CN109928999A - The preparation method and application of boron-containing compound, pharmaceutical composition and boron-containing compound - Google Patents
The preparation method and application of boron-containing compound, pharmaceutical composition and boron-containing compound Download PDFInfo
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Abstract
The invention discloses the preparation method and application of a kind of boron-containing compound, pharmaceutical composition and boron-containing compound.Wherein, the boron-containing compound has general structure (I), and ucleotides substance easily by quick value-added tumour cell huge uptake, thus makes in connection as small molecule needed for DNA synthesis10B atom enters together in the nucleus of tumour cell, and tumour can be more effectively killed after neutron irradiation.Secondly, the boron agent that the present invention synthesizes belongs to a kind of EGF-R ELISA (EGFR) inhibitor, it is generated with BNCT and cooperates with the effect for inhibiting tumour growth, competitively ATP (atriphos) is blocked to combine with receptor tyrosine kinase structural domain, with the function and effect for inhibiting EGFR to over-express, the DNA of tumour cell is hindered to repair, and then inhibits the growth of tumour cell, migration, differentiation and survival.
Description
Technical field
The present invention relates to boron-containing compound fields, and in particular to a kind of boron-containing compound and its preparation method and application.
Background technique
Currently, radiotherapy is to treat a kind of conventional treatments of tumour, but be grown on the special of deep within the body for some
Tumor effect is very poor, and boron neutron capture therapy (Boron Neutron Capture Therapy, BNCT) then has preferably
Effect.BNCT is that one kind is based on10The distinct particle radiation-therapy of B nuclear capture reaction, has treat better than conventional planning in principle
The significant advantage of method.The therapy, which mainly utilizes, contains high neutron-capture cross section10The molecule of B element reacts with neutron, puts
Particle is out to treat tumour.After patient's body injects boron agent,10B can selectively be enriched in tumor locus, be shone by thermal neutron
Penetrate tumour, neutron can be with10Neutron-capture reaction occurs for B, and the alpha energy maximum which radiates only is 2.79Mev, and
Since alpha ray penetration capacity is weak, range is only in 5 μm of -9 μ m, the generally less than average diameter of tumour cell, therefore right
Tumor vicinity without or less enrichment10The normal cell damage of B is smaller.But due to boron agent used in current (such as BPA:
Bisphenol A, bis-phenol base propane), do not have the defects of very strong targeting, accumulation ability is poor, so that BNCT is not
It is widely popularized.
Summary of the invention
The main object of the present invention is to provide a kind of boron-containing compound, it is intended to improve current boron neutron capture therapy and be used
Boron agent do not have the poor problem of very strong targeting, accumulation ability.
To achieve the above object, the present invention proposes a kind of boron-containing compound, has general structure (I):
Wherein, R1For-OH,
R2And R3One of beAnother one is-OH or R2And R3It is
Preferably, the R1For
Preferably, the R2And R3It is
In addition, the present invention also proposes a kind of preparation method of boron-containing compound, comprising the following steps: by reactant and boric acid
Mixing is added in organic solvent and forms mixed solution, heats, product centrifugal filtration is carried out being recrystallized to give precipitating with ethyl alcohol,
The boron-containing compound is obtained after drying；The reactant is that atriphos two is received, adenosine diphosphate (ADP) two is received or monophosphate gland
Glycosides two is received.
Preferably, the reactant is that atriphos two is received.
Preferably, the molar ratio of the reactant and boric acid is 1:15~1:10.
Preferably, the organic solvent is dimethyl sulfoxide.
Preferably, the temperature of the heating is 110~150 DEG C, and the time is 1.5~2h；The temperature of the drying be 80~
90℃。
In addition, the present invention also proposes a kind of pharmaceutical composition, including the above-mentioned any boron-containing compound and pharmacy
Upper acceptable carrier, diluent or auxiliary addition agent.
Furthermore the present invention also proposes that a kind of above-mentioned any boron-containing compound is preparing boron neutron capture therapy tumour
Drug in application.
