous magnesium sulfate, and the organic solvent was removed under vacuum to obtain 3 g of a pale yellow solid. 1 H NMR (400 MHz, MeOD) δ7.29 (s, J = 7.7 Hz, 6H), 2.08 (s, 6H), 2.01 (d, J = 15.3 Hz, 12H).

[0047] Example 2 Preparation of compound 2 Compound 1 (9.14 mmol, 5.14 g), 4-(methoxycarbonylmethyl)-2,3,4,5-tetramethylphenylboronic acid pinacol ester (7.77 mmol, 2.58 g), and tetra(triphenylphosphine palladium) (0.475 mmol, 0.528 g) were added to a flask, followed by the addition of tetrahydrofuran (45 mL) under a nitrogen atmosphere, and then 45 mL of an aqueous solution containing potassium carbonate (45.7 mmol, 6.3 g). The mixture was heated to reflux for 12 h. After the reaction was complete, the mixture was extracted three times with dichloromethane and water, dried over anhydrous magnesium sulfate, and the organic solvent was removed under vacuum. The crude product obtained by rotary evaporation of the organic phase was purified by silica gel column chromatography using petroleum ether / ethyl acetate (8:1, v / v) as the developing solvent, finally yielding 1.48 g of a pale yellow compound. 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 7.7 Hz, 2H), 7.34(d, J= 7.8 Hz, 2H), 7.18 (s, 2H), 7.12 (s, 4H), 3.71 (s, 3H), 3.67 (s, 2H), 2.61(s, 6H), 2.18(s, 6H), 2.06 (s, 6H), 2.01 (d, J = 4.7 Hz, 12H).

[0048] Example 3 Preparation of compound (3) Compound 1 (9.14 mmol, 5.14 g), 4-(methoxycarbonylmethyl)phenylboronic acid pinacol ester (7.77 mmol, 2.15 g), and tetrakis(triphenylphosphine palladium) (0.475 mmol, 0.528 g) were added to a flask, followed by tetrahydrofuran (45 mL) and an aqueous solution of potassium carbonate (45.7 mmol, 6.3 g) (45 mL). The mixture was heated to reflux for 12 h. After the reaction was complete, the mixture was extracted three times with dichloromethane and water, dried over anhydrous magnesium sulfate, and the organic solvent was removed under vacuum. The crude product obtained by rotary evaporation of the organic phase was purified by silica gel column chromatography using petroleum ether / ethyl acetate (8:1, v / v) as the developing solvent, finally yielding 1.36 g of a pale yellow compound. 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 7.7 Hz, 2H), 7.34 (d, J = 7.8 Hz, 2H), 7.18 (s,2H), 7.12 (s, 4H), 3.71 (s, 3H), 3.67 (s, 2H), 2.06 (s, 6H), 2.01 (d, J = 4.7Hz, 12H).

[0049] Example 4 Preparation of compound (4) Compound 3 (2 mmol, 1.26 g), cesium carbonate (8.97 mmol, 2.92 g), 2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (0.359 mmol, 0.167 g), and tris(dibenzylacetone)dipalladium (0.09 mmol, 0.16 g) were placed in a two-necked flask. Under nitrogen protection, 1,4-dioxane (25 mL) and tetrahydropyrrole (4.59 mmol, 0.378 mL) were added, and the mixture was heated to reflux for 12 h. The mixture was extracted three times with dichloromethane and water, dried over anhydrous magnesium sulfate, and the organic solvent was removed under vacuum. The crude product obtained by rotary evaporation of the organic phase was purified by silica gel column chromatography using petroleum ether / ethyl acetate (6:1, v / v) as the developing solvent, finally yielding 1.12 g of a yellow compound. 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 7.3 Hz, 2H), 7.32 (d, J = 7.6Hz, 2H), 7.15 (s, 2H), 6.47 (s, 4H), 3.41 (t, J = 4.0 Hz, 8H), 3.70 (s, 3H), 3.66 (s, 2H), 2.64 (d, J = 5.7 Hz, 8H), 2.08 (s, 6H), 2.01 (d, J = 15.3 Hz, 12H).

