CN108570044A - A kind of purposes of amides compound and its synthetic method and treating cancer - Google Patents
A kind of purposes of amides compound and its synthetic method and treating cancer Download PDFInfo
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Abstract
The invention discloses such as I compound represented of formula or its pharmaceutically acceptable salt,Wherein, R1、R2、R3、R4And R5It is independently selected from H or OH.The present invention is prepared for Formula I and carries out the Primary Study of pharmacological activity.Listed compound lacks EGFR cells to Exon19 in test example table and L858R/T790M EGFR cells all have good activity, has better choice activity compared to Wild type EGFR cell, and the compounds of this invention selectivity is suitable with AZD9291.It is possible thereby to deduce, the compounds of this invention can be developed as cancer treatment drugs, may have advantage outstanding especially in non-small cell lung cancer.
Description
Technical field
The present invention relates to a kind of amides compound and its purposes of synthetic method and treating cancer.
Background technology
Lung cancer is that the whole world is most common, the respiratory system malignant tumour that causes death toll most.It counts and reports according to Cancer in China
It accuses, China has 4.29 × 10 in 20156Example lung cancer new cases, 2.81 × 106Example lung cancer death case.Wherein, non-small cell lung
Cancer (NSCLC) accounts for 85% or more of all cases of lung cancer, and the death rate is up to 80%~90%.The drug therapy of non-small cell lung cancer
In, target therapeutic agent can more accurately act on tumor tissues, greatly reduce relative to classical cytotoxic drug
Damage to normal surrounding tissue, not only reduces the incidence of Patient drug's adverse reaction, and it is swollen also to significantly improve resistance
The accuracy of tumor.With the development and propulsion of oncomolecularbiology technology, targeted drug treatment becomes oncology in recent years
One of the research hotspot on boundary.
EGFR (Epidermal Growth Factor Receptor) is epidermal growth factor (EGF) cell Proliferation and letter
Number conduction receptor.EGFR tyrosine kinase inhibitors are the military strategist in ancient China important places of recent antitumor drug research and development, are had all over the world perhaps
More transnational medicines is looked forward to or puts into a large amount of manpower financial capacities in the research of new E GFR inhibitor.Currently, EGFR junket ammonia
The inhibitor family of acid kinase develops toward multiple target point, non-reversible type direction.Early stage studies and the reversible EGFR junket of listing
In histidine kinase inhibitor for treating, the drug resistance of drug has caused the concern of people.Patient was controlled to 1 year receiving half a year
After treatment, there are about half patients drug resistance phenomenon occurs.More and more signs show that the more safety for researching and developing new framework types has
The non-reversible type EGFR tyrosine kinase inhibitors of effect have not been allowed to delay.
AZD9291 is AstraZeneca development, and in December, 2015 FDA approvals listing, indication is that this product is suitable for previously passing through
There is progression of disease when EGF-R ELISA (EGFR) tyrosine kinase inhibitor (TKI) is treated or after treatment, and passes through
Detection confirms that there are EGFR T790M mutation positive Locally Advanceds or metastatic lung cancer in non-cellule type (NSCLC) adult patient
Treatment.The irreversible EGFR inhibitor of Catastrophic selection, shown in tumor experimental models the phase to EGFR-TKI responsive types and
T790M medicament-resistant mutations are effective, have weak selectivity to Wild type EGFR.AZD9291 has had drug resistance report, AZD9291 at present
Acquired resistance mutation mechanism include：EGFR C797S mutation, FGFR1 amplifications, HER2 amplifications, cMet amplifications or MAPK bypasses
Pathway activation, histology change (partly changing into Small Cell Lung Cancer) or compound other gene mutations.
Invention content
The present invention provides a kind of compounds of new construction type, specially as I compound represented of formula or its pharmaceutically
Acceptable salt, ester, stereoisomer, solvated compounds,
Wherein, R1、R2、R3、R4And R5It is independently selected from H or OH.