In technical solution of the present invention, received by using ucleotides substance atriphos two, adenosine diphosphate (ADP) disodium or
Boron agent needed for person's adenosine monophosphate disodium synthesizes BNCT with acid reaction.Firstly, needed for ucleotides substance is synthesized as DNA
Small molecule, easily by quick value-added tumour cell huge uptake, thus make in connection10It is thin that B atom enters tumour together
In the nucleus of born of the same parents, tumour can be more effectively killed after neutron irradiation.Secondly, the boron agent that the present invention synthesizes belongs to a kind of epidermis
Growth factor receptors (EGFR) inhibitor generates with BNCT and cooperates with the effect for inhibiting tumour growth, competitively blocks ATP (three
Adenosine phosphate) it is combined with receptor tyrosine kinase structural domain, with the function and effect for inhibiting EGFR to over-express, hinder tumour thin
The DNA of born of the same parents is repaired, and then inhibits the growth of tumour cell, migration, differentiation and survival.In the process, of the invention to contain boronation
Closing object can also combine with tumour cell, adhere to boron atom largely thereon, provide the foundation for the realization of BNCT.Furthermore
Ester type compound is very advantageous as boron carrier, because they are by enhancing permeability and retention effect, most of
Passive Accumulation in tumour has preferable tumor-targeting.
Detailed description of the invention
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technical description to be briefly described, it should be apparent that, the accompanying drawings in the following description is only this
Some embodiments of invention for those of ordinary skill in the art without creative efforts, can be with
The structure shown according to these attached drawings obtains other attached drawings.
Fig. 1 is the infrared detection figure of the embodiment of the present invention 1；
Fig. 2 is that the nuclear-magnetism of the embodiment of the present invention 1 detects figure；
Fig. 3 is the Mass Spectrometer Method figure of the trinosin of the embodiment of the present invention 1；
Fig. 4 is the atriphos diborate Mass Spectrometer Method figure of the embodiment of the present invention 1；
Fig. 5 is that the atriphos diborate of the embodiment of the present invention 1 inhibits the autophosphorylation Western Blot of EGFR
Schematic diagram；
Fig. 6 is cell irradiation and the tumor tissues irradiation experiment flow diagram of the embodiment of the present invention；
Fig. 7 is the A549 cancer cell neutron spoke after various concentration ATP borate, BPA, the boric acid contamination of the embodiment of the present invention
According to rear cell survival rate comparison diagram；
Fig. 8 is curve graph of the cell strain irradiation survival rate for not adding sensitizer of the embodiment of the present invention as control；
Fig. 9 is that the TUNEL of the nude mouse tumor histotomy of the embodiment of the present invention detects figure.
Specific embodiment
The technical scheme in the embodiments of the invention will be clearly and completely described below, it is clear that described implementation
Example is only a part of the embodiments of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, this field is general
Logical technical staff every other embodiment obtained without creative efforts belongs to what the present invention protected
Range.
It in addition, the technical solution between each embodiment of the present invention can be combined with each other, but must be general with this field
Based on logical technical staff can be realized, it will be understood that when the combination of technical solution appearance is conflicting or cannot achieve this
The combination of technical solution is not present, also not the present invention claims protection scope within.
The invention proposes a kind of boron-containing compounds, have general structure (I):
Wherein, R1For-OH,
R2And R3One of beAnother one is-OH or R2And R3It isBoron-containing compound adenosine phosphate borate of the invention belongs to EGFR inhibitor, itself had both had
Anti-tumor biological, and damage is generated free radicals to radiation have sensitization, and can more be enriched in the quick of tumour cell
Feel on target spot, keeps BNCT selectivity higher, more sensitive eradiation kills cell.
The compound of the present invention includes all stereoisomers, geometric isomer, the tautomerism for meeting general structure (I)
Body, wherein each atom includes the case where all isotopes.When there is one or more chiral centres in molecule, general structure
(I) compound can be pharmaceutically acceptable racemic mixture form or single stereoisomers form.
Boron-containing compound of the invention further includes tautomeric forms.Tautomeric forms from singly-bound with
Adjacent double bond exchanges and together with the migration of a proton.
Boron-containing compound of the invention further includes the atom of all isotopes, either in intermediate or last chemical combination
Object.The atom of isotope includes atomicity having the same, but different quality number.For example, the isotope of hydrogen includes tritium and deuterium.
