CN105884777B - One kind acts on EGFR sensitizing mutation kinases EGFRL858R, EGFR(d746‑750)6 substituted amino purine class compounds and its application - Google Patents

One kind acts on EGFR sensitizing mutation kinases EGFRL858R, EGFR(d746‑750)6 substituted amino purine class compounds and its application Download PDF

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CN105884777B
CN105884777B CN201510315178.XA CN201510315178A CN105884777B CN 105884777 B CN105884777 B CN 105884777B CN 201510315178 A CN201510315178 A CN 201510315178A CN 105884777 B CN105884777 B CN 105884777B
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egfr
substituted amino
compound
kinases
officinal salt
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CN105884777A (en
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叶发青
王宇
王跃武
俞淑芳
陈弟
陈梁芳
宋晓琴
谢自新
梁广
李校堃
刘志国
林丹
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Wenzhou Medical University
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Wenzhou Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine

Abstract

The invention discloses the 6 substituted amino purine compounds with the following chemical structure and its officinal salt,Wherein：R isOrR1 is hydrogen, fluorine, chlorine, bromine, methoxyl group or hydroxyl.The present invention provides 6 new substituted amino purine compounds and its officinal salt, and the suppression to EGFR kinases has selectivity, can effectively suppress EGFR sensitizing mutation kinases EGFRL858R, EGFR(d746‑750)Activity, but to EGFRWTKinases does not have inhibition, so can both suppress the cell propagation of the overexpression of EGFR mutant or abnormal activation, so as to efficiently treat tumour, can avoid again because suppressing to normal structure EGFR in human bodyWTThe phosphorylation of kinases and the activation of associated signal paths, so as to bring larger toxic side effect, the drug responses such as fash, vomiting occur, improve therapeutic effect, reduce side reaction.