It is described as I compound represented of formula is preferably：
The present invention also provides the synthetic method such as I compound represented of formula, synthetic route is：
Its specific synthesis step is：
1) in the presence of an inorganic base, cysteine (compound 1) and 2- (chloromethyl) -4,6- difluoros benzo [d] thiazole
(compound 2), which reacts, generates S- ((4,6- difluoros benzo [d] thiazol-2-yl) methyl) cysteine containing thioether bond
(compound 3)；
2) under alkaline condition, the amino in compound 3 is protected by (9H- fluorenes -9- bases) methylchloroformate, generates N-
(((9H- fluorenes -9- bases) methoxyl group) carbonyl)-S- ((4,6- difluoros benzo [d] thiazol-2-yl) methyl) cysteine (compound
4)；
3) in acid condition, the amino in the carboxyl in compound 4 and acridine -9- base amine reacts generation ((3-
(((4,6- difluoros benzo [d] thiazol-2-yl) methyl) sulfenyl) -1- (acridine -9- bases amino) -1- oxopropan -2- formic acid
(9H- fluorenes -9- bases) base) carbamate (compound 5)；
4) in a suitable solvent, hydrolysis generation 2- amino -3- (((4,6- occurs under alkaline condition for compound 5
Difluoro benzo [d] thiazol-2-yl) methyl) sulfenyl)-N- (acridine -9- bases) propionamide (compound 6)；
5) amino in compound 6 generates corresponding amide product with corresponding acyl chloride reaction.
Further, the alkali in the step 1) can be sodium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide is excellent
Select sodium hydroxide.
Further, the alkali in the step 2) can be sodium carbonate, sodium bicarbonate, potassium carbonate, saleratus, preferably carbon
Sour sodium.
Further, the use of acid can be methanesulfonic acid in the step 3), ethane sulfonic acid, propane sulfonic acid, p-methyl benzenesulfonic acid,
Benzene sulfonic acid, p-nitrophenyl sulfonic acid etc., preferably p-methyl benzenesulfonic acid.
Further, hydrolysis solvent can be piperidines in the step 4), second eyeball, 2,2,2- trifluoroethane -1- alcohol,
It is preferred that piperidines.
The present invention also provides described if I compound represented of formula or its pharmaceutically acceptable salt are as EGFR junket ammonia
The application of acid kinase inhibitor.
The present invention also provides described if I compound represented of formula or its pharmaceutically acceptable salt are in treating cancer medicine
Application in object.The cancer can be selected from non-small cell lung cancer, Small Cell Lung Cancer, breast cancer, cancer of pancreas, glioma,
Glioblastoma, oophoroma, cervix cancer, colorectal cancer, melanoma, carcinoma of endometrium, prostate cancer, leukaemia,
Any one of gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, acute myelocytic leukemia, nasopharyngeal carcinoma, cholangiocarcinoma.
The present invention also provides a kind of pharmaceutical compositions, including such as I compound represented of formula and/or its is pharmaceutically acceptable
Salt and one or more pharmaceutically acceptable carriers.
Medicine group can be made with pharmaceutically various typical additives (such as diluent and excipient) in the compound of the present invention
Close object.According to therapeutic purposes, pharmaceutical composition can be made to various types of administration unit dosage forms, as tablet, pill, pulvis,
Liquid, suspension, lotion, granule, capsule, suppository and injection (solution and suspension) etc..