Boron-containing compound of the invention can also exist as a pharmaceutically acceptable salt form.Pharmaceutically acceptable salt
Refer to the form for the group in parent compound being converted into salt.The form of pharmaceutically acceptable salt can be inorganic acid shape
At salt (such as hydrochloride, sulfate, sulfonate), be also possible to amine formed ammonium salt (such as triethylamine salt, piperidinium salt or
Alkaline medicine etc.), it is also possible to the metal salt (such as sodium salt, sylvite, calcium or magnesium salts) formed with alkali or alkaline earth metal.
Pharmaceutically acceptable salt of the present invention can be synthesized by parent compound, i.e., the basic group in parent compound with
The acid of 1-4 equivalent reacts in a solvent system.Pharmaceutically acceptable acid synthesis salt can be prepared by inorganic and organic acid.
Inorganic acid by derivative acid-addition salts includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc..The organic acid of salt is synthesized by derived acids
Including acetic acid, propionic acid, glycolic, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, lemon
Lemon acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, salicylic acid, benzene sulfonic acid etc..
Preferably, the R1ForAtriphos borate phosphate group containing there are three, is gathered around
There is preferable water solubility, it is easier to the intake of cell.Since atriphos boric acid rouge is controlled as boron agent for boron neutron absorption
The main molecules part for the treatment of is borate, therefore its hydrolysate adenosine monophosphate list boric acid rouge and hypoboric acid rouge, diphosphonic acid
Adenosine list boric acid rouge and hypoboric acid rouge have similar neutron irradiation effect of enhanced sensitivity.
It is highly preferred that R2And R3It isThe atriphos diborate of the present embodiment is made
For boron carrier, permeability and retention effect can be enhanced, the Passive Accumulation in most of tumours has preferable cancer target
Property.
In addition, the present invention also proposes a kind of preparation method of boron-containing compound, comprising the following steps: by reactant and boric acid
It is 1:15~1:10 mixing with molar ratio, is added in dimethyl sulfoxide and forms mixed solution, 110 in organic synthesis plant~
1.5~2h is heated under the conditions of 150 DEG C, and product centrifugal filtration is carried out being recrystallized to give precipitating with ethyl alcohol, after 80~90 DEG C of drying
Obtain the boron-containing compound of general structure of the invention (I).Wherein, reactant be atriphos two receive, adenosine diphosphate (ADP) two
It receives or adenosine monophosphate two is received, reactant is preferably that atriphos two is received.
In addition, the present invention also proposes a kind of pharmaceutical composition, including above-mentioned boron-containing compound and pharmaceutically acceptable
Carrier, diluent or auxiliary addition agent.
Furthermore the present invention also proposes a kind of containing above-mentioned boron compound and using such compound as the pharmaceutical composition of active constituent
Application of the object in the drug for preparing boron neutron capture therapy tumour.In such use, tumour can be derived from central nervous system
System.Further, tumour is glioma, meningioma, neuroblastoma, gonioma, hypophysoma, brain metastes
Tumor, peripheral nerve epithelioma, intramedullary primitive neuroectodermal tumor or arteriovenous malformation.For in the treatment of glioma, to glue
It is matter blastoma, atypical hyloma, hair cell shape astrocytoma, oligodendroglioma, human anaplastic astrocytoma, low
The effect of grade astrocytoma or brain stem glioma is more significant.Further, in such use, tumour can be evil
Property tumour or metastatic tumo(u)r, the therapeutic effect with melanoma, incidence tumor, prostate cancer, liver cancer, lung cancer or breast cancer are
It is excellent.
Embodiment 1
The synthetic route of the boron-containing compound of the present embodiment are as follows:
The preparation step of the boron-containing compound of the present embodiment are as follows: mix 100mg trinosin with 100mg boric acid
(molar ratio is about 1:10) is added 2000 μ l dimethyl sulfoxides and forms mixed solution, the 110-150 DEG C of item in organic synthesis plant
Heating reaction 1.5 hours under part；By product centrifugal filtration, carried out being recrystallized to give precipitating with ethyl alcohol, it is final after 80 DEG C of drying to obtain
To product: trinosin borate, gross production rate 32%.Wherein, trinosin has purchased from BBI life science
Limit company, boric acid are purchased from Tianjin great Mao chemical reagent factory, and dimethyl sulfoxide is purchased from BBI life science Co., Ltd.
