CN105017160B - A kind of miazines EGFRT790MInhibitor and its synthetic method and application - Google Patents

A kind of miazines EGFRT790MInhibitor and its synthetic method and application Download PDF

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Publication number
CN105017160B
CN105017160B CN201510358764.2A CN201510358764A CN105017160B CN 105017160 B CN105017160 B CN 105017160B CN 201510358764 A CN201510358764 A CN 201510358764A CN 105017160 B CN105017160 B CN 105017160B
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compound
egfr
inhibitor
miazines
medicine
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CN105017160A (en
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刘志国
张颖
宋乔乔
潘恺凌
叶清清
李珊珊
韩田振
梁广
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Yaogu (Wenzhou) Technology Development Co.,Ltd.
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Wenzhou Medical University
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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 a kind of miazines EGFRT790MInhibitor and its officinal salt, there is following general structure：.The present invention continues to use drug design and the structure activity study method of classics, oxygen atom on the bit substituent of WZ4002 pyrimidine rings 4 is replaced with into imino group, and further remove the methoxyl group on 2 phenyl ring, structural modification, which is carried out, eventually through the substituent on 4 phenyl ring substitutes original Michael acceptors, 7 novel pyrimidines for having no document report compounds have been designed and synthesized, have enriched miazines EGFRT790MThe structure type of inhibitor.Anti tumor activity in vitro test result shows that 8a and 8f are to EGFR for compoundT790MKinases has stronger proliferation inhibition activity.For the new E GFR that further design synthesizing activity is higher, selectivity is strongerT790MInhibitor provides reference.

Description

A kind of miazines EGFRT790MInhibitor and its synthetic method and application
Technical field
The invention belongs to medicinal chemistry art, and in particular to a kind of miazines EGFRT790MInhibitor and its synthetic method and Using.
Background technology
In recent years, EGF-R ELISA (EGFR) inhibitor as non-small cell lung cancer target therapeutic agent always by To the attention of chemist and medicine scholar.At present, existing a variety of EGFR inhibitor medicines enter clinical experimental stage or successively on City.Wherein, it is considered to be Iressa (Gefinitib), Erlotinib (Erlotinib) and China of first generation EGFR inhibitor are certainly Kai Meina (Icotinib, listing for 2012) of main research and development listing etc. obtains immense success in clinical NSCLC Case treatments. But obvious secondary resistance often occurs after the treatment of 6~12 months, significantly limit prolonging for survival of patients time Long, research at present thinks that this resistance is often as caused by the exon T790M of EGFR 20 dislocation mutation.2013, Boehringer Ingelheim companies successfully develop first second generation EGFR inhibitor Afatinib (BIBW2992), and it is led It is that can significantly inhibit EGFR to want featureT790M, effectively reverse the resistance caused by T790M.But Afatinib is simultaneously also strong Suppress Wild type EGFR (EGFRWT), prevent internal normal structure EGFRWTThe phosphorylation of kinases and the activation of associated signal paths, So as to bring larger poisonous side effect of medicine.
2009, Zhou etc. reported the first third generation miazines irreversible inhibitor WZ4002 (entitled N- [3- of chemistry [[the chloro- 2- of 5- [[2- methoxyl groups -4- (4- methyl isophthalic acids-piperazinyl) phenyl] amino] -4- pyrimidine radicals] epoxide] phenyl] -2- propylene Acid amides), the compound embodies good EGFR inside subsequently, in outer experimentT790MSelective inhibitory, but finally Because IP dispute stopped further research and development.In addition, second and third generation inhibitor of existing EGFR is in order to improve pair EGFRT790MInhibition, covalently bound Michael acceptors (α, β-no can be produced with target protein by generally introducing in the structure Saturation carbonyl structure fragment), so as to cause the non-specific binding with multiple proteins so that they are in preclinical and clinical examination Larger side effect and risk are shown in testing.
The content of the invention
An object of the present invention is to reduce existing compound toxic side effect, there is provided a kind of novel pyrimidines EGFRT790M Inhibitor.
The present invention provides a kind of miazines EGFRT790MInhibitor, there is following general structure (compound 8)：
Wherein n=0 or 1；R is selected from-CH3、-CH2-CH3、-F、-Cl、-Br、-CF3、-NHCOCH3,-N-CH=CH-N- ,- Any of C ≡ CH ,-NH-CH=CH-.
