CN110041336A - Pyrimidinones and its composition obtained - Google Patents
Pyrimidinones and its composition obtained Download PDFInfo
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Abstract
The present invention relates to technical field of chemical medicine, in particular disclose a kind of pyrimidinones and its Pharmaceutical composition obtained and application.The structural formula of compound of the pyrimidinones is as follows:
Description
Technical field
The present invention relates to technical field of chemical medicine, in particular disclose a kind of pyrimidinones and its combination obtained
Object.
Background technique
With the development of economy and society, living standards of the people are continuously improved, but consequent is the hair of various diseases
Sick rate persistently increases, no matter worldwide or in China, with malignant tumour (cancer), cardiovascular disease and diabetes
Deng the chronic disease (non-communicable diseases in other words) for representative, but becoming more main long-term threat.The World Health Organization
It is just explicitly pointed out in the report of its newest announcement, non-communicable diseases is becoming mankind killer the most fatal.Wherein, cancer
Disease ranks first place.In recent years, though cancer patient's bring is wished in the discovery of various therapy approach and drug,
There is an urgent need to new treatments for phenomena such as the drawbacks of conventional therapy, side effect is big, and therapeutic effect is bad, tumor prognosis recurrence, transfer
Technology solves this kind of bottleneck effect.International medical community by the basis of molecule parting Individual Chemotherapy and targeted therapy regard as
Where the hope for breaking through current lung cancer therapy bottleneck.
Tumor cells targeted therapy be based on to the closely related key molecule of tumour growth by chemistry or biology learn to do
A kind for the treatment of method of section selective killing tumour cell.The characteristics of targeted therapy are as follows: specificity is high, and selectivity is strong, and poison is secondary to be made
With relatively gently；When use in conjunction, it can reinforce the curative effect of classic chemotherapy, radiotherapy, reduce postoperative recurrence.With Gleevec
(STI571), Gefitinib, Erlotinib (OSI774), Sorafenib tosilate, sunitinib malate and
Dasatinib is that the targeted drug represented has started a new era as chemotherapy of tumors.Neoplasm targeted therapy obtains in recent years
Rapid development is arrived.Going out for neoplasm targeted therapy constitutes impact to convenient administration idea and mode, for example, because of toxic side effect
Small targeted drug is often unable to reach dose-limiting toxicity and maximum tolerated dose in Phase I clinical trial；Use targeted therapy
Without can reach satisfactory effect with maximum tolerated dose when drug.Neoplasm targeted therapy is that the hot spot of oncotherapy and development become
Gesture.
Protein tyrosine kinase (PTKs) is a kind of phenol hydroxyl that can be catalyzed on the tyrosine residue of a variety of key proteins
Phosphorylation occurs for base, and then activates the protein enzyme system of the function of functional protein.In the intracorporal 520 multiple protein kinases of people about
Half is tyrosine kinase (PTKs).Highly important status is occupied in their signal transduction pathway in the cell, is adjusted
Save a series of physiology processes such as cell growth in vivo, differentiation, death.Protein tyrosine kinase functional disturbance can cause biology
A series of intracorporal diseases.Studies have shown that the activation of proto-oncogene and oncogene more than half all with protein tyrosine kinase
It is related.The unconventionality expression of protein tyrosine kinase can lead to cell Proliferation adjusting and get muddled, and then lead to tumour.This
Outside, the unconventionality expression of tyrosine kinase also with the invasion of tumour and transfer, tumor neovasculature generation, the anti-medicine of the chemotherapy of tumour
Property is closely related.Carrying out anti-tumor drug research and development as target spot using tyrosine kinase becomes an international hot spot and various countries
The emphasis of drug development mechanism research investment.
EGF-R ELISA (EGFR), a kind of receptor tyrosine protein kinase have regulated and controled the increment of cell, survival,
Adhesion, migration and differentiation.EGFR overactivity or continuous activation in kinds of tumor cells, such as lung cancer, breast cancer, prostate
Cancer etc..EGFR is a kind of transmembrane protein, and there are four types of hypotypes for family: EGFR-1 (later known as EGFR, Erb-B1 or Her-
1), HER-2 (Erb-B2 or neu), HER-3 (Erb-B3) and HER-4 (Erb-B4).The wherein exception of EGFR and Erb-B2
Activation plays critical effect in the conversion and growth of tumour.Block EGFR and Erb-B2 activation be by clinical verification
Leading method carrys out targeting therapy on tumor cell.By taking lung cancer as an example, EGFR has expression, Er Qieqi in 50% NSCLC case
It expresses bad related to prognosis.The two factors make EGFR and its family member become the main candidate for carrying out targeted therapy
Person.The micromolecular inhibitor of two kinds of targeting EGFRs, Gefitinib and Tarceva, the quick approval for having obtained U.S. FDA are used for
Advanced NSCLC patients are treated, these patients have lost reaction to conventional chemotherapy.