Infrared detection: using 6700 type Fourier infrared spectrograph of Nicolet, detects atriphos using pressed disc method
The infrared spectrum of disodium and atriphos diborate synthetic, as the result is shown such as Fig. 1.Wherein, atriphos hypoboric acid
Ester has absorption peak at the 1076 of characteristic borate.
Nuclear-magnetism detection: using AVANCE III 600MHz type superconduction Fourier kernel nuclear magnetic resonance spectrometer, detects atriphos
The nuclear magnetic resonance 1H of disodium and atriphos borate products spectrum, solvent is deuterated dimethyl sulfoxide, and the change of element is indicated with ppm
Displacement study, as the result is shown such as Fig. 2.(a) it is trinosin room temperature test map, (b) is atriphos diborate
Map.Such as (a) of Fig. 2, δ 5.33 (s,1H ,-OH) and δ 5.92 (s,1H ,-OH) it is respectively pentose and phosphorus in trinosin
Hydroxyl peak on acid, and the peak of visible δ 5.92 reduces in 2 (b), illustrates that the hydroxylic moiety on pentose reacts to form boric acid
Ester.
Mass Spectrometer Method: liquid chromatography-mass spectrometry instrument (QTRAP6500 is produced using Singapore AB SCIEX company
+), mass spectroscopy is being carried out to trinosin and atriphos diborate product water sample, as the result is shown such as Fig. 3
And Fig. 4.Fig. 3 is the mass spectrogram of trinosin at normal temperature, and molecular weight 508 is positive ion feature peak, and Fig. 4 is triphosphoric acid
The mass spectrogram of adenosine diborate water sample, 632 positive ion feature peak of molecular weight.Comprehensive analysis results show that synthetic product is three
Adenosine phosphate diborate.
Embodiment 2
The synthetic route of the boron-containing compound of the present embodiment is same as Example 1, the system of the boron-containing compound of the present embodiment
Standby step are as follows: 100mg trinosin is mixed with 120mg boric acid, it is molten that the formation mixing of 2200 μ l dimethyl sulfoxides is added
Liquid, heating reaction 2 hours under the conditions of 110-150 DEG C in organic synthesis plant；By product centrifugal filtration, tied again with ethyl alcohol
Crystalline substance is precipitated, and finally obtains product after 90 DEG C of drying: trinosin borate.Wherein, trinosin is purchased
From BBI life science Co., Ltd, boric acid is purchased from Tianjin great Mao chemical reagent factory, and dimethyl sulfoxide is purchased from BBI life science
Co., Ltd.Conjunction is shown using infrared detection same as Example 1, nuclear-magnetism detection and Mass Spectrometer Method, Comprehensive analysis results
It is atriphos diborate at product.
The inhibitory effect of atriphos diborate EGFR phosphorylation
Atriphos diborate, which is had detected, by EGFR phosphorylation agent box inhibits EGFR autophosphorylation ability, benefit
It is studied with Western Blot of EGFR (immunoblotting of EGFR) autoradiograph to realize, as the result is shown such as Fig. 5.
ATP:ATP borate in Fig. 5 is the molar ratio of ATP (atriphos) and ATP borate (atriphos diborate),
P-EGFR is EGFR autophosphorylation albumen, and EGFR EGF-R ELISA, Actin is cytoskeletal protein-actin.Figure
5 experiment shows in the situation similar in cytoskeletal protein-actin and surface receptor EGFR, two boron of atriphos
Acid esters (ATP borate) content is higher, and EGFR autophosphorylation albumen (P-EGFR) is lower, illustrates that atriphos diborate has
There is the inhibitory effect of certain EGFR.
Boron neutron irradiation enhancement effect
Using A549 (EGFR wild type, K-ras saltant type) lung carcinoma cell as research object, cell opens up general life purchased from Shenzhen
Object Science and Technology Ltd. is cell culture fluid using DMEM-HG complete medium (dual anti-containing 10%FBS and 1%).
Three kinds of boron agent (ATP boric acid are detected with cell apoptosis detection kit (CCK-8, cell counting kit-8)
Ester, 4- dihydroxy boron acylphenylalanines, borate) to the biocompatibility of A549 cell.Specific steps are as follows: culture cell is climbed
To the sheet glass of 40mm × 10mm, cell density 106A/piece uses RPMI-1640 cell culture fluid culture cell strain.