In order to make the pharmaceutical composition of tablet form shape, it can be used this field any of and widely used figuration
Agent.For example, carrier, such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, avicel cellulose and silicon
Acid etc.；Adhesive, such as water, ethyl alcohol, propyl alcohol, common syrup, glucose solution, starch solution, penetrating judgment solution, carboxymethyl cellulose
Element, lac, methylcellulose and potassium phosphate, polyvinylpyrrolidone etc.；Disintegrant, such as dried starch, mosanom, agar powder and sea
Band powder, sodium bicarbonate, calcium carbonate, the aliphatic ester of polyethylene sorbitan, lauryl sodium sulfate, stearic acid monoglycerides,
Starch and lactose etc.；Disintegration inhibitor, such as white sugar, glycerol tristearate, coconut oil and hydrogenated oil and fat；Adsorption enhancer, such as season
Amine base and lauryl sodium sulfate etc.；Wetting agent, such as glycerine, starch；Adsorbent, such as starch, lactose, kaolin, bentonite
With colloid silicic acid etc.；And lubricant, such as pure talcum, stearate, boric acid powder and polyethylene glycol etc..If necessary
Words can also use common coated material to make tablet as sugar coated tablet, painting gelatin film tablet, enteric coated tablets, film coated tablets, double
Tunic tablet and multilayer tablet.
In order to make the pharmaceutical composition of pill shape, it can be used this field any of and widely used inborn nature
Agent, for example, carrier, such as lactose, starch, coconut oil, hardened vegetable oils, kaolin and talcum etc.；Adhesive, such as gum arabic
Powder, Huang write rubber powder, gelatin and ethyl alcohol etc.；Disintegrant, such as agar and Kelp Powder.
In order to make the pharmaceutical composition of suppository form shape, it can be used this field any known and widely used inborn nature
Agent, for example, polyethylene glycol, coconut oil, higher alcohol, the ester of higher alcohol, gelatin and semi-synthetic glyceride etc..
, can be by solution and suspension liquid disinfectant in order to prepare the pharmaceutical composition of injection form, and it is preferably added suitable chlorine
Change sodium, glucose or glycerine etc. are made and the isotonic injection of blood.When preparing injection, it is possible to use in the art any
Common carrier.For example, water, ethyl alcohol, propylene glycol, the isooctadecanol of ethoxylation, the isooctadecanol and polyethylene of polyoxy
The aliphatic ester etc. of anhydro sorbitol.In addition, common lytic agent, buffer and analgesic etc. can also be added.As needed, exist
During treating schizophrenia, colorant, preservative, fragrance, flavoring agent, sweetening agent and other medicines etc. can also be added.
In the present invention, the medication of the pharmaceutical composition is not particularly limited.Can according to patient age, gender and
Other conditions and symptom select the preparation of various dosage forms to be administered.For example, tablet, pill, solution, suspension, lotion, granule
It is oral medication with capsule；Injection can be administered alone, or (such as glucose solution and amino acid are molten with injection conveying liquid
Liquid) it is mixed into row vein injection, muscle can be carried out with injection, inject in intradermal, subcutaneous or abdomen merely if necessary；Suppository is
It is administered into rectum.
In the present invention, use can be properly selected according to method of administration, patient age, gender and other conditions and symptom
Pharmaceutical quantities.