The clinical data of early stage shows that 10% NSCLC patient has reaction to Gefitinib and Tarceva.It is this significant
Clinical efficacy be found in specific PATIENT POPULATION, including non-smoking East Asia Region women and show as bronchovesicular venereal disease
Manage the adenocarcinoma patients of type.Molecular level analysis shows, in most cases, to drug have the patient of reaction coding EGFR
With specific mutation on gene.The missing of 747th~750 amino acids of the 19th exon accounts for the 45% of mutation, also
10% mutation is in the 18th and the 20th exon.The discontinuity height of EGFR kinase domain activates kinases, so that tumour cell
Existence has dependence to mutant kinase.Having multinomial Prospective Clinical research confirms that the NSCLC of the EGFR Activating mutations positive suffers from
Person is significantly higher than EGFR wild type NSCLC patient, Progression free survival (PFS) phase and total existence to the reactivity of EGFR-TKI
(OS) phase also significantly extends.Pair however, the PFS of most of EGFR mutation positive patient is no more than 12~14 months, i.e.,
Drug resistance has occurred in TKI.The mechanism of acquired resistance and its clinical countermeasure become the another research hotspot in targeted therapy field.
Targeting EGFR inhibitor resistance mechanism can be divided into two classes: medicament-resistant mutation and alternative activation pathway.Resistance mechanism 1:
T790M mutation is a point mutation in 20 exon of EGFR, is one of the resistance mechanism more approved at present.T790M is led
The drug resistant mechanism of TKI is caused to be not fully understood.Initial studies have shown that T790M may change kinases area adenosine triphosphate
(ATP) crystal structure of binding pocket encloses the combination of TKI and kinases area.Current research shows that L858R merges T790M
Mutation is stronger than simple L858R to the affinity of ATP, and TKI is ATP competitiveness kinase inhibitor, therefore TKI and kinases area is caused to tie
Conjunction rate reduces.Dispute about T790M first is that, which is to generate after TKI treatment or there is, control originally through TKI
It is just found after treating selection.Initially, T790M is only found in NSCLC patient's sample of TKI treatment failure, but then not
Also be found in sample through any treatment, therefore it is now recognized that the mutation exist in without TKI treatment tumor tissues in,
But it is detected in a few cell clone, since these cell clones are selected the repellence of TKI after the treatment.With
There are also D761Y, L747S and T854A etc., these mutation to be referred to as " non-T790M secondary mutation " for the similar medicament-resistant mutation of T790M,
Its total incidence is lower than 5%.Resistance mechanism 2:MET amplification is the another EGFR-TKI acquired resistance mechanism of discovery in 2007.
MET is a kind of transmembrane tyrosine kinase receptor.It is mutated in positive NSCLC patient in the EGFR to TKI acquired resistance, about
20% has wild type MET gene magnification, and most of before the treatment without MET amplification.MET combines ErbB family member, bypasses
EGFR activates the signal path that downstream AKT is mediated, and promotes growth of tumour cell, inhibits its apoptosis.In vitro experiment, pass through
RNA perturbation technique inhibits MET signal path, can restore drug resistance person to the sensibility of Gefitinib.Inhibit EGFR and MET simultaneously,
The TKI drug resistance that MET amplification can be overcome to mediate.It is similar with MET effect that there is also a little receptors.Nearest external TKI resistant models
It has been shown that, type-1 insulin like growth factor receptor (IGF-1R) also can bypass EGFR, activate signal path downstream, but due to technology
Reason is difficult to carry out IGF-1R activation detection in patient's sample.These drug resistances for bypassing EGFR, activating signal path downstream
Mechanism is referred to as " alternative activation pathway ".EGFR drug resistant to TKI is mutated positive patient, and about 30%~40% both without secondary prominent
Become, is also expanded without MET, the resistance mechanism of these patients is also in exploration.