[0050] Example 5 Preparation of compound (5) Compound 3 (2 mmol, 1.26 g), cesium carbonate (8.97 mmol, 2.92 g), 2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (0.359 mmol, 0.167 g), and tris(dibenzylacetone)dipalladium (0.09 mmol, 0.16 g) were placed in a two-necked flask. Under nitrogen protection, 1,4-dioxane (25 mL) and morpholine (4.59 mmol, 0.4 mL) were added, and the mixture was heated to reflux for 12 h. The mixture was extracted three times with dichloromethane and water, dried over anhydrous magnesium sulfate, and the organic solvent was removed under vacuum. The crude product obtained by rotary evaporation of the organic phase was purified by silica gel column chromatography using petroleum ether / ethyl acetate (5:1, v / v) as the developing solvent, finally yielding 0.96 g of a bright yellow compound. 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 7.3 Hz, 2H), 7.32 (d, J = 7.6Hz, 2H), 7.15 (s, 2H), 6.47 (s, 4H), 3.85 (t, J = 4.0 Hz, 8H), 3.70 (s, 3H), 3.66 (s, 2H), 3.21 (d, J = 5.7 Hz, 8H), 2.08 (s, 6H), 2.01 (d, J = 15.3 Hz, 12H).

[0051] Example 6 Preparation of compound (6) Compound 4 (1.33 mmol, 0.80 g) was placed in a two-necked flask. Under nitrogen protection, a mixed solution of tetrahydrofuran and water (40 mL, v / v = 3:2) was added, followed by lithium hydroxide (10.68 mmol, 0.26 g), and the reaction was carried out at room temperature for 3 h. After the reaction was completed, the organic solvent was removed under vacuum, water was added, and the pH was adjusted to 4 with dilute hydrochloric acid. The compound was filtered to give 0.7 g of a pale yellow solid. 1 H NMR (400 MHz, MeOD) δ 7.59 (d, J = 7.1 Hz, 2H), 7.34 (d, J = 7.8 Hz,2H), 7.18 (s, 2H), 6.54 (s, 4H), 3.41 (t, J = 3.8 Hz, 8H), 3.63 (s, 2H), 2.64(d, J = 4.9 Hz, 8H), 2.07 (s, 6H), 2.00 (d, J = 9.5 Hz, 12H).

[0052] Example 7 Preparation of compound (7)

[0053] Compound 5 (1.33 mmol, 0.86 g) was placed in a two-necked flask. Under nitrogen protection, a mixed solution of tetrahydrofuran and water (40 mL, v / v = 3:2) was added, followed by lithium hydroxide (10.68 mmol, 0.26 g), and the reaction was carried out at room temperature for 3 h. After the reaction was completed, the organic solvent was removed under vacuum, water was added, and the pH was adjusted to 4 with dilute hydrochloric acid. The compound was filtered to give 0.75 g of a pale yellow solid. 1 H NMR (400 MHz, MeOD) δ 7.59 (d, J = 7.1 Hz, 2H), 7.34 (d, J = 7.8 Hz,2H), 7.18 (s, 2H), 6.54 (s, 4H), 3.81 (t, J = 3.8 Hz, 8H), 3.63 (s, 2H), 3.18(d, J = 4.9 Hz, 8H), 2.07 (s, 6H), 2.00 (d, J = 9.5 Hz, 12H).

[0054] Example 8 Preparation of compound (8) Compound 6 (0.793 mmol, 0.47 g) was added to a flask. Under nitrogen protection, 15 mL of dichloromethane solution was added, followed by diisopropylethylamine (3.17 mmol, 0.55 mL), and the mixture was stirred at room temperature for 5–10 min. The flask was then cooled to 0 °C, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.95 mmol, 0.36 g) was added, and the mixture was stirred at 0 °C for 15 min. Finally, 0.95 mmol, 0.168 g of 1-(2-aminoethyl)-1H-pyrrole-2,5-dione was added, and the mixture was stirred at room temperature for 12 h. After the reaction was complete, the mixture was extracted with dilute hydrochloric acid, sodium bicarbonate, saturated brine, and dichloromethane, respectively. The extract was dried over anhydrous magnesium sulfate, and the organic solvent was removed under vacuum. Purified by silica gel column chromatography with petroleum ether / ethyl acetate (1:1.5, v / v) as the developing solvent, 0.65 g of bright yellow compound was finally obtained. 1 H NMR (400 MHz, MeOD) δ 7.97 (s, 2H), 7.57 (d, J = 7.8 Hz, 2H), 7.28 (d, J = 7.7 Hz, 2H), 7.17 (s, 2H), 6.73 (s, 2H), 6.53 (s,4H), 3.41 (t, J = 4.1 Hz, 8H), 3.62 (t, J = 5.2 Hz, 2H), 3.45 (s, 2H), 3.39 (t, J =5.3 Hz, 2H), 2.64 (t, J = 4.7 Hz, 8H), 2.07 (s, 6H), 2.01 (s, 12H).

