CN108033950B - EGFR tyrosine kinase inhibitor BF with anti-tumor activity3- AZD9291 and its preparation method and application - Google Patents
EGFR tyrosine kinase inhibitor BF with anti-tumor activity3- AZD9291 and its preparation method and application Download PDFInfo
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- CN108033950B CN108033950B CN201810097974.4A CN201810097974A CN108033950B CN 108033950 B CN108033950 B CN 108033950B CN 201810097974 A CN201810097974 A CN 201810097974A CN 108033950 B CN108033950 B CN 108033950B
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Abstract
The invention discloses EGFR tyrosine kinase inhibitor BF with anti-tumor activity3- AZD9291 and its preparation method and application belongs to biomedicine field.The present invention is optimized and is improved by the chemical structure to AZD9291, has been obtained completely new EGFR TKI, has been named as BF3- AZD9291 (Formulas I), research shows that EGFR TKI-BF that the present invention synthesizes3- AZD9291 can effectively inhibit the drug resistance of tumour cell, compared with AZD9291, have stronger inhibition drug-resistant effect to mutation EGFR lung cancer cell line H1975T790M, therefore clinically can be used as antitumor agent application.In addition, the invention also discloses the epidermal growth factor recipient tyrosine kinase inhibitor BF for preparing the tool anti-tumor activity3The method of-AZD9291.It is proposed of the invention is that the treatment of oncotherapy, especially non-small cell lung cancer provides a kind of effective technological means.
Description
Technical field
The present invention relates to pyrimidine acrylamides more particularly to EGFR TKI-BF with anti-tumor activity3-
AZD9291 and preparation method thereof, the application the invention further relates to the medicine as antitumor agent, belongs to biomedicine field.
Background technique
The energy-rich phosphate bond that presently found EGFR tyrosine kinase (EGFR TK) can be catalyzed ATP is transferred to EGFR's
Several tyrosine sites, make its phosphorylation, to activate the signal paths such as PI3K/Akt, the Ras/MAPK in downstream, promote cell
Into growing multiplication, metabolism, inhibit Apoptosis.When EGFR is over-expressed and is mutated in cell, meeting block cell programmed cell death makes
The growth regulating of cell is out of control, and obtains infinite multiplication and invasive ability, that is, develops into malignant cell.EGFR TKI is logical
The binding site for competing tyrosine kinase intracellular with ATP is crossed, the autophosphorylation by internal tyrosine is prevented, inhibits EGFR junket
Histidine kinase activation inhibits angiogenesis and tumour cell leaching to inhibit growth of tumour cell, accelerate apoptosis of tumor cells
Profit, transfer.The basic structure of small molecule EGFR TKI is quinazoline amine.EGFR TKI can be divided into: 1) invertibity TKI mainly has:
Gefitinib (gefitinib), Tarceva (erlotinib), Lapatinib (Lapatinib), 2) irreversibility TKI master
Have: Afatinib (Afatinib), Buddhist nun (Dacomitinib) can be replaced by reaching.Currently, invertibity and irreversibility EGFR TKI
There is significant curative effect to being mutated in the EGFR non-small cell lung cancer short time, but finally cause to control because generating acquired resistance
Failure is treated, is not obviously prolonged the life cycle of patient.Therefore, developing and develop has stronger, more longlasting anti-tumor activity
New E GFR TKI will likely bring life for mutation EGFR Patients with Non-small-cell Lung.
Summary of the invention
An object of the present invention is to provide completely new epidermal growth factor recipient tyrosine kinase inhibitor (EGFR
TKI)—BF3- AZD9291 and preparation method thereof.
The second object of the present invention is to provide BF3- AZD9291 is promoting the purposes in apoptosis of tumor cells, and mechanism is
By inhibiting epidermal growth factor recipient tyrosine kinase phosphorylation to promote apoptosis of tumor cells, inhibit tumor vessel raw
At, invasion and transfer.