For drug resistance, the strategy clinically used is: strategy 1 continues to use EGFR-TKI, Gefitinib and E Luo are replaced
The cross-reference of Buddhist nun.In short, continuing to use TKI seemingly after TKI progress has certain benefit, but it is very limited to benefit degree.Strategy 2,
Develop new E GFR-TKI.Preclinical study shows that EGFR irreversible inhibitor can inhibit T790M in vitro, hereafter, very much
EGFR irreversible inhibitor is developed, referred to as " two generation EGFR-TKI ", gradually moves towards clinical from preclinical study at present,
Studying more has neratinib, XL647, BIBW 2992 and PF-00299804.Neratinib be general ErbB (EGFR,
ErbB2 and ErbB3) irreversible TKI.Based on I phase result of study, currently carry out clinical research, inquire into Gefitinib or
In the NSCLC patient being in progress after Tarceva treatment, whether neratinib (240mg/d) can overcome T790M mutation or MET to expand
TKI drug resistance caused by increasing.But some preclinical studies show unfavorable as a result, a kind of cell strain of 19 Exon deletion of EGFR
PC-9 produces T790M mutation when being exposed to neratinib；In mouse L858R-T790M tumor model, it is applied alone
Neratinib does not make Tumor response.Therefore whether neratinib does not learn T790M mutation person still effectively.XL647 can be irreversible
Inhibit EGFR, HER2, VEGF R2 (VEGFR-2) and EphB4, in L858R-T790M catastrophic model,
It can inhibit tumour growth.2008, an II phase clinical research about XL647 was tentatively shown, in 34 Gefitinibs or strategic point
Lip river for Buddhist nun treat alleviate more than 3 months after occur progression of disease or with T790M be mutated NSCLC patient in, use XL647
After (300mg/d) treatment, only 1 part is alleviated, patient's non-smoking, 19 Exon deletions, is mutated in blood plasma without T790M；And
None alleviation of the positive patient of T790M mutation, it is most of to be in progress in 2 months.BIBW 2992 be EGFR and ErbB2 can not
Inverse TKI.In II phase clinical research, BIBW 2992 makes have 19 Exon deletions, and L858R, L861Q and G719S/S768I are prominent
Become patient to alleviate.One 2,992 3 line of BIBW treatment chemotherapy failure, Gefitinib or Tarceva are in progress after benefiting
The clinical research of NSCLC is being carried out.BIBW 2992 compares placebo, and three lines treat Gefitinib or Tarceva treatment is lost
The random IIb/III phase clinical research for losing NSCLC is also underway.These researchs will be helpful to determine that can BIBW 2992 to
Gefitinib or Tarceva drug resistance patient bring benefit.PF-00299804 is general ErbB TKI inhibitor.It is ground in I phase clinic
In studying carefully, there is remission in 1 T790M mutation positive.PF-00299804 (45mg/d) treat KRAS wild type, chemotherapy and
The II phase clinical research of Tarceva treatment failure NSCLC patient is being carried out.Strategy 3, for other target treatments.Due to
" alternative activation pathway " plays a significant role in EGFR-TKI drug resistance, continues to bring out for the targeted drug of these bypasses.
MET-TKI may play a role in the patient expanded with MET.Preclinical study shows that EGFR-TKI and MET-TKI join
It closes, it is positive to EGFR mutation and effective with the cell strain of MET amplification, but the two exclusive use is invalid.One important to ask
Topic is that about half patient with MET amplification has T790M mutation simultaneously, therefore MET-TKI may need and T790M inhibitor
Joint.XL184 is a kind of novel TKI, has inhibiting effect to MET, VEGFR-2 and RET.Other MET inhibitor, as ARQ197,
PF-2341066, SGX523 etc. also have relevant clinical research carrying out.PF-2341066 be a kind of selectivity c-MET and ALK by
Body tyrosine kinase inhibitor illustrates preferable tumour control effect in I phase clinical research, especially melts to ALK-EML4
Close gene masculine patient.II/III phase clinical research about PF-2341066 is being carried out, and targeted therapy neck is already become
One new hot spot in domain.For other possible alternative activation pathways, some drugs, such as IGF-1R inhibitor, heat shock protein
The correlative study of 90 inhibitor etc. is also in process.
In short, current EGFR-TKI not can solve clinical pressure caused by drug resistance, and existing medicine still
Object is mostly with EGFR that quinazoline or quinoline amine are basic parent nucleus is reversible or irreversible inhibitor, to wild-type cell
Poor selectivity bring toxic side effect is also inevitable.Therefore, the drug of a new generation is developed to overcome solution drug resistance, is selected
The problems such as selecting property is poor improves clinical effectiveness, is of great significance.
Summary of the invention
In order to overcome shortcoming and defect existing in the prior art, the purpose of the present invention is to provide can be effectively exciting female
The compound of hormone cognate receptor, the compound can effectively excitement be such as ERR α, the estrogen-related receptors such as beta, gamma, and is used in and controls
Treat metabolic disease such as diabetes and hyperlipidemia relevant to diabetes B, hypercholesterolemia, hypertriglyceridemia etc.
Disease or symptom.