Specific implementation mode
Embodiment 1：3- (((4,6- difluoros benzo [d] thiazol-2-yl) methyl) sulfenyl) -2- (2- (benzofuran -2- bases)
Acetylamino)-N- (acridine -9- bases) propionamide synthesis
1, the synthesis of S- ((4,6- difluoros benzo [d] thiazol-2-yl) methyl) cysteine
Cysteine (compound 1) (4.85g, 0.04mol) is dissolved in NaOH (80mL) solution of 2mol/L, is then existed
2- (chloromethyl) -4,6- difluoros benzo [d] thiazole (compound 2) (13.18g, 0.06mol) is added under condition of ice bath, then will
Mixture solution is stirred at room temperature to uniform.PH=5 is adjusted using acetic acid, a large amount of solid precipitations is generated, then filters and be used in combination
Water washing obtains S- ((4,6- difluoro benzo [d] thiazol-2-yl) methyl) cysteine (compound 3), 9.74g, yield
80%.1H-NMR(400MHz,CDCl3)δ:1.89(s,1H),2.02(s,1H),2.90(dd,1H),3.15(dd,1H),4.02
(t,1H),4.45(s,2H),7.34(t,1H),7.80(d,1H).13C-NMR(125MHz,CDCl3)δ:30.56,33.43,
56.03,104.03,112.59,137.51,138.68,156.01,158.07,159.06,173.56.LC-MS(ESI,pos,
ion)m/z:305[M+H]。
2, N- (((9H- fluorenes -9- bases) methoxyl group) carbonyl)-S- ((4,6- difluoros benzo [d] thiazol-2-yl) methyl) half Guang
The synthesis of propylhomoserin
Compound 3 (9.74g, 0.032mol) and (9H- fluorenes -9- bases) methylchloroformate (8.80g, 00.34mol) are added
To 10% Na2CO3In the mixture of (35mL) aqueous solution and the ethyl alcohol (30mL) newly distilled, and reaction is stirred 64 hours.Add
After entering water (80mL), reaction mixture is washed 3 times with ether.Water layer is carefully acidified to pH=3 with HCl, and gained is contained
There is the system of sediment in 4 DEG C of cool overnights, filters and washed with cold water.Obtain sepia solid N- (((9H- fluorenes -9- bases) first
Oxygroup) carbonyl)-S- ((4,6- difluoro benzo [d] thiazol-2-yl) methyl) cysteine (compound 4), 11.51g, yield
68.3%.1H-NMR(400MHz,CDCl3)δ:2.89(m,1H),3.14(m,1H),3.95(t,1H),4.42(s,2H),5.15-
5.21(m,3H),5.26(s,1H),7.23(t,2H),7.33(t,3H),7.64(d,2H),7.79(d,1H),7.89(d,2H)
.13C-NMR(125MHz,CDCl3)δ:30.56,32.36,48.95,56.36,66.63,104.03,112.59,120.89,
125.07,126.18,127.52,137.51,138.68,139.81,143.41,156.01,158.07,158.48,159.06,
174.84.LC-MS(ESI,pos,ion)m/z:527[M+H]。
3, ((3- (((4,6- difluoros benzo [d] thiazol-2-yl) methyl) sulfenyl) -1- (acridine -9- amino) -1- oxos third
Alkane -2- formic acid (9H- fluorenes -9- bases) base) carbamate synthesis
By compound 4 (11.51g, 0.022mol), acridine -9- bases amine (0.022mol) and p-methyl benzenesulfonic acid (~0.40g)
Suspension be placed in equipped with mechanical agitator, in the round-bottomed flask of oil bath and Dean-Stark condensers, by reaction mixture plus
Heat reflux (150-155 DEG C of internal temperature, 170-180 DEG C of oil bath temperature) 15-18 hours, while being monitored and being reacted by TLC.Reaction
After the completion, reactant is cooled to 80 DEG C, methanol (27mL) is slowly added to by dropping funel, after being added dropwise, keep reaction mixed
It closes object to be slowly cooled to room temperature under stiring, the solid being obtained by filtration simultaneously is washed with methanol (45mL), and is done at 100-120 DEG C
Dry 2 hours, obtain white solid ((3- (((4,6- difluoro benzo [d] thiazol-2-yl) methyl) sulfenyl) -1- (acridine -9- base ammonia
Base) -1- oxopropan -2- formic acid (9H- fluorenes -9- bases) base) carbamate (compound 5), 11.13g, yield 72%.1H-
