CN105017160A - Pyrimidine EGFRT790M inhibitors and their synthesis method and use - Google Patents
Pyrimidine EGFRT790M inhibitors and their synthesis method and use Download PDFInfo
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- CN105017160A CN105017160A CN201510358764.2A CN201510358764A CN105017160A CN 105017160 A CN105017160 A CN 105017160A CN 201510358764 A CN201510358764 A CN 201510358764A CN 105017160 A CN105017160 A CN 105017160A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
Abstract
The invention discloses pyrimidine EGFRT790M inhibitors and their medicinal salt. The pyrimidine EGFRT790M inhibitors have a general structural formula shown in the following description. By a classical drug design and a structure-function relationship research method, an oxygen atom on a substituent group at a 4-site of a WZ4002 pyrimidine ring is replaced by an imino group, a methoxy group at the 2-site of a phenyl ring is further removed, the substituent group at a 4-site of the phenyl ring is subjected to structural modification, the modified structure replaces the original Michael receptor, seven unknown novel pyrimidine compounds are designed and synthesized so that more structure types of the pyrimidine EGFRT790M inhibitors are obtained. An in-vitro tumor activity test result shows that the compounds 8a and 8f have strong EGFRT790M kinase propagation inhibition activity. The pyrimidine EGFRT790M inhibitors provide reference for further design and synthesis of novel EGFRT790M inhibitors with higher activity and better selectivity.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of miazines EGFR
t790Minhibitor and synthetic method thereof and application.
Background technology
In recent years, EGF-R ELISA (EGFR) inhibitor is subject to the attention of chemist and medicine scholar always as nonsmall-cell lung cancer target therapeutic agent.At present, existing multiple EGFR inhibitor medicine enters clinical experimental stage or goes on the market successively.Wherein, be considered to the Iressa (Gefinitib) of first-generation EGFR inhibitor, the Kai Meina (Icotinib, listing in 2012) etc. of Erlotinib (Erlotinib) and China independent research listing obtains immense success in clinical NSCLC patient.But often obvious secondary resistance occurs after the treatment of 6 ~ 12 months, significantly limit the prolongation of survival of patients time, research at present thinks this resistance normally because EGFR 20 exon T790M misplaces caused by sudden change.2013, Boehringer Ingelheim company successfully developed first s-generation EGFR inhibitor Afatinib (BIBW2992), and its principal feature significantly can suppress EGFR
t790M, effectively reverse the resistance caused by T790M.But, Afatinib simultaneously also strongly inhibited Wild type EGFR (EGFR
wT), stop healthy tissues EGFR in body
wTthe activation of kinase whose phosphorylation and associated signal paths, thus bring larger poisonous side effect of medicine.
2009, Zhou etc. report first third generation miazines irreversible inhibitor WZ4002 (chemistry N-by name [3-[[the chloro-2-of 5-[[2-methoxyl group-4-(4-methyl isophthalic acid-piperazinyl) phenyl] is amino]-4-pyrimidyl] oxygen base] phenyl]-2-acrylamide), and this compound all embodies good EGFR in the inside and outside test of follow-up body
t790Mselective inhibitory, but finally because IP dispute stopped further research and development.In addition, existing EGFR second and third inhibitor in order to improve EGFR in generation
t790Minhibition, usually introduce in the structure and can produce covalently bound Michael acceptor (α with target protein, beta-unsaturated carbonyl structure fragment), thus cause the non-specific binding with multiple proteins, make them before clinical and show larger side effect and risk in clinical trial.
Summary of the invention
An object of the present invention is for reducing existing compound toxic side effect, provides a kind of novel pyrimidines EGFR
t790Minhibitor.
The invention provides a kind of miazines EGFR
t790Minhibitor, has following general structure (compound 8):
Wherein n=0 or 1; R is selected from-CH
3,-CH
2-CH
3,-F ,-Cl ,-Br ,-CF
3,-NHCOCH
3, any one in-N-CH=CH-N-,-C ≡ CH ,-NH-CH=CH-.
Further, described miazines EGFR
t790Minhibitor and pharmacologically acceptable salt thereof comprise:
8a：R＝4-NHCOCH
3，n＝0；
8b：R＝3-Br，n＝0；
8c：R＝3-CF
3，n＝0；
8d：R＝3，4，5-F，n＝0；
8e：R＝4-F，n＝1；
8f：R＝3-N-CH＝CH-N-4，n＝0；
8g：R＝3-C≡CH，n＝0。
The present invention also provides a kind of above-mentioned miazines EGFR
t790Mthe preparation method of inhibitor, its synthetic route is as follows:
With 2,4,5-trichloropyrimidine for raw material, under DIEA (DIPEA) base catalysis condition, there is nucleophilic substitution reaction with compound 2a-g, obtain compound 3a-g;
To fluoronitrobenzene under the weak base condition of salt of wormwood, be obtained by reacting compound 6 with compound 5, described compound 6 is obtained compound 7 by hydrogen reducing do the condition of catalyzer at palladium carbon under;
Described compound 7, under the effect of 2-butanols, reacts with described compound 3a-g, obtains target compound 8a-g.