The purpose of the invention is achieved by the following technical solution: pyrimidinones, the pyrimidinones
Structural formula is as follows:
Wherein, the R1 is selected from
1) H；
2) aryl；
3) methyl, ethyl, isopropyl, tert-butyl；
4) methoxyl group；
Wherein, the R2 is selected from
1) H；
2) aryl；
3) methyl, ethyl, isopropyl, tert-butyl；
4) methoxyl group；
5) carboxyl
Wherein, the R3 is selected from
1) H；
2) methyl, ethyl, isopropyl, tert-butyl；
3) C1-C5 contains fluoroalkyl；
4) halogen；
Wherein, the R4 is selected from
1) H；
2) methyl, ethyl, isopropyl, tert-butyl；
3) aryl；
4) hydroxyl；
Further, in the pyrimidinones, R1 is methyl, and R2 is methoxyl group, R3 H, R4 H.
Further, in the pyrimidinones, R1 is isopropyl, and R2 is methyl, and R3 is tert-butyl, and R4 is benzene
Base.
Further, in the pyrimidinones, R1 is methyl, and R2 is carboxyl, and R3 H, R4 are methyl.
Further, in the pyrimidinones, R1 is phenyl, and R2 is methoxyl group, and R3 H, R3 are hydroxyl.
Further, in the pyrimidinones, R1 is methyl, and R2 H, R3 are trifluoromethyl, and R4 is ethyl.
The present invention also provides a kind of Pharmaceutical composition, the Pharmaceutical composition includes a effective amount of above-mentioned estrogen correlated acceptor 2
Body regulator and pharmaceutically acceptable carrier or excipient.It is anti-swollen that the pyrimidinones are applied to preparation treatment
Tumor drug.
Beneficial effects of the present invention: pyrimidinones of the invention can be used as that protease inhibitors has can be effective
The growth for inhibiting kinds of tumor cells, to EGFR, the protease of Her family, such as EGFR L858R/T790M, EGFR
E745_A750/T790 etc. generates inhibiting effect, can be used for preparing anti-tumor drug, and can overcome existing drug-induced resistance to
Pharmacological property.Compound according to the present invention and its pharmaceutically acceptable pharmaceutical compositions can be used for preparing the treatment mankind and other food in one's mouths
Newborn animal anti-tumor drug.
Specific embodiment
For the ease of the understanding of those skilled in the art, below with reference to embodiment, the present invention is further illustrated, real
The content that the mode of applying refers to not is limitation of the invention.
Embodiment 1
In the present embodiment, pyrimidinones, the structural formula of compound is as follows:
Wherein, R1 is methyl, and R2 is methoxyl group, R3 H, R4 H.
The compound is denoted as compound D1, the preparation method of the compound D1 the following steps are included:
(1) the chloro- 2- first mercaptopyrimidine -5- ethyl carbonate (23.3g, 100mmol) of 4-, N-Boc m-phenylene diamine (MPD) (20.8g,
1.0eq), K2CO3(27.6g, 2.0eq) is dissolved in 300ml anhydrous DMF, under nitrogen protection, is heated to 80 DEG C, is stirred overnight.It is cold
But to room temperature, it is added with stirring 1000ml ice water, a large amount of solids are precipitated.It is filtered under diminished pressure, is dried in vacuo to obtain white solid 38.8g
(96%).
1H NMR (400Hz, CDCl3) δ 10.37 (s, 1H), 8.76 (s, 1H), 7.90 (s, 1H), 7.34 (d, J=
8.0Hz, 1H), 7.24 (t, J=8.0Hz, 1H), 7.02 (d, J=8.0Hz, 1H), 6.53 (s, 1H), 4.38 (q, J=7.2,
14.4Hz, 2H), 2.55 (s, 3H), 1.52 (s, 9H), 1.40 (t, J=7.2Hz, 3H)
(2) 4- (3- t-butoxycarbonyl amino aniline) -2- first mercaptopyrimidine -5- ethyl carbonate (20.2g, 50mmol) is dissolved in
The anhydrous THF of 500ml is cooled to -40 DEG C, and the Lithium Aluminium Hydride (50ml, 2.0eq) of 2M is slowly added drop-wise in above-mentioned reaction solution, heating
To room temperature, continue to stir 2h.Under ice bath, 20ml methanol quenching reaction is added dropwise, adds saturation NaHCO3Aluminium hydroxide is precipitated in solution,
It is filtered under diminished pressure using diatomite, concentrated solvent, column chromatography for separation obtains yellow solid 10.33g (57%).