Description

One kind acts on EGFR sensitizing mutation kinases EGFRL858R, EGFR(d746-750)6- take For adenine phosphate class compound and its application
Technical field
The invention belongs to technical field of medical chemistry, more particularly to one kind to act on selective depression EGFR sensitizing mutations and swash Enzyme EGFRL858R, EGFR(d746-750)Active 6- substituted amino purines class compound and its application.
Background technology
Increasing with the life stress of people, living environment worse and worse, also get over compared to past by the incidence of disease of cancer Come higher, therefore, the method for the treatment of of cancer and the effect for the treatment of are increasingly by the care and concern of medical personal.It is near several Year, antineoplastic there has also been new progress, study more popular new antitumoral so far with the development of science and technology Medicine has：Novel cell cytotoxic drug, endocrine therapeutic agents, genomic medicine, immunotherapy medicaments and molecular targeted antineoplastic Thing.Wherein, the receptor tyrosine kinase inhibitors in molecular targeted antineoplastic and angiogenesis pathway inhibitor have good Good prospect.
EGF-R ELISA (EGFR) is a kind of phosphorylating protein, is arranged by specific tyrosine residue sequence The protein of row.EGF-R ELISA (EGFR) belongs to one of ErbB family members, and it is common with HER2, HER3 and HER4 Form ErbB extended familys.Research shows high expression or the unconventionality expression that EGFR in many entity tumors be present.EGFR and tumour The propagation of cell, angiogenesis, tumor invasion, transfer and the suppression of Apoptosis are relevant.Its mechanism has：EGFR height Expression causes the enhancing of downstream signal transduction；The increase of mutant egf R acceptors or ligand expression causes EGFR continuous activation； The effect enhancing of autocrine loop；The destruction of receptor down-regulated mechanism；Activation of abnormal signal conduction path etc..EGFR overexpression exists Played an important role in the evolution of malignant tumour, in the tissue such as spongiocyte, kidney, lung cancer, prostate cancer, cancer of pancreas, breast cancer There is EGFR overexpression.Research to spongiocytoma finds that EGFR high expression is mainly relevant with its gene magnification.But have When EGFR expressions dysregulation exist in translation and translation after.High expression of the EGFR in tumour is also possible to and activated Degraded is reduced relevant afterwards, and some researchs point out that c-Src can raise EGFR water by suppressing acceptor ubiquitination and endocytosis It is flat.With the presence of mutant egf R in many tumours, it has now been found that many kinds of EGFR saltant types.Mutant egf R effect may Including：Cell continuous activation with part independent form acceptor；Caused due to EGFR some domains missing under acceptor The destruction of tune mechanism, the activation of abnormal signal conduction path, suppression of Apoptosis etc..The generation of mutant is due to EGFR bases Missing, mutation and the rearrangement of cause.
At present, the structure-activity relationship of EGFR inhibitor and uncertain, the compound of some structural difference very littles, it is directed to EGFR The effect of suppression but differs greatly.The present inventor passes through painstaking efforts, and synthesize has choosing unexpectedly to EGFR mutant The compound of selecting property inhibitory action, so as to the treatment for tumour, reduce the side reaction of inhibitor.
The content of the invention
The problem of an object of the present invention is low to solve EGFR inhibitor action effect, and side reaction is big, there is provided a kind of Act on EGFR sensitizing mutation kinases EGFRL858R, EGFR(d746-750)6- substituted amino purine class compounds and its application.
The invention provides the 6- substituted amino purines compound with the following chemical structure and its officinal salt,
Wherein：
R is
R1 is hydrogen, fluorine, chlorine, bromine, methoxyl group or hydroxyl.
Further, the compound is selected from 6- (the chloro- pyrroles -2- methylaminos of 5-) purine or the 6- (chloro- pyrimidine -4- first of 6- Amido) purine.
The present invention also provides a kind of above-mentioned 6- substituted amino purines compound and its officinal salt is preparing antineoplastic In application.
The present invention provides a kind of above-mentioned 6- substituted amino purines compound and its officinal salt and dashed forward in preparation suppression EGFR again Application in the cell proliferation of variant overexpression or abnormal activation.
The present invention provides a kind of medicine, drug regimen or reagent again, including above-mentioned 6- substituted amino purines compound and Its officinal salt.
Further, the medicine, drug regimen or reagent are used to suppress the overexpression of EGFR mutant or abnormal activation Cell propagation.
Further, the EGFR mutant is the EGFR kinases that mutation is produced in L858R or (d746-750) site.
Further, the medicine, drug regimen 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 provides new 6- substituted amino purines compound and its officinal salt, Suppression to EGFR kinases has selectivity, can effectively suppress EGFR sensitizing mutation kinases EGFRL858R, EGFR(d746-750)'s Activity, but to EGFRWTKinases do not have inhibition, so can both suppress the overexpression of EGFR mutant or abnormal activation Cell is bred, and so as to efficiently treat tumour, can be avoided again because suppressing to normal structure EGFR in human bodyWTThe phosphoric acid of kinases Change the activation with associated signal paths, so as to bring larger toxic side effect, the drug responses such as fash, vomiting occur.
Brief description of the drawings