Further, described synthetic route comprises the following steps:
Compound 2a-g and 2,4,5-trichloropyrimidine are dissolved in dry DMF, under agitation condition, add DIEA, back flow reaction, reaction terminates to add ultrapure water in backward reaction solution, separate out precipitation, will suction filtration be precipitated, washing leaching cake post-drying, and obtain compound 3a-g;
P-fluoronitrobenzene and 4-methylpiperazine (compound 5) are dissolved in dimethyl sulfoxide (DMSO), add salt of wormwood in stirring to react, react in backward reaction solution and add water, precipitation is separated out after cooling, by described precipitation suction filtration, filter cake obtains compound 6 after drying, described compound 6 is dissolved in methyl alcohol, slowly 10%Pd/C is added under stirring, and pass into hydrogen, normal-temperature reaction, after having reacted, by reaction solution suction filtration, use methanol wash filter cake, filtrate decompression revolves methyl alcohol, obtain concentrated solution, be extracted with ethyl acetate concentrated solution, merge organic phase, described organic phase is first washed with saturated nacl aqueous solution, use anhydrous sodium sulfate drying again, filter after dry, concentrating under reduced pressure filtrate, filtrate after described concentrating is obtained compound 7 through pillar layer separation,
Compound 3a-g and compound 7 are dissolved in 2-butanols, add trifluoroacetic acid under agitation condition, reflux, after reaction terminates, cool to room temperature, after reaction solution is regulated PH to neutrality with saturated sodium bicarbonate solution, is extracted with ethyl acetate, merge organic phase, by described organic phase first with saturated nacl aqueous solution washing, then use anhydrous sodium sulfate drying, filter after dry, concentrating under reduced pressure filtrate, obtains target compound 8a-g by the filtrate after described concentrating with pillar layer separation.
The present invention reoffers a kind of above-mentioned miazines EGFR
t790Minhibitor and the application of pharmacologically acceptable salt in preparation treatment antitumor drug thereof.
Further, described miazines EGFR
t790Minhibitor and pharmacologically acceptable salt thereof are preparing the application in the cell proliferation suppressing EGFR mutant overexpression or abnormal activation.
The present invention reoffers a kind of medicine, pharmaceutical composition or reagent, comprises above-mentioned miazines EGFR
t790Minhibitor and pharmacologically acceptable salt thereof.
Further, described medicine, pharmaceutical composition or reagent are for suppressing the cell proliferation of the overexpression of EGFR mutant or abnormal activation.
Further, described EGFR mutant is the EGFR kinases producing sudden change in T790M site.
Further, described medicine, pharmaceutical composition or reagent are used for the treatment of or prophylaxis of tumours.
Further, described tumour is EGFR dependent tumors.
Further, described tumour comprises lung cancer, intestinal cancer, ovarian cancer, kidney, bladder cancer, cavity cancer, cancer of the stomach or mammary cancer.
Beneficial effect of the present invention is: the present invention continues to use classical medicinal design and structure activity study method, Sauerstoffatom on WZ4002 pyrimidine ring 4-bit substituent is replaced with imino-, and the methoxyl group removed further on the phenyl ring of 2-position, carry out structural modification eventually through the substituting group on the phenyl ring of 4-position and substitute original Michael acceptor, design and synthesize the new pyrimidine compounds that 7 have no bibliographical information, enrich miazines EGFR
t790Mthe structure type of inhibitor.Anti tumor activity in vitro test result shows, compound 8a and 8f is to EGFR
t790Mkinases has stronger proliferation inhibition activity.Because of the Michael receptor structure fragment that such inhibitor eliminates, the covalent attachment of the residual generation of halfcystine in each albumen in inhibitor and body can be effectively avoided to react, reducing the toxic side effect in body, is the new E GFR that further design and synthesis activity is higher, selectivity is stronger
t790Minhibitor provides reference.
Embodiment
Hereafter will describe the present invention in detail in conjunction with specific embodiments.It should be noted that the combination of technical characteristic or the technical characteristic described in following embodiment should not be considered to isolated, they can mutually be combined thus be reached better technique effect.