Above-mentioned purpose of the invention is achieved through the following technical solutions:
The present invention by irreversibility molecular targeted anti-tumor agents-osimertinib (AZD9291) chemical structure into
Row optimization and improvement, have obtained completely new EGFR TKI-BF3- AZD9291, due to introducing the organic trifluoroborate of amphoteric ion
Group reduces the uptake ratio of liver to improve inhibitor hydrophily, improves tumor uptake rate and smaller toxic side effect, simultaneously
Have mutation EGFR non-small cell lung cancer compared with strong inhibitory activity, and illustrating its mechanism is by inhibiting tumour cell epidermal growth
Factor receptor tyrosine tyrosine phosphorylation hinders downstream signaling pathway activation, to inhibit growth of tumour cell, proliferation, promotes
Apoptosis of tumor cells.
A kind of epidermal growth factor recipient tyrosine kinase inhibitor provided by the invention or its pharmaceutical salt, are named as
BF3- AZD9291, the epidermal growth factor recipient tyrosine kinase inhibitor have structure shown in Formulas I:
Of course, it is possible to prepare the salt of the compounds of this invention acid addition, these salt are included in the present invention.
The acid-addition salts of the compounds of this invention are preferably pharmaceutically acceptable, with it is appropriate acid (such as hydrochloric acid, acetic acid,
Sulfuric acid) nontoxic salt is formed, other than pharmaceutically acceptable salt, other salt are also included in the present invention.
Further, the invention also provides the epidermal growth factor recipient tyrosine kinase inhibitor or its can medicine
Purposes of the salt in the drug that preparation promotes apoptosis of tumor cells.
Wherein, the promotion apoptosis of tumor cells is by inhibiting epidermal growth factor recipient tyrosine kinase phosphorylation
And realize.
Wherein, it is preferred that the tumour cell is the non-small cell lung cancer cell of EGFR mutation.
Further, above-described epidermal growth factor recipient tyrosine kinase is prepared the invention also provides a kind of
The method of inhibitor or its pharmaceutical salt, comprising the following steps:
(1) by (2- chlorine pyrimidine-4-yl) -1- methyl -3a, 7a- dihydro -1H- indoles, the fluoro- 2- methoxy of 4- under nitrogen protection
Base -5- nitroaniline and p-methyl benzenesulfonic acid are mixed in 2- amylalcohol, and mechanic whirl-nett reaction 2-3h, is cooled to room at 100-110 DEG C
Wen Hou, filters, and filter cake is washed with 2- amylalcohol, drains to obtain light tan solid, be purified by column chromatography for separation, using methanol and two
The eluent that chloromethanes is mixed to get according to volume ratio 1:100 finally obtains pale yellow needles solid, i.e. compound one；
(2) by compound one, N, N, N'- trimethyl ethylenediamine and n,N-diisopropylethylamine is miscible stirs in DMF solvent
It mixes, 115-125 DEG C of reaction 3-5h, solution is poured into ice water after cooling room temperature and is diluted, is extracted with dichloromethane three times, is associated with
Machine Xiang Bingyong saturated common salt is washed three times, and organic phase is dry using anhydrous sodium sulfate, is filtered, is passed through column chromatography for separation after being spin-dried for
It is needle-shaped to finally obtain rufous for purification, the eluent being mixed to get using methanol and methylene chloride according to volume ratio 3:100
Solid, i.e. compound two；
(3) compound two, iron powder and ammonium chloride are added in round-bottomed flask, it is molten with the mixing of the second alcohol and water in flask
Liquid is miscible, heating reflux reaction 2-4h, cooling to filter, and filtrate concentration is spin-dried for, is purified by SCX post separation, eluent is first
Alcohol ammonia solution obtains brown solid, i.e. compound three；
(4) compound three and diisopropylethylamine are dissolved in methylene chloride, the agitation and dropping acryloyl chloride under ice salt bath