1H NMR (400Hz, CDCl3) δ 8.02 (s, 1H), 7.86 (s, 1H), 7.80 (s, 1H), 7.36 (dd, J=1.2,
8.0Hz, 1H), 7.22 (t, J=8.0Hz, 1H), 6.95 (dd, J=1.2,8.0Hz, 1H), 6.52 (s, 1H), 4.61 (s,
2H), 2.52 (s, 3H), 1.52 (s, 9H).
(3) tert-butyl -3- (5- (methylol) -2- (first sulfydryl) pyrimidine -4- substituted-amino) benzamide carbonic ester (10g,
It 27.6mmol) is dissolved in 300ml DCM, active MnO is added portionwise2(24g, 10eq), is stirred overnight at room temperature.Subtracted using diatomite
Press filtration, the lower evaporation solvent that pressurizes obtain yellow solid 8.36g (84%).
1HNMR (400Hz, CDCl3) δ 10.61 (s, 1H), 9.77 (s, 1H), 8.43 (s, 1H), 7.98 (s, 1H), 7.36
(dd, J=0.8,8.0Hz, 1H), 7.25-7.29 (m, 1H), 7.03 (dd, J=1.2,8.0Hz, 1H), 6.51 (s, 1H),
2.59 (s, 3H), 1.53 (s, 9H)
(4) tert-butyl -3- (5- (formoxyl) -2- (first sulfydryl) pyrimidine -4- substituted-amino) benzamide carbonic ester (7.21g,
It 20mmol) is dissolved in 200ml MeOH, it is 0 DEG C cooling, it is added methylamine hydrochloride (6.75g, 5.0eq), sodium acetate (8.2g,
5.0eq), it moves to and 1h is stirred at room temperature.It is 0 DEG C cooling, NaBH4 (1.51g, 2.0eq) is added portionwise, moves to and is stirred overnight at room temperature.It is dense
Contracting solution, DCM extraction, saturation NaHCO3 solution washing, saturated common salt water washing, anhydrous Na2SO4Dry, group chromatographs white
Solid 5.25g (71%).
1HNMR (400Hz, CDCl3) δ 10.12 (s, 1H), 7.89 (s, 1H), 7.78 (s, 1H), 7.35 (d, J=8.8Hz,
1H), 7.21 (t, J=8.0Hz, 1H), 6.97 (dd, J=1.2,8.0Hz, 1H), 6.50 (s, 1H), 3.74 (s, 2H), 3.55
(s, 3H), 2.44 (d, J=0.4Hz, 3H), 1.52 (s, 9H)
(5) tert-butyl -3- (5- ((methylamino) methyl) -2- (first sulfydryl) pyrimidine -4- substituted-amino) benzamide carbonic ester
(5.2g, 13.8mmol), DIEA (8ml, 4.0eq) are dissolved in 140ml THF, are cooled to 0 DEG C.Three light of 0.2M are slowly added dropwise
Gas THF solution (25ml, 1.1/3eq), moves to and 1h is stirred at room temperature.Concentrated solvent, DCM extraction are washed three times, saturated salt solution
Primary, anhydrous Na 2SO4 drying is washed, lower evaporation solvent is depressurized, re-crystallizing in ethyl acetate obtains white solid 4.71g (85%).
1H NMR (400Hz, CDCl3) δ 8.10 (s, 1H), 7.44 (s, 1H), 7.34 (t, J=8.0Hz, 1H), 7.23 (d,
J=7.2Hz, 1H), 6.90 (d, J=8.0Hz, 1H), 6.55 (s, 1H), 4.46 (s, 2H), 3.08 (s, 3H), 2.14 (s,
3H), 1.50 (s, 9H)
(6) tert-butyl -3- (3- methyl -7- (first sulfydryl) -2- oxygen -3,4- dihydro-pyrimidin [4,5-d] pyrimidine -1 (2 hydrogen)-substitution)
Benzamide carbonic ester (4.0g, 10mmol) is dissolved in 100mlDCM, is cooled to 0 DEG C, be added portionwise 85% MCPBA (6.1g,
3.0eq), 3h is stirred at room temperature.DCM dilution, saturation NaHCO3 solution wash 3 times, and saturated common salt washing is primary, anhydrous Na 2SO4
It is dry, lower evaporation solvent is depressurized, re-crystallizing in ethyl acetate obtains white solid 4.1g (89%)
1H NMR (400Hz, CDCl3) δ 8.45 (s, 1H), 7.58 (s, 1H), 7.35 (t, J=8.0Hz, 1H), 7.15 (dd, J=
1.2,8.0 Hz, 1H), 6.89 (dd, J=1.2,8.0Hz, 1H), 6.67 (s, 1H), 4.62 (s, 2H), 3.11 (s, 3H), 2.98
(s, 3H), 1.48 (s, 9H).