Embodiment one
1.1 synthetic route
The synthesis of target compound is with 2,4,5-trichloropyrimidine (compound 1) is raw material, under DIEA alkaline condition, with tool there is nucleophilic substitution reaction in various substituent benzene (benzyl) amine (compound 2a-g), obtains 4-benzene (benzyl) amine pyrimidine class intermediate 3a-3g.Meanwhile, to fluoronitrobenzene (compound 4) at salt of wormwood (K
2cO
3) weak base condition under, be obtained by reacting compound 6 with to methylpiperazine (chemical combination 5), compound 6, through under Pd/C condition, is obtained Aniline intermediates 7 by hydrogen reducing.Finally, intermediate 7, under the effect of 2-butanols, reacts with 4-benzene (benzyl) the amine pyrimidine class intermediate 3a-3g previously obtained, obtains target compound 8a-8g respectively.
1.2 compound experiment
1.2.1 method (for 3a) is led in the synthesis of compound 3a ~ 3g
By 1.0g (6.66mmol) acetparaminosalol aniline (compound 2a), 1.22g (6.66mmol) 2,4,5-trichloropyrimidine (compound 1) is dissolved in the DMF (DMF) of 10mL drying.Under agitation condition, slowly add 0.9g (6.66mmol) salt of wormwood, 60 DEG C of back flow reaction 2h.Reaction terminates to add a large amount of ultrapure water in backward reaction solution, after separating out precipitation, and suction filtration.Filter cake obtains white intermediate (compound 3a) 1.5g after drying.Reaction yield 69.3% ~ 75.8%.
1.2.2 the synthesis of 4-(4-methylpiperazine) oil of mirbane (compound 6)
5.0g (35.44mmol) p-fluoronitrobenzene (compound 4) and 7.10g (70.87mmol) N methyl piperazine (compound 5) are dissolved in 20mL dimethyl sulfoxide (DMSO) (DMSO), 9.79g (70.87mmol) salt of wormwood is slowly added, after reaction 5h in stirring.Water is added in reaction solution, after precipitation is separated out in cooling, suction filtration.Filter cake obtains yellow target compound (compound 6), reaction yield 75.25% after drying.
1.2.3 the synthesis of 4-(4-methylpiperazine) aniline (compound 7)
1.0g 4-(4-methylpiperazine) oil of mirbane (compound 6) is dissolved in 20mL methyl alcohol, slowly adds the 10%Pd/C of catalytic amount under stirring, normal-temperature reaction 5h.Reaction solution suction filtration removing Pd/C, uses methanol wash filter cake.Filtrate decompression revolves methyl alcohol, ethyl acetate (30mL × 3) extracts, merge organic phase, saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure filtrate, pillar layer separation obtains 4-(4-methylpiperazine) aniline (compound 7) of 0.72g, reaction yield 83.2%.
1.2.4 method (for 8a) is led in the synthesis of target compound 8a ~ 8g
Midbody compound 3a and 0.5g (2.62mmol) 4-(4-methylpiperazine) aniline (compound 7) previously obtained by 1.56g (3.87mmol) is dissolved in 2-butanols (30mL), slowly instillation 0.19mL trifluoroacetic acid (TFA) under agitation condition.Reaction system is reflux 2h at 100 DEG C.After reaction terminates, cool to room temperature, adjust PH to neutral with saturated sodium bicarbonate solution successively, ethyl acetate (30mL × 3) extracts, and merges organic phase, saturated nacl aqueous solution washs, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure filtrate, pillar layer separation obtains the brown target product 8a of 1.414g, reaction yield 81%.
The physics and chemistry of 7 target compounds of synthesis and spectral data are in table 1.