Then cellular morphology on fluorescence microscopy under the microscope each sheet glass will carry cell sheet glass and be individually positioned in equipped with 4ml
A night is incubated in the test tube of culture solution.All kinds of boron agent (ATP borate, BPA, borate), BPA is added into each test tube respectively
The entitled 4- dihydroxy boron acylphenylalanines of Chinese, making its molar concentration is 4.5mMol, and appropriate alkaline solution is added
(NaOH), pH is adjusted to neutrality, while positive controls are set and (50 μ l 30%H are added2O2) and negative control group, 37 DEG C of conditions
Lower culture.After being incubated for 24 hours, CCK-8 reagent is instilled in the ratio of total volume 10% into each test tube, is mixed completely to it,
Continue to cultivate 4h under conditions of temperature is 37 DEG C.Use the suction of 754NPC type ultraviolet-uisible spectrophotometer detection mixed solution
Luminosity compares cell survival rate, and (groups of cells solution absorbance-positive is thin after contamination by cell survival rate cell viability=
Born of the same parents organize solution absorbance)/compare the absorbance for not adding contamination molecule and non-irradiated groups of cells solution.
Boron neutron irradiation enhancement effect research: as shown in fig. 6,4ml culture solution is added in test tube, by A549 lung carcinoma cell glass
Glass piece is put into test tube one by one, and a night is cultivated under the conditions of 37 DEG C.It prepares and different boron agent (ATP borate, BPA, boric acid) is added
Culture solution (molar concentration is 4.5mMol, 1.1mMol) is in test tube.Any load cell sheet glass is taken, it is immersed in and adds
In the culture solution for entering boron agent.Slide is taken out after 5h, is successively rinsed in 3 test tubes equipped with clean culture solution, removal remains in
The medicament of cell surface, then slide is put into the new test tube equipped with 4ml culture solution, test tube sealing is sealed with electric iron, this is
One group of sample is used for neutron irradiation.According to the above operation, two kinds of concentration of each reagent respectively prepare one group of sample, in addition take two groups
The Cell sheet glass that do not contaminate irradiates control group as empty, totally ten groups of samples.Cell survival rate before neutron irradiation (CCK8 experiment and
Micro- sem observation) without significant difference.Its survival rate shows such as Fig. 7 after neutron irradiation.
As shown in fig. 7, the first row in Fig. 7 under each concentration indicates that ATP borate+NR, secondary series indicate BPA+NR, the
Three column indicate H3BO3+NR.By various concentration ATP borate (ATP Borate), BPA, boric acid (H3BO3) A549 after contamination
Cancer cell is 1 × 10 in neutron flux9cm-2s-1Under conditions of irradiate 3 minutes (NR is neutron irradiation), use CCK-8 kit
Detect cell survival rate.Irradiate enhanced sensitivity value=cellular control unit survival rate/plus boron agent experimental group cell survival rate) p < 0.05 *, it uses
T test is compared each group, and group difference causes p value < 0.05 to be considered significant.
The cell strain irradiation survival rate for not adding sensitizer in Fig. 7 is drawn as curve, such as Fig. 8 as control.It can be clear by Fig. 8
Chu finds out that enhanced sensitivity value of the ATP borate under lower culture concentration under (1-3mMol) more than BPA is high, in 2.3mMol, increases
Quick value (=control survival rate/sample-adding survival rate) is respectively 2.1 and 9.1.It can be seen that ATP borate of the invention will be one
A more superior neutron irradiation sensitizer.