(7) tert-butyl -3- (3- methyl -7- (methylsulfonyl) -2- oxygen -3,4- dihydro-pyrimidin [4,5-d] pyrimidine -1 (2 hydrogen)-take
Generation) benzamide carbonic ester (260mg, 0.6mmol) is dissolved in 1ml dioxane, it is added methylamine hydrochloride (405mg, 10eq),
Sodium acetate (492mg, 10eq) is heated to 100 DEG C of tube sealing reactions for 24 hours.DCM dilution, is saturated NaHCO3Solution washing, saturation food
Salt washing is primary, and anhydrous Na 2SO4 is dry, evaporates solvent under depressurizing, column chromatographs to obtain white solid 205mg (89%).
1H NMR (400Hz, CDCl3) δ 7.93 (s, 1H), 7.39 (s, 1H), 7.32 (t, J=8.0Hz, 1H), 7.23 (s,
1H), 6.91 (d, J=8.0Hz, 1H), 6.52 (s, 1H), 4.36 (s, 2H), 3.54 (m, 4H), 3.06 (s, 3H), 2.31 (m,
4H), 2.56 (s, 3H), 1.49 (s, 9H)
(8) tert-butyl -3- (5- (formoxyl) -2- (first sulfydryl) pyrimidine -4- substituted-amino) benzamide carbonic ester (7.21g,
It 20mmol) is dissolved in 200ml MeOH, it is 0 DEG C cooling, it is added methylamine hydrochloride (6.75g, 5.0eq), sodium acetate (8.2g,
5.0eq), it moves to and 1h is stirred at room temperature.It is 0 DEG C cooling, NaBH is added portionwise4(1.51g, 2.0eq), moves to and is stirred overnight at room temperature.It is dense
Contracting solution, DCM extraction, saturation NaHCO3 solution washing, saturated common salt water washing, anhydrous Na2SO4Dry, group chromatographs white
Solid 5.25g (71%).
1HNMR (400Hz, CDCl3) δ 10.12 (s, 1H), 7.89 (s, 1H), 7.78 (s, 1H), 7.35 (d, J=8.8Hz,
1H), 7.21 (t, J=8.0Hz, 1H), 6.97 (dd, J=1.2,8.0Hz, 1H), 6.50 (s, 1H), 3.74 (s, 2H), 3.55
(s, 3H), 2.44 (d, J=0.4Hz, 3H), 1.52 (s, 9H).
(8) tert-butyl -3- (3- methyl -7- (methylamino) -2- oxygen -3,4- dihydro-pyrimidin [4,5-d] pyrimidine -1 (2 hydrogen)-take
Generation) benzamide carbonic ester (205mg, 0.53mmol) is dissolved in 1ml DCM, and it is added 0.4ml TFA (10eq), is stirred at room temperature
4h.Solvent is concentrated under reduced pressure, DCM dilution is saturated NaHCO3Solution washing, saturated common salt washing is primary, anhydrous Na2SO4It is dry, subtract
Pressure evaporation solvent, obtains yellow solid 140mg (93%).
(9) 1- (3- aminophenyl) -3- methyl -7- (methylamino) -3,4- dihydro-pyrimidin [4,5-d] pyrimidine -2 (1 hydrogen) -one
(128mg, 0.45mmol) is dissolved in 2ml DCM, and 65 μ l (1.0eq) of DIEA is added, is cooled to 0 DEG C, pipettes 37 μ l of acryloyl chloride
(1.0eq) is slowly added drop-wise in above-mentioned reaction solution, and 1h is stirred at room temperature.Solvent is evaporated under reduced pressure, column chromatographs to obtain white solid 114mg
(75%).
1H NMR (400Hz, DMSO-d6) δ 10.23 (s, 1H), 8.01 (s, 1H), 7.61 (d, J=8.0Hz, 1H), 7.55
(s, 1H), 7.36 (t, J=8.0Hz, 1H), 6.91 (d, J=7.6Hz, 1H), 6.71 (s, 1H), 6.43 (dd, J=10.0,
16.8Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 5.76 (d, J=10.4Hz, 1H), 4.37 (s, 2H), 2.93 (s, 3H),
2.59 (s, 3H) LCMS (ESI): m/z 339.1 [M+H]+.
Embodiment 2
In the present embodiment, pyrimidinones, the structural formula of compound is as follows:
Wherein, R1 is isopropyl, and R2 is methyl, and R3 is tert-butyl, and R4 is phenyl.
The compound is denoted as compound D2, the preparation method reference compound D1 of the compound D2.