Table 1 target compound physics and spectroscopic data 8a ~ 8g
Embodiment two
Anti tumor activity in vitro is tested
Adopt the method test target compound 8a ~ 8g of ELISA to EGFR
t790Mthe inhibit activities of protein kinase.Compound DMSO is diluted to institute's test concentrations from liquid storage.Enzyme reaction substrate Poly (Glu, Tyr) 4:1 coated elisa plate, puts 37 DEG C of reactions 12 ~ 16 hours.Discard liquid in hole.Plate is washed three times, dry enzyme plate 1 ~ 2 hour in 37 DEG C of baking ovens with PBST.Every hole adds with reaction buffer (50mM HEPES pH 7.4,50mM MgCl
2, 0.5mM MnCl
2, 0.2mM Na
3vO
4, 1mM DTT) and the ATP solution that dilutes, add compound to be tested, then add with the EGFR of reaction buffer dilution
t790Mkinase promoter reacts.Put 37 DEG C of shaking tables (100rpm) and react 1h.Discard liquid in hole, PBST washes plate three times.Add antibody PY99 diluent (the T-PBS 1:500 of antibody containing BSA 5mg/mL dilutes), 37 DEG C of shaking table reaction 0.5h.Discard liquid in hole, T-PBS washes plate three times.Add the anti-diluent of sheep anti mouse two (the T-PBS 1:2000 of antibody containing BSA5mg/mL dilutes) of horseradish peroxidase-labeled again, 37 DEG C of shaking table reaction 0.5h.Discard liquid in hole, PBST washes plate three times.Add OPD nitrite ion, 25 DEG C of lucifuge reaction 1-10 minute.Add 2M H
2sO
4termination reaction is that 490nm place measures absorbance, and the inhibiting rate of computerized compound when each concentration by the wavelengthtunable orifice plate microplate reader that declines at wavelength.Be positive control with WZ4002, experimental result is in table 2.Result display compound 8a and 8f all effectively can suppress EGFR under three concentration
t790Mactive (inhibiting rate is all greater than 50%), wherein the inhibit activities of 8f is the highest, and other target compounds are to EGFR
t790Mall more weak (the 0.1 μm of olL of kinase inhibiting activity
-1inhibiting rate is all less than 50%).
Table 2 target compound is to EGFR
t790Minhibit activities
The present invention continues to use classical medicinal design and structure activity study method, Sauerstoffatom on WZ4002 pyrimidine ring 4-bit substituent is replaced with imino-, and the methoxyl group removed further on the phenyl ring of 2-position, carry out structural modification eventually through the substituting group on the phenyl ring of 4-position and substitute original Michael acceptor, design and synthesize the new pyrimidine compounds that 7 have no bibliographical information.
The present invention with third generation EGFR inhibitor WZ4002 for lead compound, main to the Michael receptor structure fragment of poisonous side effect of medicine may be caused to transform, acrylamide group in WZ4002 pyrimidine parent nucleus 4-anilino is replaced with other non-Michael receptor structures, expects that improved compound retains EGFR by other non covalent bond reactive forces
t790Mrestraining effect.Utilize brief, effective chemical synthesis route, we have synthesized 7 new compounds altogether, have enriched miazines EGFR
t790Mthe structure type of inhibitor.Anti tumor activity in vitro test result shows, compound 8a and 8f is to EGFR
t790Mkinases has stronger proliferation inhibition activity, and close to the activity of positive control medicine WZ4002, and other compounds embody more weak anti-tumor activity.Molecular docking result shows, and defines Hyarogen-bonding with the carbonyl of the quinazoline group in compound 8f structure and amino-acid residue Gln-791, compensate for the loss of activity after this position removing Michael acceptor to a certain extent.For the new E GFR that further design and synthesis activity is higher, selectivity is stronger
t790Minhibitor provides reference.
Although give some embodiments of the present invention, it will be understood by those of skill in the art that without departing from the spirit of the invention herein, can change embodiment herein.Above-described embodiment is exemplary, should using embodiment herein as the restriction of interest field of the present invention.
Claims (10)
1. a miazines EGFR
t790Minhibitor and pharmacologically acceptable salt thereof, have following general structure:
Wherein n=0 or 1; R is selected from-CH
3,-CH
2-CH
3,-F ,-Cl ,-Br ,-CF
3,-NHCOCH
3, any one in-N-CH=CH-N-,-C ≡ CH ,-NH-CH=CH-.
2. miazines EGFR as claimed in claim 1
t790Minhibitor and pharmacologically acceptable salt thereof, is characterized in that, described miazines EGFR
t790Minhibitor and pharmacologically acceptable salt thereof comprise:
8a：R＝4-NHCOCH
3，n＝0；
8b：R＝3-Br，n＝0；
8c：R＝3-CF
3，n＝0；
8d：R＝3，4，5-F，n＝0；
8e：R＝4-F，n＝1；
8f：R＝3-N-CH＝CH-N-4，n＝0；
8g：R＝3-C≡CH，n＝0。
3. miazines EGFR as claimed in claim 1
t790Mthe preparation method of inhibitor, its synthetic route is as follows:
With 2,4,5-trichloropyrimidine for raw material, under DIEA base catalysis condition, there is nucleophilic substitution reaction with compound 2a-g, obtain compound 3a-g;
To fluoronitrobenzene under the weak base condition of salt of wormwood, be obtained by reacting compound 6 with compound 5, described compound 6 is obtained compound 7 by hydrogen reducing do the condition of catalyzer at palladium carbon under;
Described compound 7, under the effect of 2-butanols, reacts with described compound 3a-g, obtains target compound 8a-g.