Fig. 1 show the synthetic route of 6- of the present invention (the chloro- pyrroles -2- methylaminos of 5-) purine.
Fig. 2 show the synthetic route of 6- of the present invention (the chloro- pyrimidine -4- methylaminos of 6-) purine.
Embodiment
The specific embodiment of the invention is described in detail below in conjunction with specific accompanying drawing.It should be noted that in following embodiments The combination of the technical characteristic or technical characteristic of description is not construed as isolated, and they can be mutually combined so as to reach To superior technique effect.
The synthesis of the compound 6- of embodiment 1 (the chloro- pyrroles -2- methylaminos of 5-) purine (A1)
The synthetic route of 1 compound
Specific synthetic route is as shown in Figure 1.
It is 2-in-1 into step
The preparation of 2.16- (the chloro- pyrroles -2- methylaminos of 5-) purine (A1)
5ml n-butanol is measured, weighs 80mg 6-chloropurine and 100mg (the chloro- 1H- pyrroles -2- bases of 5-) methylamine, It is put into 25ml round-bottomed flask, and the triethylamine for adding 50 μ l adds stirrer as catalyst.In 110 DEG C of oil bath heatings Flow back 5h, cooling, treats that white solid separates out, and decompression filters, and is washed twice with n-butanol, dries, obtains the 6- (chloro- pyrroles -2- of 5- Methylamino) purine (A1).
The physical features of 2.26- (the chloro- pyrroles -2- methylaminos of 5-) purine (A1)
1H-NMR(DMSO-d6)δ(ppm):12.987 (s, 1H, 7'or 9'-Purine-H), 8.220 (s, 1H ,-NH), 8.140-8.15 (m, 2H, 2', 8'-Purine-H), 7.858 (s, 1H, 1'-Pyrrole-H), 6.432-6.446 (m, 1H, 4'-Pyrrole-H), 6.252-6.283 (m, 1H, 3'-Pyrrole-H), 4.760 (s, 2H ,-CH2)。ESI-MS:249.1[M +H]+。
The synthesis of the compound 6- of embodiment 2 (the chloro- pyrimidine -4- methylaminos of 6-) purine (A2)
The synthetic route of 1 compound
Specific synthetic route is as shown in Figure 2.
It is 2-in-1 into step
The preparation of 2.16- (the chloro- pyrimidine -4- methylaminos of 6-) purine (A2)
5ml n-butanol is measured, 80mg 6-chloropurine and 120mg (6- chlorine pyrimidine-4-yl) methylamine is weighed, is put into In 25ml round-bottomed flask, and the triethylamine for adding 50 μ l adds stirrer as catalyst.Flowed back in 110 DEG C of oil bath heatings 5h, cooling, treat that white solid separates out, decompression filters, and is washed twice with n-butanol, dries, obtains the 6- (chloro- pyrimidine -4- methylamines of 6- Base) purine (A2).
The physical features of 2.26- (the chloro- pyrimidine -4- methylaminos of 6-) purine (A2)
1H-NMR(DMSO-d6)δ(ppm)：13.276 (s, 1H, 7'or 9'-Purine-H), 9.432 (s, 1H, 2'- Pyrimidine-H), 8.720 (s, 1H ,-NH-), 8.125-8.243 (m, 2H, 2', 8'-Purine-H), 7.673 (s, 1H, 5'-Pyrimidine-H), 4.980 (s, 2H ,-CH2)。ESI-MS:262.6[M+H]+。
The Compound ira vitro EGFR inhibitory activity of embodiment 3 is tested
EGFR kinases external activity screens：The method that experiment uses is Caliper Mobility Shift Assay, should Experiment is the detection platform using the mobility detection technique of microfluidic chip technology as core.Specifically experimental procedure is：Configuration 1.25x kinase reactions buffer solution (62.5mmol/L HEPES, pH7.5；0.001875%Brij-35；12.5mmol/L MgCl2；2.5mmol/L DTT) and kinase reaction terminate liquid (100mmol/L HEPES, pH7.5；0.015%Brij-35； 0.2%Coating Reagent#3)；(DMSO dissolves, and is diluted with water 10 times) adds in 5 μ l 5x concentration compound solutions 10 μ l 2.5x EGFR kinase solutions (in 1.25x kinase reaction buffer solutions plus kinases), are added after reacting at room temperature 10min 10 μ l 2.5x substrates peptide solution (in 1.25x kinase reaction buffer solutions plus FAM marks peptide and ATP), reacts special at 28 DEG C 25 μ l kinase reaction terminate liquids are added after the fixed time.The gather data on Caliper, to the inhibiting rate of kinase activity= (max-conversion)/(max-min) ×100。
Compound A1 and compound A2 are determined to FGFR1, KDR, wild type under 5 μm of ol/L concentration by the above method EGFR kinases, EGFR sensitizing mutation kinases EGFRL858R, EGFR(d746-750)And EGFR mutant drug-resistant kinases EGFRT790MDeng kinases Inhibitory activity, only the inhibition of EGFR mutant strains, inhibiting rate see the table below with characterizing inhibitor.
Compound A1 and compound A2 is under 5 μm of ol/L concentration to EGFRWT、EGFRL858R、EGFR(d746-750)It is and various The inhibiting rate of kinases
By the above method respectively in 10000,3333,1111,370,123,41,14,5,2,1 (units：Nmol/L) etc. Compound A1 and compound A2 is determined under 10 concentration to Wild type EGFR kinases, EGFR sensitizing mutation kinases EGFRL858R, EGFR(d746-750)Inhibitory activity, IC50 results see the table below.
Compound A1 and compound A2 are to EGFRWT、EGFRL858RAnd EGFR(d746-750)IC50Value
Kinase assay shows：Compound A1 and compound A2 has very high selectivity to the EGFR kinases of mutation, especially It is to EGFR sensitizing mutation kinases EGFRL858R, EGFR(d746-750)With good inhibiting effect, reach nmol/L level, But to FGFR1, the EGFR of KDR and wild type does not have inhibitory action.
The new 6- substituted amino purines compound and its officinal salt of the present invention, the suppression to EGFR kinases have selection Property, it can effectively suppress EGFR sensitizing mutation kinases EGFRL858R, EGFR(d746-750)Activity, but to EGFRWTKinases does not have Inhibition, the cell propagation of the overexpression of EGFR mutant or abnormal activation so can be both suppressed, so as to efficiently treat Tumour, it can avoid again because suppressing to normal structure EGFR in human bodyWTThe phosphorylation of kinases and the activation of associated signal paths, So as to bring larger toxic side effect, the drug responses such as fash, vomiting occur, improve therapeutic effect, reduce side reaction.
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 (7)