Dichloromethane solution, react 0.5-1.5h, then adding sodium hydroxide aqueous solution the reaction was continued 3-5h at room temperature, filter, collect
Solid is dried to obtain product, i.e. compound four；
(5) compound four is set in a round bottom flask under room temperature under nitrogen protection, anhydrous tetrahydro furan dissolution is added；Separately take
Anhydrous tetrahydro furan and iodomethyl pinacol borate, and repeated flushing pipette tips are added in round-bottomed flask, by iodomethyl boric acid frequency
Which alcohol ester tetrahydrofuran solution is slowly added in the solution of compound four, and suction filtration obtains white solid after stirring 10-14h, that is, is changed
Close object five；
(6) compound five is put into round-bottomed flask, sequentially adds KHF2Aqueous solution, HCL aqueous solution, deionized water and DMF
Solution reacts 2h at 40-50 DEG C, NH is added after cooling4The quenching of OH aqueous solution, is added drop-wise on small silicagel column with dropper and is used respectively
Water and ethyl acetate washing, collect cleaning solution and are extracted with anhydrous ether, merge organic phase, dry, filter rotation with anhydrous sodium sulfate
It is dry, obtain solid product, as epidermal growth factor recipient tyrosine kinase inhibitor shown in Formulas I.
The present invention has been obtained completely new by the way that osimertinib (AZD9291) chemical structure is optimized and improved
EGFR TKI—BF3- AZD9291, through biological evaluation, EGFR TKI-BF of the present invention3- AZD9291 can effectively inhibit swollen
The proliferation of oncocyte has outstanding anti-tumor activity, clinically can be used as antitumor agent application.
The present invention also provides a kind of antitumor medicine composition, the pharmaceutical composition is by a effective amount of chemical combination of the present invention
Object or its pharmaceutical salt cooperate with pharmaceutically acceptable carrier, in other words, by the sheet of pharmaceutically acceptable dosage
After invention compound and pharmaceutically acceptable carrier or diluent cooperation, it is prepared by the formulation method of this field routine
Any one suitable pharmaceutical composition.A effective amount of the compounds of this invention is matched with pharmaceutically acceptable carrier or diluent
After conjunction, any one suitable pharmaceutical composition is prepared by the formulation method of this field routine.Usual the composition is suitable
Together in oral administration and drug administration by injection, also it is suitble to other medications.The composition can be tablet, capsule, pulvis,
The liquid forms such as granula, pastille, suppository or oral solution.According to different medications, pharmaceutical composition of the present invention can be with
Contain 0.1%-99% weight, the preferably the compounds of this invention of 10-60% weight.
Detailed description of the invention
Fig. 1 is EGFR TKI-BF of the present invention3The disjunctive path figure of-AZD9291 compound；
Fig. 2 is BF3High performance liquid chromatography (HPLC) result of-AZD9291；
Fig. 3 is BF3The nuclear magnetic spectrum result of-AZD9291；
(1)1H-NMR；(2)19F-NMR
Fig. 4 is BF3The mass spectral results of-AZD9291；
Fig. 5 is to measure BF by mtt assay3Cell viability result after-AZD9291 processing 24 hours；
Fig. 6 is to measure BF by mtt assay3Cell viability result after-AZD9291 processing 48 hours.
Specific embodiment
The invention will now be further described with reference to specific embodiments, the advantages and features of the present invention will be with description and
It is apparent.But examples are merely exemplary for these, and it is not intended to limit the scope of the present invention in any way.Those skilled in the art
Member it should be understood that without departing from the spirit and scope of the invention can details to technical solution of the present invention and form into
Row modifications or substitutions, but these modifications and replacement are fallen within the protection scope of the present invention.