Further, described miazines EGFRT790MInhibitor and its officinal salt include：
8a：R=4-NHCOCH3, n=0；
8b：R=3-Br, n=0；
8c：R=3-CF3, 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 EGFRT790MThe preparation method of inhibitor, its synthetic route are as follows：
With 2,4,5- trichloropyrimidines for raw material, under the conditions of DIEA (DIPEA) base catalysis with compound Nucleophilic substitution occurs for 2a-g, obtains compound 3a-g；
To fluoronitrobenzene under the conditions of the weak base of potassium carbonate, compound 6 is obtained with the reaction of compound 5, the compound 6 exists Under conditions of palladium carbon makees catalyst, compound 7 is obtained by hydrogen reducing；
The compound 7 is reacted with the compound 3a-g under the effect of 2- butanol, obtains target compound 8a-g.
Further, the synthetic route comprises the following steps：
By compound 2a-g and 2,4,5- trichloropyrimidines are dissolved in dry DMF, stirring condition Under, DIEA, back flow reaction are added, reaction terminates to add ultra-pure water in backward reaction solution, separates out precipitation, precipitation is filtered, washing Dried after filter cake, obtain compound 3a-g；
P-fluoronitrobenzene and 4- methyl piperazines (compound 5) are dissolved in dimethyl sulfoxide (DMSO), potassium carbonate is added in stirring Reacted, react and add water in backward reaction solution, precipitation is separated out after cooling, the precipitation is filtered, filter cake is changed after drying Compound 6, the compound 6 is dissolved in methanol, 10%Pd/C is slowly added under stirring, and be passed through hydrogen, normal-temperature reaction, After the completion of reaction, reaction solution is filtered, washs filter cake with methanol, filtrate decompression rotation removes methanol, obtains concentrate, use ethyl acetate Concentrate is extracted, merges organic phase, the organic phase is first washed with saturated nacl aqueous solution, then with anhydrous sodium sulfate drying, Filtered after drying, be concentrated under reduced pressure filtrate, and the filtrate after the concentration is obtained into compound 7 through pillar layer separation；
Compound 3a-g and compound 7 are dissolved in 2- butanol, trifluoroacetic acid is added under stirring condition, is heated to reflux, instead After should terminating, room temperature is cooled to, by reaction solution with after saturated sodium bicarbonate solution regulation PH to neutrality, is extracted with ethyl acetate, Merge organic phase, the organic phase first washed with saturated nacl aqueous solution, then with anhydrous sodium sulfate drying, filtered after drying, Be concentrated under reduced pressure filtrate, and the filtrate after the concentration is obtained into target compound 8a-g with pillar layer separation.
The present invention provides a kind of above-mentioned miazines EGFR againT790MInhibitor and its officinal salt are preparing treatment antineoplastic Application in thing.
Further, described miazines EGFRT790MInhibitor and its officinal salt are preparing suppression EGFR mutant mistakes Application in the cell proliferation of degree expression or abnormal activation.
The present invention provides a kind of medicine, pharmaceutical composition or reagent, including above-mentioned miazines EGFR againT790MInhibitor and Its officinal salt.
Further, the medicine, pharmaceutical composition or reagent are used to suppress EGFR mutant overexpression or abnormal sharp Cell propagation living.
Further, the EGFR mutant is to produce the EGFR kinases of mutation in T790M sites.
Further, the medicine, pharmaceutical composition or reagent are used to treat or prevent tumour.
Further, the tumour is EGFR dependent tumors.
Further, the tumour includes lung cancer, intestinal cancer, oophoroma, kidney, carcinoma of urinary bladder, cavity cancer, stomach cancer or mammary gland Cancer.
The beneficial effects of the present invention are：The present invention continues to use drug design and the structure activity study method of classics, will Oxygen atom on WZ4002 pyrimidine ring 4- bit substituents replaces with imino group, and further removes the methoxyl group on the phenyl ring of 2- positions, Structural modification is carried out eventually through the substituent on the phenyl ring of 4- positions and substitutes original Michael acceptors, has designed and synthesized 7 The novel pyrimidines compound of document report is had no, enriches miazines EGFRT790MThe structure type of inhibitor.Extracorporeal anti-tumor Active testing result shows that 8a and 8f are to EGFR for compoundT790MKinases has stronger proliferation inhibition activity.Because such inhibitor is gone Except Michael receptor structure fragments, it is possible to prevente effectively from caused by inhibitor and cysteine in internal each albumen are residual altogether Valency association reaction, internal toxic side effect is reduced, for further design synthesizing activity is higher, selectivity is stronger new EGFRT790MInhibitor provides reference.