1H NMR (400Hz, DMSO-d6) δ 8.25 (s, 1H), 7.95 (s, 1H), 7.53 (s, 1H), 7.38 (d, J=
7.6Hz, 1H), 7.23-7.27 (m, 1H), 6.88 (d, J=7.6Hz, 1H), 6.32 (d, J=16.4Hz, 1H), 6.12 (dd, J
=10.0,16.4Hz, 1H), 5.64 (d, J=10.0Hz, 1H), 4.41 (s, 2H), 3.52 (m, 4H), 3.10 (s, 3H), 2.30
(m, 4H), 2.25 (s, 3H) LCMS (ESI): m/z 408.2 [M+H]+.
Embodiment 3
In the present embodiment, pyrimidinones, the structural formula of compound is as follows:
Wherein, R1 is phenyl, and R2 is methoxyl group, and R3 H, R3 are hydroxyl.
The compound is denoted as compound D3, the preparation method reference compound D1 of the compound D3.
1H NMR (400Hz, DMSO-d6) δ 10.31 (s, 1H), 8.11 (s, 1H), 7.81 (d, J=7.6Hz, 1H), 7.56
(s, 1H), 7.48 (s, 1H), 7.43 (t, J=8.0Hz, 1H), 7.27 (d, J=8.4Hz, 1H), 6.95 (d, J=8.0Hz,
1H), 6.51 (s, 1H), 6.44 (dd, J=10.0,16.8Hz, 1H), 6.25 (d, J=16.8Hz, 1H), 6.02 (d, J=
8.0Hz, 1H), 5.76 (d, J=10.0Hz, 1H), 4.46 (s, 2H), 3.76 (s, 3H), 2.99 (m, 4H), 2.96 (s, 3H),
2.50 (m, 4H), 2.22 (s, 3H) LCMS (ESI): m/z 529.2 [M+H]+.
Embodiment 4
In the present embodiment, pyrimidinones, the structural formula of compound is as follows:
Wherein, R1 is methyl, and R2 is carboxyl, and R3 H, R4 are methyl.
The compound is denoted as compound D4, the preparation method reference compound D1 of the compound D4.
1H NMR (400Hz, DMSO-d6) δ 10.30 (s, 1H), 8.11 (s, 1H), 7.82 (d, J=8.0Hz, 1H), 7.56
(s, 1H), 7.47 (s, 1H), 7.43 (t, J=8.0Hz, 1H), 7.25 (d, J=8.0Hz, 1H), 6.95 (d, J=8.0Hz,
1H), 6.49 (d, J=2.2Hz, 1H), 6.43 (dd, J=8.0,16.0Hz, 1H), 6.25 (dd, J=1.6,8.0Hz, 1H),
6.02 (d, J=7.4Hz, 1H), 5.76 (dd, J=1.6,8.0Hz, 1H), 4.46 (s, 2H), 3.75 (s, 3H), 2.96 (m,
7H), 1.59 (m, 4H), 1.49-1.504 (m, 2H) .LCMS (ESI): m/z 514.2 [M+H]+.
Embodiment 5
In the present embodiment, pyrimidinones, the structural formula of compound is as follows:
Wherein, R1 is methyl, and R2 H, R3 are trifluoromethyl, and R4 is ethyl.
The compound is denoted as compound D5, the preparation method reference compound D1 of the compound D5.
1H NMR (400Hz, DMSO-d6) δ 10.31 (s, 1H), 8.07 (s, 1H), 7.77 (d, J=8.0Hz, 1H), 7.59
(s, 1H), 7.41 (t, J=8.0Hz, 1H), 7.15 (d, J=8.0Hz, 1H), 6.95 (d, J=8.0Hz, 1H), 6.44 (dd, J
=10.0,16.8 Hz, 1H), 6.25 (d, J=16.4Hz, 1H), 6.10 (s, 1H), 5.76 (d, J=10.0Hz, 2H), 4.44
(s, 2H), 3.74 (s, 3H), 3.14 (m, 4H), 2.96 (s, 3H), 1.92 (m, 4H) .LCMS (ESI): m/z 500.2 [M+H]+.
Embodiment 6
Kinase activity detection: it (is detected using fluorescence, enzyme unconjugated form, with phosphorylation and non-using z'-LYTeM technology
Based on the sensitivity differences that phosphorylated polypeptide cuts proteolysis), using fluorescence resonance energy transfer (FRET) principle,
Using Z'LYTE FRET peptides substrate, second order reaction detection compound is to kinase activity.(invi trogen ,Z' -
LYTE breathe out (INASE ASSAY KIT-TYR 2PEPTIDE, PV3191) by EGFR-T7 90M kinases (invi trogen,
PV4803 FRET peptide is added after) diluting step by step, ATP adds various concentration compound, and after reacting 1h, it is special that site is added
Foreign preteins enzyme, identifies and cuts the FRET peptide of non-phosphorylating, reacts 1h, using 400nm excitation wavelength, detect 445nm and
520nm。
It show that inhibiting rate is positively correlated with drug concentration, makes kinase activity and concentration relationship curve, calculate IC50Value.Table 1
For D1-D5 pairs of compound and corresponding kinase activity result.