Embodiment 1EGFR TKI-BF3The preparation of-AZD9291
The BF3The molecular structural formula of-AZD9291 is shown in formula I:
Preparation flow figure as shown in Figure 1, it is specific the preparation method is as follows:
(1) by 50g (2- chlorine pyrimidine-4-yl) -1- methyl -3a, 7a- dihydro -1H- indoles, 38.03g 4- under nitrogen protection
Fluoro- 2- methoxyl group -5- nitroaniline and 37.09g p-methyl benzenesulfonic acid are mixed in 580ml 2- amylalcohol, and mechanical stirring is anti-at 105 DEG C
2.5h is answered, after being cooled to room temperature, is filtered, filter cake is washed with 2- amylalcohol, drains to obtain light tan solid, be mentioned by column chromatography for separation
It is solid to finally obtain pale yellow needles for eluent that is pure, being mixed to get using methanol and methylene chloride according to volume ratio 1:100
Body, that is, compound one, yield 85%；
(2) by 65g compound one, 19.65gN, N, N'- trimethyl ethylenediamine and 26.93N, N- diisopropylethylamine are miscible
It is stirred in 600mlDMF solvent, 120 DEG C of reaction 4h, solution is poured into ice water after cooling room temperature and is diluted, with 50ml dichloromethane
Alkane extracts three times, merges organic phase and is washed three times with saturated common salt, and organic addition anhydrous sodium sulfate is dry, filters, is spin-dried for
It is purified afterwards by column chromatography for separation, the eluent being mixed to get using methanol and methylene chloride according to volume ratio 3:100,
Finally obtain rufous needle-like solid, i.e. compound two, yield 62%；
(3) by 3.22g compound two, 9.62g iron powder and ammonium chloride are added in round-bottomed flask, with the 120mL in flask
The mixed solution of ethyl alcohol and 30ml water is miscible, heating reflux reaction 3h, cooling to filter, and filtrate concentration is spin-dried for, SCX column point is passed through
From purification, eluent is the methanolic ammonia solution of 0.35M, obtains brown solid, i.e. compound three, yield 85%；
(4) 1.7g compound three and 0.73ml diisopropylethylamine are dissolved in 50ml methylene chloride, are stirred under ice salt bath
The 1ml dichloromethane solution that 0.34ml acryloyl chloride is added dropwise is mixed, 1h is reacted, then adds 30ml 0.5g sodium hydroxide water at room temperature
Solution the reaction was continued 4h.It filters, collects solid and be dried to obtain product, i.e. compound four, yield 39%；
(5) 9.2mg compound four is placed in 25ml round-bottomed flask by nitrogen protection at room temperature, and the anhydrous tetrahydro furan of 2ml is added
It mutters dissolution；The iodomethyl pinacol borate that 2ml anhydrous tetrahydro furan and 3 μ l are added in 25ml round-bottomed flask is separately taken, and repeatedly
Rinse pipette tips.Iodomethyl pinacol borate tetrahydrofuran solution is slowly added in four solution of compound in 5min or so, is stirred
Suction filtration obtains white solid, i.e. compound five, yield 49% after mixing 12h；
(6) compound five is put into round-bottomed flask, sequentially adds 3M, the KHF of 300 μ l2Aqueous solution, 4M, the HCl of 300 μ l
Aqueous solution, 200 μ l deionized waters and 600 μ l DMF solutions react 2h at 45 DEG C, 10 μ l NH are added after cooling4OH aqueous solution
Quenching is added drop-wise on small silicagel column with dropper with being washed respectively with water and ethyl acetate, is collected cleaning solution and is extracted with anhydrous ether,
Merge organic phase, dried, filtered and be spin-dried for anhydrous sodium sulfate, obtains solid product, i.e. compound six, the i.e. epidermal growth
Factor receptor tyrosine kinase inhibitor BF3- AZD9291, yield 85%.
BF3High performance liquid chromatography (HPLC) result of-AZD9291 is as shown in Fig. 2, can be seen that this hair from HPLC result
The bright BF being prepared3- AZD9291 pharmaceutical purity is single, free from admixture.BF3The nuclear magnetic spectrum and mass spectral results of-AZD9291 point
Not not as shown in Figure 3 and 4.