Embodiment
The present invention is described in detail below in conjunction with specific embodiment.It should be noted that the skill described in following embodiments The combination of art feature or technical characteristic is not construed as isolated, and they can be mutually combined so as to reach more preferable Technique effect.
Embodiment one
1.1 synthetic route
The synthesis of target compound be with 2,4,5- trichloropyrimidines (compound 1) for raw material, under DIEA alkalescence conditions with Nucleophilic substitution occurs for benzene (benzyl) amine (compound 2a-g) for having various substituents, obtains among 4- benzene (benzyl) amine pyrimidine class Body 3a-3g.Meanwhile to fluoronitrobenzene (compound 4) in potassium carbonate (K2CO3) weak base under the conditions of, and to methyl piperazine (chemical combination 5) reaction obtains compound 6, and compound 6 is through under the conditions of Pd/C, Aniline intermediates 7 are obtained by hydrogen reducing.Finally, intermediate 7 under the effect of 2- butanol, is reacted with 4- benzene (benzyl) the amine pyrimidine class intermediate 3a-3g previously obtained, respectively obtains targeted Compound 8a-8g.
1.2 compound experiment
1.2.1 method is led in compound 3a~3g synthesis (by taking 3a as an example)
1.0g (6.66mmol) acetparaminosalol aniline (compound 2a), 1.22g (6.66mmol) 2,4,5- trichlorines is phonetic Pyridine (compound 1) is dissolved in the N,N-dimethylformamide (DMF) of 10mL dryings.Under stirring condition, 0.9g is slowly added into (6.66mmol) potassium carbonate, 60 DEG C of back flow reaction 2h.Reaction terminates to add a large amount of ultra-pure waters in backward reaction solution, separates out precipitation Afterwards, filter.White intermediate (compound 3a) 1.5g is obtained after filter cake drying.Reaction yield 69.3%~75.8%.
1.2.2 the synthesis of 4- (4- methyl piperazines) nitrobenzene (compound 6)
By 5.0g (35.44mmol) p-fluoronitrobenzene (compound 4) and 7.10g (70.87mmol) N methyl piperazine (chemical combination Thing 5) it is dissolved in 20mL dimethyl sulfoxide (DMSO)s (DMSO), 9.79g (70.87mmol) potassium carbonate is slowly added into stirring, reacts 5h Afterwards.Water is added into reaction solution, after cooling separates out precipitation, is filtered.Yellow target compound (compound is obtained after filter cake drying 6), reaction yield 75.25%.
1.2.3 the synthesis of 4- (4- methyl piperazines) aniline (compound 7)
1.0g 4- (4- methyl piperazines) nitrobenzene (compound 6) is dissolved in 20mL methanol, is slowly added to urge under stirring The 10%Pd/C of change amount, normal-temperature reaction 5h.Reaction solution, which filters, removes Pd/C, and filter cake is washed with methanol.Methanol is removed in filtrate decompression rotation, Ethyl acetate (30mL × 3) extracts, and merges organic phase, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filters, decompression Filtrate is concentrated, pillar layer separation obtains 0.72g 4- (4- methyl piperazines) aniline (compound 7), reaction yield 83.2%.
1.2.4 method is led in target compound 8a~8g synthesis (by taking 8a as an example)
Midbody compound 3a and 0.5g (2.62mmol) 4- (4- methyl piperazines that 1.56g (3.87mmol) had previously been obtained Piperazine) aniline (compound 7) is dissolved in 2- butanol (30mL), 0.19mL trifluoroacetic acids (TFA) are slowly dropped under stirring condition.Instead System is answered to be heated to reflux 2h at 100 DEG C.After reaction terminates, room temperature is cooled to, adjusts PH extremely with saturated sodium bicarbonate solution successively Neutrality, ethyl acetate (30mL × 3) extraction, merge organic phase, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, filter, Be concentrated under reduced pressure filtrate, and pillar layer separation obtains 1.414g brown target product 8a, reaction yield 81%.