NMR(400MHz,CDCl3)δ:2.90(m,1H),3.15(m,1H),4.18(t,1H),4.61(s,2H),5.39(t,1H),
5.75(d,1H),5.85(s,1H),7.20-7.35(m,5H),7.60-7.68(m,4H),7.80-7.90(m,7H),8.31
(dd,2H),9.85(s,1H).13C-NMR(125MHz,CDCl3)δ:30.56,32.17,48.95,53.3,66.63,104.03,
112.59,119.27,120.89,123.02,124.58,125.07,126.18,127.52,129.76,131.62,137.51,
138.68,139.81,143.41,143.89,148.9,156.01,158.07,158.48,159.06,168.37.LC-MS
(ESI,pos,ion)m/z:703[M+H]。
4,2- amino -3- (((4,6- difluoros benzo [d] thiazol-2-yl) methyl) sulfenyl)-N- (acridine -9- bases) propionamide
Synthesis
Compound 5 (11.13g, 0.016mol) is dissolved in CHCl3In (25.0mL), and be added piperidines (44mL,
0.48mol).Reaction mixture is stirred 24 hours, is evaporated in vacuo and removes volatile matter.Pass through column chromatography (SiO2；DCM/MeOH
=10:1) purified mixture obtains yellowish grease 2- amino -3- (((4,6- difluoro benzo [d] thiazol-2-yl) methyl)
Sulfenyl)-N- (acridine -9- bases) propionamide (compound 6), 5.77g, yield 75%.1H-NMR(400MHz,CDCl3)δ:1.72
(s,1H),2.47(s,1H),2.90(m,1H),3.14(m,1H),4.26(t,1H),4.55(s,2H),7.33(td,1H),
7.62(td,2H),7.79-7.85(m,5H),8.30(dd,2H),9.69(s,1H).13C-NMR(125MHz,CDCl3)δ:
30.56,34.13,53.19,104.03,112.59,119.27,123.02,124.58,129.76,131.62,137.51,
138.68,143.89,148.9,156.01,158.07,159.06,166.62.LC-MS(ESI,pos,ion)m/z:481[M+
H]。
5,3- (((4,6- difluoros benzo [d] thiazol-2-yl) methyl) sulfenyl) -2- (2- (benzofuran -2- bases) acetyl ammonia
Base)-N- (acridine -9- bases) propionamide synthesis
Compound 6 (5.77g, 0.012mol) is added in absolute ethyl alcohol (25.0mL), 2- (benzos are then gradually added into
Furans -2- bases) chloroacetic chloride (0.017mol), stirring, which is warming up to, reacts reflux.It reacts and finishes after about 6 hours, TLC monitorings reaction is eventually
Point.It after reaction solution is stood cooling, filters, a small amount of absolute ethyl alcohol washing filter cake is used in combination, obtains white solid product 3- (((4,6-
Difluoro benzo [d] thiazol-2-yl) methyl) sulfenyl) -2- (2- (benzofuran -2- bases) acetylamino)-N- (acridine -9- bases) third
Amide, 6.67g, yield 89%.1H-NMR(400MHz,CDCl3)δ:2.92(m,1H),3.16(m,1H),4.53(s,2H),
5.15(t,1H),7.22-7.38(m,5H),7.50(dd,1H),7.59-7.63(m,3H),7.80-7.86(m,5H),8.31
(dd,2H),9.60(s,1H).13C-NMR(125MHz,CDCl3)δ:30.56,32.17,52.37,104.03,110.52,
112.59,112.76,119.27,123.02,123.11,123.5,124.58,125.05,129.1,129.76,131.62,
137.51,138.68,143.89,148.9,149.82,154.43,156.01,158.07,159.06,159.75,
168.37.LC-MS(ESI,pos,ion)m/z:625[M+H]。
Embodiment 2：3- (((4,6- difluoros benzo [d] thiazol-2-yl) methyl) sulfenyl) -2- (2- (3- hydroxyls-benzo furan
Mutter -2- bases) acetylamino)-N- (acridine -9- bases) propionamide synthesis
Compound 6 (5.77g, 0.012mol) is added in absolute ethyl alcohol (25.0mL), 2- (3- hydroxyls are then gradually added into
Base-benzofuran -2- bases) chloroacetic chloride (0.017mol), stirring, which is warming up to, reacts reflux.It reacts and finishes after about 6 hours, TLC prisons
Survey reaction end.It after reaction solution is stood cooling, filters, a small amount of absolute ethyl alcohol washing filter cake is used in combination, obtains white solid product
3- (((4,6- difluoros benzo [d] thiazol-2-yl) methyl) sulfenyl) -2- (2- (3- hvdroxv-benzofuran -2- bases) acetyl ammonia
Base)-N- (acridine -9- bases) propionamide, 6.30g, yield 82%.LC-MS(ESI,pos,ion)m/z:641[M+H].