Zoopery
Grouping: Model in Nude Mice has Wild type EGFR expression using a Non-small Cell Lung Cancer A 549
Model (is built up by Guangdong Experimental Animal Center).Reach 9 to 11 millimeters of diameter after tumour transplatation, these carry tumor nude mices by with
In anti-tumor experiment.All nude mices are female, weight 14-16g.These mouse are randomly divided into 3 groups and different drink: deionized water
For negative control be group (A), deionized water+(BPA acid ester solution) is group (B) and deionized water+(ATP acid ester solution)
(C)。
Zoopery oral dose and the analysis of immune group apoptosisization: boric acid ester concentration is that ((pH=7) is used 9.0mMol
NaOH solution is adjusted).Free drinking water and food, daily mouth pour into 2 times sooner or later, and each 0.1ml (carries tumor nude mice 15g, front left
Upper limb carries tumor 10mm diameter), after feeding 4 days, after drug withdrawal 48h, put to death mouse, Partial tumors 0.2g, blood, periphery normal muscle
Content of each 0.2g for ICP-MS detection elements B is organized, table 1 is listed in.Another 0.5g tumor mass of taking out is packed into 3ml culture solution, envelope
After pipe irradiates 3min, tumor tissues are taken out after continuing culture 24 hours and are fixed with formalin, the end of immunohistochemical analysis is carried out
DUTP Nick End label (TUNEL) method of deoxynucleotidyl transferase (TDT) is held to detect apoptosis of tumor cells, immunohistochemistry is aobvious
Show such as Fig. 9.TUNEL technology, i.e. deoxynucleotide terminal enzyme (DNA) (Terminal deoxynucleotidyl
Transferase, TdT) mediate dUTP Nick End label (TdT-mediated dUTP nick-end labeling,
TUNEL) technology is most sensitive, quick, the special new method of current in situ detection Apoptosis, is widely used in biology, medicine
Research field.
As can be seen from Figure 9, it is evident that TUNEL positive cell is significantly high in C group tumour cell, illustrates the spoke of ATP boric acid rouge
It is strong compared with BPA boric acid rouge to penetrate enhanced sensitivity, is enriched with more B, and may be enriched on sensitive target molecule (RNA, DNA etc.), and
Itself have the effect of thus stronger EGFR inhibitor causes radiation damage effects to enhance, Apoptosis is more.
After 1 feeding boron agent of table, the content (n=5) of B in the tumor tissues and blood of ICP-MS measurement
Although ATP boric acid rouge and tumour enrichment B relative value T (tumour B/ normal muscle B) of BPA boron agent are small seen from table 1
A bit (respectively 1.2 and 1.3), but the absolute value B/ higher of its enrichment, Radiosensitizing Effect will be more preferable.
Main molecules part due to ATP boric acid rouge as boron agent for boron neutron capture therapy is borate,
The mono- boric acid rouge of hydrolysate AMP and hypoboric acid rouge, the mono- boric acid rouge of ADP and hypoboric acid rouge have similar neutron irradiation enhanced sensitivity
Effect.
Conclusion: ATP boric acid rouge has Radiosensitizing Effect more higher than existing BPA boron agent and AMP, ADP borate
Equally there is similar neutron irradiation effect of enhanced sensitivity.Statistical analysis uses t-test, and P value carries out bilateral comparison, and P≤0.05 is recognized
It is statistically significant.
The above is only a preferred embodiment of the present invention, is not intended to limit the scope of the invention, all in the present invention
Design under, using equivalent transformation made by description of the invention, or directly/to be used in other related technical areas equal indirectly
It is included within the scope of the present invention.
Claims (10)
1. a kind of boron-containing compound, which is characterized in that have general structure (I):
Wherein, R1For-OH,
R2And R3One of beAnother one is-OH or R2And R3It is
2. boron-containing compound as described in claim 1, which is characterized in that the R1For
3. boron-containing compound as claimed in claim 2, which is characterized in that the R2And R3It is
4. a kind of preparation method of boron-containing compound, which comprises the following steps: mix reactant with boric acid, add
Enter and form mixed solution in organic solvent, heats, product centrifugal filtration is carried out being recrystallized to give precipitating with ethyl alcohol, after drying
Obtain the boron-containing compound；The reactant is that atriphos two is received, adenosine diphosphate (ADP) two is received or adenosine monophosphate two is received.
5. preparation method as claimed in claim 4, which is characterized in that the reactant is that atriphos two is received.
6. preparation method as claimed in claim 5, which is characterized in that the molar ratio of the reactant and boric acid is 1:15~1:
10。
7. preparation method as claimed in claim 5, which is characterized in that the organic solvent is dimethyl sulfoxide.
8. preparation method as claimed in claim 5, which is characterized in that the temperature of the heating is 110~150 DEG C, and the time is
1.5~2h；The temperature of the drying is 80~90 DEG C.
9. a kind of pharmaceutical composition, which is characterized in that including the boron-containing compound as described in any one of claims 1 to 3,
And pharmaceutically acceptable carrier, diluent or auxiliary addition agent.
10. a kind of boron-containing compound as described in any one of claims 1 to 3 is preparing boron neutron capture therapy tumour
Application in drug.
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