Embodiment 2AZD9291 and BF3- AZD9291 merges the non-small thin of T790M bis- times mutation to EGFR L858R mutation
The inhibiting effect of born of the same parents' lung cancer cell line H1975 is tested
1, test compound: AZD9291 and BF3- AZD9291 (is prepared) by 1 method of embodiment
2, test method:
The non-small cell lung cancer cell H1975 cell of EGFR bis- times mutation of logarithmic growth phase, is connect with 10000/hole
Kind is in 96 orifice plates, in 37 DEG C of 5%CO2Under the conditions of cultivate 24 hours after, administration group be added test compound BF3- AZD9291,
Making its final concentration is respectively 0.0125,0.125,1.25,2.5,5,10,20,40 μM, and blank control group is that 0.08% dimethyl is sub-
Sulfone, in 37 DEG C of 5%CO2Under the conditions of cultivate 24 hours and 48 hours after, using MTT colorimetric method, extinction is measured at Yu Bochang 490nm
Spend OD value.Drug is calculated to the half inhibiting rate (IC50) of growth of tumour cell according to OD value.
3, test result
Fig. 5 is to measure BF by mtt assay3- AZD9291 handle 24 hours after cell viability as a result, can be with from Fig. 5 result
Find out BF3- AZD9291 can inhibit H1975 cell to grow strongly, and IC50=0.019 ± 0.00439 μM illustrates BF3-
AZD9291 is mutated EGFR L858R and merges compared with prototype medicine AZD9291 (IC50=0.0208 ± 0.00616 μM)
The Lines of T790M bis- times mutation have stronger inhibiting effect (P < 0.001).
Fig. 6 is to measure BF by mtt assay3- AZD9291 handle 48 hours after cell viability as a result, can be with from Fig. 6 result
Find out BF3- AZD9291 can inhibit H1975 cell to grow strongly, and IC50=0.014063 ± 0.003716 μM illustrates BF3-
AZD9291 is mutated EGFR L858R and merges compared with prototype medicine AZD9291 (IC50=0.017333 ± 0.004006 μM)
The Lines of T790M bis- times mutation have stronger inhibiting effect (P < 0.001).
These results suggest that the compounds of this invention BF3- AZD9291 is compared with AZD9291, to the non-small thin of secondary mutation
Born of the same parents' lung cancer cell line H1975 has stronger Inhibit proliferaton effect.
Claims (10)
1. epidermal growth factor recipient tyrosine kinase inhibitor or its pharmaceutical salt, are named as BF3- AZD9291, feature
It is that the epidermal growth factor recipient tyrosine kinase inhibitor has structure shown in Formulas I:
2. epidermal growth factor recipient tyrosine kinase inhibitor described in claim 1 or its pharmaceutical salt promote in preparation
Purposes in the drug of apoptosis of tumor cells.
3. purposes as claimed in claim 2, it is characterised in that the promotion apoptosis of tumor cells is by inhibiting epidermis raw
Growth factor receptor body tyrosine kinase phosphorylation and realize.
4. purposes as claimed in claim 2 or claim 3, it is characterised in that the tumour cell is the non-small cell lung of EGFR mutation
Cancer cell.