4. miazines EGFR as claimed in claim 3
t790Mthe preparation method of inhibitor, is characterized in that, described synthetic route comprises the following steps:
Compound 2a-g and 2,4,5-trichloropyrimidine are dissolved in dry DMF, under agitation condition, add DIEA, back flow reaction, reaction terminates to add ultrapure water in backward reaction solution, separate out precipitation, will suction filtration be precipitated, washing leaching cake post-drying, after obtain compound 3a-g;
Be dissolved in dimethyl sulfoxide (DMSO) by p-fluoronitrobenzene and 4-methylpiperazine, add salt of wormwood and react in stirring, react in backward reaction solution and add water, separate out precipitation after cooling, by described precipitation suction filtration, filter cake obtains compound 6 after drying; Described compound 6 is dissolved in methyl alcohol, slowly adds 10%Pd/C under stirring, and pass into hydrogen, normal-temperature reaction, after having reacted, by reaction solution suction filtration, use methanol wash filter cake, filtrate decompression revolves methyl alcohol, obtains concentrated solution, be extracted with ethyl acetate concentrated solution, merge organic phase, described organic phase is first washed with saturated nacl aqueous solution, use anhydrous sodium sulfate drying again, filter after dry, concentrating under reduced pressure filtrate, the filtrate after described concentrating is obtained compound 7 through pillar layer separation;
Compound 3a-g and compound 7 are dissolved in 2-butanols, add trifluoroacetic acid under agitation condition, reflux, after reaction terminates, cool to room temperature, after reaction solution is regulated PH to neutrality with saturated sodium bicarbonate solution, is extracted with ethyl acetate, merge organic phase, by described organic phase first with saturated nacl aqueous solution washing, then use anhydrous sodium sulfate drying, filter after dry, concentrating under reduced pressure filtrate, obtains target compound 8a-g by the filtrate after described concentrating with pillar layer separation.
5. miazines EGFR as claimed in claim 1
t790Minhibitor and the application of pharmacologically acceptable salt in preparation treatment antitumor drug thereof.
6. miazines EGFR as claimed in claim 1
t790Minhibitor and pharmacologically acceptable salt thereof are preparing the application in the cell proliferation suppressing EGFR mutant overexpression or abnormal activation.
7. a medicine, is characterized in that, comprises miazines EGFR according to claim 1
t790Minhibitor and pharmacologically acceptable salt thereof.
8. medicine as claimed in claim 7, it is characterized in that, described medicine is for suppressing the cell proliferation of the overexpression of EGFR mutant or abnormal activation.
9. medicine as claimed in claim 8, is characterized in that, described EGFR mutant is the EGFR kinases producing sudden change in T790M site.
10. medicine as claimed in claim 9, it is characterized in that, described medicine is used for the treatment of or prophylaxis of tumours; Described tumour is EGFR dependent tumors, comprises lung cancer, intestinal cancer, ovarian cancer, kidney, bladder cancer, cavity cancer, cancer of the stomach or mammary cancer.
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| WO2022206797A1 (en) * | 2021-03-30 | 2022-10-06 | 贝达药业股份有限公司 | Egfr inhibitor, and composition and use thereof |
| CN114105887A (en) * | 2021-09-16 | 2022-03-01 | 沈阳药科大学 | Aminopyrimidine derivative and preparation method and application thereof |
| WO2023040537A1 (en) * | 2021-09-16 | 2023-03-23 | 沈阳药科大学 | Aminopyrimidine derivative, preparation method therefor and use thereof |
| CN114105887B (en) * | 2021-09-16 | 2023-12-01 | 沈阳药科大学 | Aminopyrimidine derivative and preparation method and application thereof |
| CN114957216A (en) * | 2022-05-25 | 2022-08-30 | 四川省医学科学院·四川省人民医院 | Target inhibitor, preparation method, application and pharmaceutical composition thereof |
| CN114957216B (en) * | 2022-05-25 | 2024-03-08 | 四川省医学科学院·四川省人民医院 | Target inhibitor, preparation method, application and pharmaceutical composition thereof |
| CN115181100A (en) * | 2022-07-27 | 2022-10-14 | 广西大学 | Sulfonamide micromolecule inhibitor with purine and pyrrolopyrimidine parent nucleus |
| CN115894381A (en) * | 2022-11-11 | 2023-04-04 | 温州医科大学 | 2,4,5-trisubstituted pyrimidine compound and preparation method and application thereof |
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