Table 1
Embodiment 7
The active cell tests of EGFR
The influence of MTT detection compound cell proliferation: 1500/every hole, NCI-H820 (lung carcinoma cell, EGFR wild type),
A431 (people's epidermal carcinoma, EGFR high expression), HCC827 (lung carcinoma cell, EGFR E746-A750 deletion), H1975 (lung
Cancer cell, EGFR L858R&T790M) 96 orifice plates of paving, for 24 hours after, (DMSO is whole for the various concentration compound processing prepared with DMSO
Concentration 1 ‰, parallel control 3-5), MTT (thiazolyl blue, 5mg/ml, the hole 10ul/) is added after 72h, 37 degree of incubation 4h.It sucks
Clearly, DMSO150ul is added and detects OD570 sufficiently after oscillation, is handled using GraphPad Prism 4Demo software.As a result it sends out
Existing, 7- (substituted-amino) -3,4- dihydro-pyrimidin [4,5-d] pyridine-(1 hydrogen) -one class compound processing can obviously reduce above-mentioned thin
Absorption of the born of the same parents to MTT illustrates that 7- (substituted-amino) -3,4- dihydro-pyrimidin [4,5-d] pyridine-(1 hydrogen) -one class compound can be shown
The proliferation for inhibiting above-mentioned cell is write, especially inhibition H1975 (L858R/T790), two class cell of HCC827 (DEL746-750)
Increment, inhibiting rate is positively correlated with drug concentration.According to 7- (substituted-amino) -3,4- dihydro-pyrimidin [4,5-d] pyridine-(1
Hydrogen) for -one class compound to the growth inhibition effects of these cells, inventor calculates its half-inhibitory concentration (IC50) value (μM)
As described by table 22.
Table 2
The present invention also provides a kind of Pharmaceutical composition, comprising a effective amount of pyrimidinones and pharmaceutically acceptable
Carrier or excipient.Pyrimidinones stem cell of the invention can be administered individually or in the form of pharmaceutical composition.Its
Dosage form depends on selected administration route, can be manufactured according to common sense well known in the art.
The above is only a preferred embodiment of the present invention, for those of ordinary skill in the art, according to the present invention
Thought, there will be changes in the specific implementation manner and application range, and the content of the present specification should not be construed as to the present invention
Limitation.
Claims (8)
1. pyrimidinones, it is characterised in that: the structural formula of the pyrimidinones is as follows:
Wherein, the R1 is selected from
H；
Aryl；
Methyl, ethyl, isopropyl, tert-butyl；
Methoxyl group；
Wherein, the R2 is selected from
H；
Aryl；
Methyl, ethyl, isopropyl, tert-butyl；
Methoxyl group；
Carboxyl
Wherein, the R3 is selected from
H；
Methyl, ethyl, isopropyl, tert-butyl；
C1-C5 contains fluoroalkyl；
Halogen；
Wherein, the R4 is selected from
H；
Methyl, ethyl, isopropyl, tert-butyl；
Aryl；
Hydroxyl.
2. pyrimidinones according to claim 1, it is characterised in that: R1 is methyl, and R2 is methoxyl group, R3 H, R4
For H.
3. pyrimidinones according to claim 1, it is characterised in that: R1 is isopropyl, and R2 is methyl, and R3 is tertiary fourth
Base, R4 are phenyl.
4. pyrimidinones according to claim 1, it is characterised in that: R1 is methyl, and R2 is carboxyl, and R3 H, R4 are
Methyl.
5. pyrimidinones according to claim 1, it is characterised in that: R1 is phenyl, and R2 is methoxyl group, R3 H,
R3 is hydroxyl.
6. pyrimidinones according to claim 1, it is characterised in that: R1 is methyl, and R2 H, R3 are trifluoromethyl,
R4 is ethyl.
7. a kind of Pharmaceutical composition, it is characterised in that: the Pharmaceutical composition includes a effective amount of claim 1-5 arbitrarily described
Pyrimidinones and pharmaceutically acceptable carrier or excipient.
8. the application of the pyrimidinones as described in claim 1-6 is any, it is characterised in that: the Pyrimdinone chemical combination
Object is applied to preparation and treats antitumor drug.
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