[0055] Example 9 Preparation of compound (9)

[0056] Compound 7 (0.793 mmol, 0.5 g) was added to a flask. Under nitrogen protection, 15 mL of dichloromethane solution was added, followed by diisopropylethylamine (3.17 mmol, 0.55 mL), and the mixture was stirred at room temperature for 5–10 min. The flask was then cooled to 0 °C, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.95 mmol, 0.36 g) was added, and the mixture was stirred at 0 °C for 15 min. Finally, 0.95 mmol, 0.168 g of 1-(2-aminoethyl)-1H-pyrrole-2,5-dione was added, and the mixture was stirred at room temperature for 12 h. After the reaction was complete, the mixture was extracted with dilute hydrochloric acid, sodium bicarbonate, saturated brine, and dichloromethane, respectively. The extract was dried over anhydrous magnesium sulfate, and the organic solvent was removed under vacuum. Purified by silica gel column chromatography with petroleum ether / ethyl acetate (1:1.5, v / v) as the developing solvent, 0.6 g of bright yellow compound was finally obtained. 1 H NMR (400 MHz, MeOD) δ 7.97 (s, 2H), 7.57 (d, J =7.8 Hz, 2H), 7.28 (d, J = 7.7 Hz, 2H), 7.17 (s, 2H), 6.73 (s, 2H), 6.53 (s,4H), 3.80 (t, J = 4.1 Hz, 8H), 3.62 (t, J = 5.2 Hz, 2H), 3.45 (s, 2H), 3.39 (t, J =5.3 Hz, 2H), 3.17 (d, J = 4.7 Hz, 8H), 2.07 (s, 6H), 2.01 (s, 12H).

[0057] The compound (9) synthesized in Example 9 was used for neutron capture therapy. Experimental procedure: BT-20 cells (5 × 10⁶ cells per mouse) 6 (10 mg / kg cells) were subcutaneously injected into the left thigh of BALB / c mice, and the tumor growth period was approximately 2-3 weeks. After the tumor matured, the drug was injected via the tail vein (10 mg / kg per mouse). The mice were placed on a support frame fixed to a 5 mm thick thermoplastic material containing 40% [the drug's components]. 6 To mitigate the side effects of thermal neutrons, LiF was used. Mice had their left leg placed in the hollow part of the original plate. After 3 hours, they received neutron therapy for 45 minutes at a neutron source intensity of 10 kW. The neutron source was located at the China Spallation Neutron Source in Dongguan City, Guangdong Province, China.

[0058] Experimental results: The drug inhibited the growth of all tumors, and some mice showed a cure for their tumors. Compared to the experimental group, the tumors in the control group continued to grow, showing no significant inhibitory effect.

[0059] Experimental analysis: In the experimental group 10 B was more abundant. 10 B has a larger cross-sectional area, making the drug more easily activated and causing boron neutron capture to release alpha particles. 7 Li particles break the DNA double strand.

[0060] Please note to all technical personnel: Although the present invention has been described according to the specific embodiments above, the inventive concept of the present invention is not limited to this invention. Any modifications that utilize the inventive concept will be included within the scope of patent protection of this patent.

[0061] The above description is merely a preferred embodiment of the present invention. The scope of protection of the present invention is not limited to the above embodiments. All technical solutions falling within the scope of the present invention's concept are within the scope of protection of the present invention. It should be noted that for those skilled in the art, any improvements and modifications made without departing from the principles of the present invention should also be considered within the scope of protection of the present invention.

Claims

1. An arylboron compound and its racemic, stereoisomer, tautomer, isotopic derivative, or pharmaceutically acceptable salt, characterized in that, As shown in Equation I: Q1 and Q2 may be the same or different, and are selected independently from each other. , , , One or more of them; Q3 is selected from , , , One of them; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 They are either the same or different, and are independently selected from H, F, Cl, Br, I, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-C(O)NH-, C 1-6 Alkyl-C(O)O-, C 6-14 Aryl, 3-12 membered heterocyclic group, C 6-14 aryl-NH-, 5-14-membered heteroaryl-NH-, 3-12-membered heterocyclic-O-, C 6-14 One or more of aryl-O- and 5-14 heteroaryl-O-; Y1 is selected from O and S; Y2 is selected from N, O and S. n, m, z are 0, 1, 2, 3.