  1. A kind of 1. application of 6- substituted amino purines compound and its officinal salt in antineoplastic is prepared；Its feature exists In the structure of described 6- substituted amino purine compounds is as follows：
    Wherein：
    R is
    R1It is hydrogen, fluorine, chlorine, bromine, methoxyl group or hydroxyl.
  2. 2. 6- substituted amino purines compound as claimed in claim 1 and its officinal salt answering in antineoplastic is prepared With, it is characterised in that the compound is selected from 6- (the chloro- pyrroles -2- methylaminos of 5-) purine or the 6- (chloro- pyrimidine -4- methylamines of 6- Base) purine.
  3. 3. 6- substituted amino purines compound and its officinal salt as described in any one of claim 1 or 2 prepare it is antitumor Application in medicine, it is characterised in that described antineoplastic is to suppress the overexpression of EGFR mutant or abnormal activation Cell proliferation.
  4. 4. 6- substituted amino purines compound as claimed in claim 3 and its officinal salt answering in antineoplastic is prepared With, it is characterised in that the EGFR mutant is in EGFRL858ROr EGFR(d746-750)Site produces the EGFR kinases of mutation.
  5. 5. 6- substituted amino purines compound as claimed in claim 3 and its officinal salt answering in antineoplastic is prepared With, it is characterised in that the antineoplastic is used to treat or prevent tumour.
  6. 6. 6- substituted amino purines compound as claimed in claim 5 and its officinal salt answering in antineoplastic is prepared With, it is characterised in that the tumour is EGFR dependent tumors.
  7. 7. 6- substituted amino purines compound as claimed in claim 6 and its officinal salt answering in antineoplastic is prepared With, it is characterised in that the tumour includes lung cancer, intestinal cancer, oophoroma, kidney, carcinoma of urinary bladder, cavity cancer, stomach cancer or breast cancer.
CN201510315178.XA 2015-06-09 2015-06-09 One kind acts on EGFR sensitizing mutation kinases EGFRL858R, EGFR(d746‑750)6 substituted amino purine class compounds and its application Active CN105884777B (en)

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CN106831730B (en) * 2017-01-11 2019-11-26 温州医科大学 A kind of substituted diaminopyrimidines and its preparing the purposes in anti-malignant tumor medicine
CN113582995B (en) * 2021-08-17 2022-08-16 西安交通大学 9-9H-purine compound containing acrylamide amino fragment at 9-position, and salt and application thereof

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WO2011113802A3 (en) * 2010-03-17 2012-08-02 F. Hoffmann-La Roche Ag Imidazopyridine and purine compounds, compositions and methods of use
WO2014124458A1 (en) * 2013-02-11 2014-08-14 The Regents Of The University Of California Compositions and methods for treating neurodegenerative diseases

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WO2003022805A2 (en) * 2001-09-11 2003-03-20 Albany Molecular Research, Inc. Heterocycle substituted purines as antiproliferative agents
WO2011113802A3 (en) * 2010-03-17 2012-08-02 F. Hoffmann-La Roche Ag Imidazopyridine and purine compounds, compositions and methods of use
WO2014124458A1 (en) * 2013-02-11 2014-08-14 The Regents Of The University Of California Compositions and methods for treating neurodegenerative diseases

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