The physics and chemistry and spectral data of 7 target compounds of synthesis are shown in Table 1.
The target compound physics of table 1 and spectroscopic data 8a~8g
Embodiment two
Anti tumor activity in vitro is tested
Using ELISA method test target compound 8a~8g to EGFRT790MThe inhibitory activity of protein kinase.By chemical combination Thing is diluted to institute's test concentrations with DMSO from liquid storage.Enzyme reaction substrate Poly (Glu, Tyr) 4:1 coated elisa plate, put 37 DEG C instead Answer 12~16 hours.Discard liquid in hole.With PBST board-washings three times, ELISA Plate is dried in 37 DEG C of baking ovens 1~2 hour.Per hole Add with reaction buffer (50mM HEPES pH 7.4,50mM MgCl2, 0.5mM MnCl2, 0.2mM Na3VO4, 1mM DTT) the ATP solution of dilution, adds compound to be tested, adds the EGFR diluted with reaction bufferT790MKinase promoter is anti- Should.Put 37 DEG C of shaking table (100rpm) reaction 1h.Liquid in hole is discarded, PBST board-washings are three times.It is (anti-to add antibody PY99 dilutions Body 5mg/mL containing BSA T-PBS 1:500 dilutions), 37 DEG C of shaking tables react 0.5h.Discard liquid in hole, T-PBS board-washings three It is secondary.Add sheep anti mouse secondary antibody dilution (antibody 5mg/mL containing the BSA T-PBS 1 of horseradish peroxidase-labeled: 2000 dilutions), 37 DEG C of shaking tables react 0.5h.Liquid in hole is discarded, PBST board-washings are three times.Add OPD nitrite ions, 25 DEG C of lucifuges React 1-10 minutes.Add 2M H2SO4Terminating reaction, with wavelengthtunable decline orifice plate ELIASA wavelength be at 490nm determine Absorbance, and calculate inhibiting rate of the compound in each concentration.Using WZ4002 as positive control, experimental result is shown in Table 2.Knot Fruit shows that compound 8a and 8f can effectively suppress EGFR under three concentrationT790MActive (inhibiting rate is all higher than 50%), wherein 8f inhibitory activity highest, other target compounds are to EGFRT790MWeaker (the 0.1 μm of olL of kinase inhibiting activity-1Suppress 50%) rate is respectively less than.
The target compound of table 2 is to EGFRT790MInhibitory activity
The present invention continues to use drug design and the structure activity study method of classics, by WZ4002 pyrimidine ring 4- bit substituents Oxygen atom replace with imino group, and the methoxyl group on the phenyl ring of 2- positions is further removed, eventually through the substitution on the phenyl ring of 4- positions Base carries out structural modification and substitutes original Michael acceptors, has designed and synthesized 7 novel pyrimidines for having no document report Compound.
The present invention is using third generation EGFR inhibitor WZ4002 as lead compound, mainly to that may cause poisonous side effect of medicine Michael receptor structure fragments transformed, acrylamide group in WZ4002 pyrimidine parent nucleus 4- anilino-s is replaced with it His non-Michael receptor structures, expect that improved compound can be tried hard to keep by other non-covalent bond effects and stay to EGFRT790M's Inhibitory action.Using brief, effective chemical synthesis route, we have synthesized 7 new compounds, have enriched miazines altogether EGFRT790MThe structure type of inhibitor.Anti tumor activity in vitro test result shows that 8a and 8f are to EGFR for compoundT790MKinases Have stronger proliferation inhibition activity, close to positive control medicine WZ4002 activity, and other compounds embody it is weaker Antitumor activity.Molecular docking result is shown, with the quinazoline group in compound 8f structures and amino acid residue Gln-791 Carbonyl form Hyarogen-bonding, compensate for a certain extent on the position remove Michael acceptors after loss of activity.For Further design the new E GFR that synthesizing activity is higher, selectivity is strongerT790MInhibitor provides reference.
Although having been presented for some embodiments of the present invention herein, it will be appreciated by those of skill in the art that Without departing from the spirit of the invention, the embodiments herein can be changed.Above-described embodiment be it is exemplary, no Restriction that should be using the embodiments herein as interest field of the present invention.