2. The arylboron compound and its racemic, stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt according to claim 1, characterized in that, The Q3 mentioned is selected from , , , Or one of H.

3. The arylboron compound according to claim 1 and its racemic, stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt, characterized in that, The R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 It is one or more of F, Cl, Br, I, H, CH3, and CH2CH3.

4. The arylboron compound according to claim 1 and its racemate, stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt, characterized in that, The R mentioned 13 R 14 R 15 R 16 It is one or more of F, Cl, Br, I, H, CH3, CH2CH3, OCH3, N(CH3)2, and NHCH3.

5. The arylboron compound according to claim 1 and its racemic, stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt, characterized in that, The arylborane compounds described above have the following structures: 。 6. A method for preparing an arylboron compound according to claim 1, characterized in that, The reaction formula is as follows: ； Step a is as follows: reacting compound (VI) with boron trifluoride diethyl ether (BF3·Et2O) solution to obtain compound (V); Step b is: to mix compound (V) with... The reaction yields compound (IV); Step c is: reacting compound (IV) with Q1 and Q2 to obtain compound (III); Step d is: reacting compound (III) under alkaline conditions to obtain compound (II); Step e is as follows: when Q3 is absent, the compound shown in formula (I) is obtained; when Q3 is present, compound (II) is further reacted with... The reaction yields the compound shown in formula (I); In compound (VI-I), Ln, L1, L2, and L3 are selected from F, Cl, Br, and I; Q1 and Q2 may be the same or different and are independently selected from each other. , , , One or more of them; Q3 is selected from , , , One of them; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 They are either the same or different, and are independently selected from H, F, Cl, Br, I, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-C(O)NH-, C 1-6 Alkyl-C(O)O-, C 6-14 Aryl, 3-12 membered heterocyclic group, C 6-14 aryl-NH-, 5-14-membered heteroaryl-NH-, 3-12-membered heterocyclic-O-, C 6-14 One or more of aryl-O- and 5-14 heteroaryl-O-; Y1 is selected from O and S; Y2 is selected from N, O and S. n, m, z are 0, 1, 2, 3.

7. The preparation method according to claim 6, characterized in that, The reaction in step a is carried out under organic solvent or organic base conditions.

8. The preparation method according to claim 6, characterized in that, In step a, the molar ratio of compound (VI) to boron trifluoride ether (BF3·Et2O) is 1:(2-10).

9. The preparation method according to claim 6, characterized in that, The reaction in step b is carried out under a palladium catalyst, which is at least two of tetra(triphenylphosphine)palladium, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, and Lindra reagent.

10. The preparation method according to claim 6, characterized in that, In step b, compound (V) and The molar ratio is 1:(1-2).

11. The preparation method according to claim 6, characterized in that, In step b, the molar ratio of compound (V) to palladium catalyst is 1:(1-2).

12. The preparation method according to claim 6, characterized in that, The reaction in step c is carried out under a catalyst, which is at least two of tetra(triphenylphosphine)palladium, tris(dibenzylacetone)dipalladium, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, and 2-dicyclohexylphosphine-2,6'-diisopropoxy-1,1'-biphenyl, and the molar ratio of compound (IV) to catalyst is 1:(0.1-0.5).

13. The preparation method according to claim 6, characterized in that, In step c, the molar ratio of compound (IV) to Q1 and Q2 heteroalicylic rings is 1:(1-4).

14. The preparation method according to claim 6, characterized in that, The reaction in step e is carried out in the presence of a condensing agent, which is one of dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, diisopropylcarbodiimide, or 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.

15. The use of an arylboron compound of claim 1 and its racemic, stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt in the preparation of an antitumor drug.

16. The application according to claim 15, characterized in that, The aforementioned anti-tumor drugs are used to treat various tumor cells, including lung cancer, colon cancer, breast cancer, cholangioma, melanoma, pancreatic cancer, and liver cancer.

17. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises at least one of the arylborane compounds of claim 1, and their racemic, stereoisomer, tautomer, isotopic label, or pharmaceutically acceptable salt thereof.

18. The use of an arylboron compound of claim 1 and its racemic, stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt in the preparation of boron preparations for boron neutron capture therapy.

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