Embodiment 3：3- (((4,6- difluoros benzo [d] thiazol-2-yl) methyl) sulfenyl) -2- (2- (7- hydroxyls-benzo furan
Mutter -2- bases) acetylamino)-N- (acridine -9- bases) propionamide synthesis
Compound 6 (5.77g, 0.012mol) is added in absolute ethyl alcohol (25.0mL), 2- (7- hydroxyls are then gradually added into
Base-benzofuran -2- bases) chloroacetic chloride (0.017mol), stirring, which is warming up to, reacts reflux.It reacts and finishes after about 6 hours, TLC prisons
Survey reaction end.It after reaction solution is stood cooling, filters, a small amount of absolute ethyl alcohol washing filter cake is used in combination, obtains white solid product
3- (((4,6- difluoros benzo [d] thiazol-2-yl) methyl) sulfenyl) -2- (2- (7- hvdroxv-benzofuran -2- bases) acetyl ammonia
Base)-N- (acridine -9- bases) propionamide, 6.53g, yield 85%.LC-MS(ESI,pos,ion)m/z:641[M+H].
Test example part：
Test 1：Exon19 lacks EGFR (activation single mutant) cells phosphorylation test
Human pneumonocyte system PC9 (Exon19 lack EGFR) is maintained containing 10% fetal calf serum and 2mM glutamine
In RPMI1640.Cell is set to have 5%CO2Humidified incubator in 37 DEG C growth.By 40 μ L cells sowing (10000 cells/
Hole) in growth medium in 384 orifice plate of Coming black transparents bottom, in 5%CO under 37 degree2Middle overnight incubation.It uses
Echo555 sound waves determine dosage, and the compound of serial dilution in 100%DMSO is added to cell.Culture plate is further cultured for 2 hours,
After soft mixed culture medium, 40 μ L lysis buffers are added in each hole.By 384 orifice plate of Greiner black high-bond
With antibody covering is captured, then closed with 3%BSA.Then confining liquid is removed, 15 μ L lysates are transferred to Greiner
In 384 orifice plate of black high-bond, cultivate 2 hours.After softly mixing and cleaning culture plate with PBS, 20 μ L detections of addition are anti-
Body is cultivated 2 hours.After softly mixing and cleaning culture plate with PBS, 20 μ LQuantaBlu fluorescence peroxidase bottoms are added
Object is cultivated 1 hour.20 μ LQuantaBlu stop baths are added in culture plate, 352nm excitation wavelengths and 460nm are being used
The Envision micropore board detectors of launch wavelength read fluorescence.The data that each compound is obtained input suitable software package with
Execute curve fitting analysis.The compound concentration needed for 50% effect is obtained to determine IC based on this data and by calculating50Value.
Test 2：L858R/T790MEGFR (double-mutant) cells phosphorylation is tested
Human pneumonocyte system NCI-H1975 is maintained in the RPMI1640 containing 10% fetal calf serum and 2mM glutamine.
Cell is set to have 5%CO2Humidified incubator in 37 DEG C growth.By 40 μ L cells sowing (10000 cells/well) in Coming
In growth medium in 384 orifice plate of black transparent bottom, in 5%CO under 37 degree2Middle overnight incubation.Use Echo555 sound waves
Determine dosage, the compound of serial dilution in 100%DMSO is added into cell.Culture plate is further cultured for 2 hours, it is soft to be mixed
After base, 40 μ L lysis buffers are added in each hole.384 orifice plate of Greiner black high-bond is covered with capture antibody
Lid, is then closed with 3%BSA.Then confining liquid is removed, 15 μ L lysates are transferred to Greiner black high-bonds
In 384 orifice plates, cultivate 2 hours.After softly mixing and cleaning culture plate with PBS, 20 μ L of addition detect antibody, cultivate 2 hours.