Claims (10)

  1. A kind of 1. miazines EGFRT790MInhibitor and its officinal salt, it is compound 8a or 8f, there is following general structure：
    8a：R=4-NHCOCH3, n=0；
    8f：R=3-N-CH=CH-N-4, n=0.
  2. 2. miazines EGFR as claimed in claim 1T790MThe preparation method of inhibitor, its synthetic route are as follows：
    2a、3a、8a：R=4-NHCOCH3, n=0；
    2f、3f、8f：R=3-N-CH=CH-N-4, n=0
    It is anti-with compound 2a or 2f generation nucleophilic displacement of fluorine under the conditions of DIEA base catalysis with 2,4,5- trichloropyrimidines for raw material Should, obtain compound 3a or 3f；
    To fluoronitrobenzene under the conditions of the weak base of potassium carbonate, compound 6 is obtained with the reaction of compound 5, the compound 6 is in palladium carbon Under conditions of making catalyst, compound 7 is obtained by hydrogen reducing；
    The compound 7 is reacted with the compound 3a or 3f under the effect of 2- butanol, obtains target compound 8a or 8f.
  3. 3. miazines EGFR as claimed in claim 2T790MThe preparation method of inhibitor, it is characterised in that the synthetic route Comprise the following steps：
    By compound 2a or 2f and 2,4,5- trichloropyrimidines are dissolved in dry DMF, under stirring condition, DIEA, back flow reaction are added, reaction terminates to add ultra-pure water in backward reaction solution, separates out precipitation, precipitation is filtered, wash filter cake After dry, after obtain compound 3a or 3f；
    P-fluoronitrobenzene and 4- methyl piperazines are dissolved in dimethyl sulfoxide (DMSO), potassium carbonate is added in stirring and is reacted, is reacted Add water in backward reaction solution, precipitation is separated out after cooling, the precipitation is filtered, filter cake obtains compound 6 after drying；By describedization Compound 6 is dissolved in methanol, and 10%Pd/C is slowly added under stirring, and is passed through hydrogen, normal-temperature reaction, will be anti-after the completion of reaction Answer liquid to filter, wash filter cake with methanol, filtrate decompression rotation removes methanol, obtains concentrate, concentrate is extracted with ethyl acetate, merges Organic phase, the organic phase is first washed with saturated nacl aqueous solution, then with anhydrous sodium sulfate drying, filtered after drying, depressurized Filtrate is concentrated, the filtrate after the concentration is obtained into compound 7 through pillar layer separation；
    Compound 3a or 3f and compound 7 are dissolved in 2- butanol, trifluoroacetic acid is added under stirring condition, is heated to reflux, is reacted After end, room temperature is cooled to, by reaction solution with after saturated sodium bicarbonate solution regulation PH to neutrality, is extracted with ethyl acetate, closes And organic phase, the organic phase is first washed with saturated nacl aqueous solution, then with anhydrous sodium sulfate drying, filter, subtract after drying Pressure concentration filtrate, target compound 8a or 8f are obtained by the filtrate after the concentration with pillar layer separation.
  4. 4. miazines EGFR as claimed in claim 1T790MInhibitor and its officinal salt are in treatment antineoplastic is prepared Application.
  5. 5. miazines EGFR as claimed in claim 1T790MInhibitor and its officinal salt are preparing suppression EGFR mutant mistakes Application in the cell proliferation of degree expression or abnormal activation.
  6. 6. a kind of medicine, it is characterised in that including the miazines EGFR described in claim 1T790MInhibitor and its officinal salt.
  7. 7. medicine as claimed in claim 6, it is characterised in that the medicine is used to suppress the overexpression or different of EGFR mutant The cell propagation often activated.
  8. 8. medicine as claimed in claim 7, it is characterised in that the EGFR mutant is to produce mutation in T790M sites EGFR kinases.
  9. 9. medicine as claimed in claim 8, it is characterised in that the medicine is used to treat or prevent tumour；The tumour choosing From EGFR dependent tumors.
  10. 10. medicine according to claim 9, it is characterised in that described tumour is selected from lung cancer, intestinal cancer, oophoroma, kidney Cancer, carcinoma of urinary bladder, cavity cancer, stomach cancer or breast cancer.
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