5. a kind of epidermal growth factor recipient tyrosine kinase inhibitor described in claim 1 or its pharmaceutical salt of preparing
Method, which comprises the following steps:
(1) by (2- chlorine pyrimidine-4-yl) -1- methyl -3a, 7a- dihydro -1H- indoles, the fluoro- 2- methoxyl group -5- of 4- under nitrogen protection
Nitroaniline and p-methyl benzenesulfonic acid are mixed in 2- amylalcohol, mechanic whirl-nett reaction 2-3h at 100-110 DEG C, after being cooled to room temperature,
It filters, filter cake is washed with 2- amylalcohol, drains to obtain light tan solid, be purified by column chromatography for separation, using methanol and dichloromethane
The eluent that alkane is mixed to get according to volume ratio 1:100 finally obtains pale yellow needles solid, i.e. compound one；
(2) by compound one, N, N, N'- trimethyl ethylenediamine and n,N-diisopropylethylamine is miscible stirs in DMF solvent,
Solution is poured into ice water after cooling room temperature and is diluted, is extracted with dichloromethane three times, merge organic by 115-125 DEG C of reaction 3-5h
Xiang Bingyong saturated common salt is washed three times, and organic phase is dry using anhydrous sodium sulfate, is filtered, is mentioned after being spin-dried for by column chromatography for separation
Eluent that is pure, being mixed to get using methanol and methylene chloride according to volume ratio 3:100, it is needle-shaped solid to finally obtain rufous
Body, i.e. compound two；
(3) compound two, iron powder and ammonium chloride are added in round-bottomed flask, it is mixed with the mixed solution of the second alcohol and water in flask
Molten, heating reflux reaction 2-4h is cooling to filter, and filtrate concentration is spin-dried for, is purified by SCX post separation, eluent is methanol ammonia
Solution obtains brown solid, i.e. compound three；
(4) compound three and diisopropylethylamine are dissolved in methylene chloride, the two of agitation and dropping acryloyl chloride under ice salt bath
Chloromethanes solution reacts 0.5-1.5h, then adding sodium hydroxide aqueous solution the reaction was continued 3-5h at room temperature, filters, collects solid
It is dried to obtain product, i.e. compound four；
(5) compound four is set in a round bottom flask under room temperature under nitrogen protection, anhydrous tetrahydro furan dissolution is added；Separately take round bottom
Anhydrous tetrahydro furan and iodomethyl pinacol borate, and repeated flushing pipette tips are added in flask, by iodomethyl boric acid pinacol
Ester tetrahydrofuran solution is slowly added in the solution of compound four, and suction filtration obtains white solid, i.e. compound after stirring 10-14h
Five；
(6) compound five is put into round-bottomed flask, sequentially adds KHF2Aqueous solution, HCL aqueous solution, deionized water and DMF solution,
2h is reacted at 40-50 DEG C, and NH is added after cooling4The quenching of OH aqueous solution, with dropper be added drop-wise on small silicagel column respectively with water and
Ethyl acetate washing is collected cleaning solution and is extracted with anhydrous ether, merges organic phase, dried, filtered and be spin-dried for anhydrous sodium sulfate, obtained
To solid product, as epidermal growth factor recipient tyrosine kinase inhibitor shown in Formulas I.
6. a kind of antineoplastic pharmaceutical compositions, it is characterised in that by a effective amount of epidermal growth factor receptor described in claim 1
Body tyrosine kinase inhibitor or its pharmaceutical salt and pharmaceutically acceptable auxiliary material composition.
7. antineoplastic pharmaceutical compositions as claimed in claim 6, it is characterised in that described pharmaceutical composition is tablet, capsule
Agent, pulvis, granule, pastille, suppository or oral solution.
8. antineoplastic pharmaceutical compositions as claimed in claim 6, it is characterised in that the right containing 0.1%-99% weight is wanted
Epidermal growth factor recipient tyrosine kinase inhibitor described in asking 1 or its pharmaceutical salt.
9. antineoplastic pharmaceutical compositions as claimed in claim 6, it is characterised in that the claim 1 containing 10-60% weight
The epidermal growth factor recipient tyrosine kinase inhibitor or its pharmaceutical salt.
10. the purposes of the described in any item pharmaceutical compositions of claim 6-9 in the preparation of antitumor drugs.
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| CN112645934A (en) * | 2020-12-25 | 2021-04-13 | 中山奕安泰医药科技有限公司 | Ostinib intermediate and refining method thereof |
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