After softly mixing and cleaning culture plate with PBS, 20 μ LQuantaBlu fluorescence peroxidase substrates are added, are cultivated 1 hour.
20 μ LQuantaBlu stop baths are added in culture plate, using 352nm excitation wavelengths and 460nm launch wavelengths
Envision micropore board detectors read fluorescence.The data that each compound obtains are inputted suitable software package to execute curve to intend
Close analysis.The compound concentration needed for 50% effect is obtained to determine IC based on this data and by calculating50Value.
Test 3：Wild type EGFR cells phosphorylation is tested
People's colon cell line LoVo is stored in the RPMI1640 of fetal calf serum and 2mM glutamine containing 3% stripping
In.Cell is set to have 5%CO2Humidified incubator in 37 DEG C growth.By 40 μ L cells sowing (10000 cells/well) in
In growth medium in 384 orifice plate of Corning black transparents bottom, in 5%CO under 37 degree2Middle overnight incubation.It uses
Echo555 sound waves determine dosage, and the compound of serial dilution in 100%DMSO is added to cell.Culture plate is further cultured for 2 hours,
After soft mixed culture medium, 40 μ L lysis buffers are added in each hole.By 384 orifice plate of Greiner black high-bond
With antibody covering is captured, then closed with 3%BSA.Then confining liquid is removed, 15 μ L lysates are transferred to Greiner
In 384 orifice plate of black high-bond, cultivate 2 hours.After softly mixing and cleaning culture plate with PBS, 20 μ L detections of addition are anti-
Body is cultivated 2 hours.After softly mixing and cleaning culture plate with PBS, 20 μ LQuantaBlu fluorescence peroxidase bottoms are added
Object is cultivated 1 hour.20 μ LQuantaBlu stop baths are added in culture plate, 352nm excitation wavelengths and 460nm are being used
The Envision micropore board detectors of launch wavelength read fluorescence.The data that each compound is obtained input suitable software package with
Execute curve fitting analysis.The compound concentration needed for 50% effect is obtained to determine IC based on this data and by calculating50Value.
Experimental result see the table below：
As seen from the above table, listed compound lacks EGFR (activation single mutant) cells and L858R/ to Exon19 in table
T790MEGFR (double-mutant) cell all has good activity, has better choice activity compared to Wild type EGFR cell,
And the compounds of this invention selectivity is suitable with AZD9291.It is possible thereby to deduce, the compounds of this invention can be used as treatment of cancer
Drug is developed, and may have advantage outstanding especially in non-small cell lung cancer.
Claims (7)
1. such as I compound represented of formula or its pharmaceutically acceptable salt,
Wherein, R1、R2、R3、R4And R5It is independently selected from H or OH.
2. formula I as described in claim 1, characterized in that be selected from following compound：
3. as described in claim 1 if I compound represented of formula or its pharmaceutically acceptable salt are as EGFR tyrosine-kinases
The application of enzyme inhibitor.
4. as described in claim 1 if I compound represented of formula or its pharmaceutically acceptable salt are in treating cancer drug
Application.
5. as described in claim 1 as the synthesis step of I compound represented of formula is：
6. a kind of pharmaceutical composition, it is characterised in that comprising such as I compound represented of formula and/or its pharmaceutically acceptable salt,
And one or more pharmaceutically acceptable carriers.
7. pharmaceutical composition as claimed in claim 5, it is characterized in that：Pharmaceutical composition be made tablet, pill, pulvis, liquid,
The dosage forms such as suspension, lotion, granule, capsule, suppository or injection.
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