CN104693189B - A kind of pyrimidine compound and its preparation method and application - Google Patents
A kind of pyrimidine compound and its preparation method and application Download PDFInfo
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- CN104693189B CN104693189B CN201510007559.1A CN201510007559A CN104693189B CN 104693189 B CN104693189 B CN 104693189B CN 201510007559 A CN201510007559 A CN 201510007559A CN 104693189 B CN104693189 B CN 104693189B
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- aurora
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- pyrimidine compound
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses a kind of pyrimidine compound and its synthetic method and applications.The general structure of pyrimidine compound is
Description
Technical field
The present invention relates to a kind of noval chemical compounds and its preparation method and application.
Background technique
Aurora A is a kind of serine/threonine kinase in cell growth cycle with important regulating and controlling effect,
It participates in adjusting spindle formation, centrosome maturation, chromosome differentiation and cytokinesis process, have to the stability for maintaining genome
There is key effect.The study found that the overexpression of Aurora A easily leads to cell mitogen exception, it is close with the formation of tumour
Cut phase is closed.Aurora A excessive table in many cancer cells (such as lung cancer, breast cancer, the carcinoma of the rectum, thyroid cancer, cancer of pancreas)
It reaches, inhibits the activity of Aurora A that can lead to the aggregation of tumour cell polyploid, promote Apoptosis, cell is blocked to increase
It grows.Aurora A is just expressed and activates in mitosis, they are invalid for non-proliferative cell, and big in human body
The growth rate of most normal cells is simultaneously unhappy.Therefore Aurora A inhibitor belongs to anti-tumor drugs targeting, and other non-
Specific cell cytotoxic drug is compared, will with greater advantage.
According to the difference of amino acid sequence, mankind's Aurora A is divided into Aurora A, Aurora B and Aurora C tri-
Kind hypotype.These three hypotypes have the very conservative end C- catalytic domain and the end N- variable region, i.e. the ATP with very high homology is combined
Site (end C- catalytic domain), but have larger difference on the amino acid length of the end N- and sequence.
Aurora A kinase gene is positioned as 20q13, and coding albumen contains 403 amino acid, molecular weight 46KD.Aurora
A kinases participates in the regulation of the processes such as centrosome maturation, mitosis starting and the bipolar formation of spindle.In various kinds of cell strain,
The overexpression of Aurora A gene can cause the multipolarization of spindle, cause chromosome separation abnormal, it is non-whole to generate chromosome
Times body cell.Conversely, the expression of Aurora A kinase protein is inhibited to can inhibit the formation of normal bipolar spindle, cell is caused to spin
The single polarization of hammer body, and then Arrested Cell period cause apoptosis.Existing result of study shows that Aurora A is adjusting spindle
It plays a crucial role in polarity and its assembling, elimination inherence Aurora A albumen is immunized or over-expresses inactive mutant protein
Lead to tubulin retard motion, eventually leads to and maintain the spindle of chromosome stabilityX destructurized.
The normal height of the mRNA of Aurora A is expressed in the tumor tissues of the epithelial cells such as the poor mammary gland of prognosis and intestines origin.
Solid tumor at many positions, in breast cancer, gastric cancer, liver cancer, the cancer of the esophagus, lung cancer, cancer of pancreas, oophoroma and bladder cancer,
It was found that the gene magnification of Aurora A, mutation or the expression of albumen height.The amplification of Aurora A, high expression or Mutation and tumour
The classification of cell, by stages, invasion and prognosis be closely connected.In the highly expressed cell of Aurora A, centerbody can be observed
Amplification, the formation of chromosome aneuploid and the cancer conversion of normal cell；Cell forms colony on soft agar culture plate, will be thin
Born of the same parents, which are transplanted in nude mouse, further to confirm that the unconventionality expression of Aurora A is tumorigenic major reason with tumorigenesis.It grinds
Studying carefully the drug resistance of the expression and chemotherapeutics that show Aurora A, there are important relationships.In ovarian cancer cell, Aurora A mistake
Express apoptosis capable of inhibiting cell；Aurora A missing can increase cell to the sensibility of cis-platinum；Squamous cell carcinoma of esophagus
In, the overexpression of Aurora A can resist the apoptosis of cisplatin induction；In prostate gland cancer cell, inhibit Aurora A can collaborative
Treat drug killing tumor cell, prompt Aurora A kinases unconventionality expression may be cause clinically drug susceptibility it is low, treat
Imitate one of the reason of difference.
Central role based on Aurora kinase families played in normal cell division, with to the kinase activity position
Point crystal structure illustrates, and the top manufacturer in the world of some anticancer drugs, such as Merck, AstraZeneca etc. are dedicated to small point one after another
The design and research of sub- Aurora A inhibitor, reported small molecule Aurora A inhibitor include ZM447439,
Hesperadin and VX-680 etc..In vitro test finds that they have anti-tumor activity, this may be extremely promising antitumor
New drug development direction.The targeted therapy of Aurora A micromolecular inhibitor has been tried out with the low advantage of its selectivity Qiang ﹑ toxicity
In clinical treatment, the superior curative effect of this novel targets is shown, Aurora A is made to become new in cancer generation, the research treated
Hot spot.Currently, Aurora inhibitor MLN8054, MLN8237 (Alisertib), PHA-739358, AMG 900, SNS-
314 etc. study all in clinical I, II or III phase, need to be become high efficiency anti-tumor drug of new generation.
Leukaemia is a kind of candidate stem cell malignant clone disease.Clonal leukaemia cell because proliferation out of control, point
Change obstacle, apoptosis mechanism largely proliferation accumulation in marrow and other hematopoietic tissues such as to be obstructed, and infiltrate its hetero-organization and organ,
Normal hematopoiesis is suppressed simultaneously.Clinical visible different degrees of anaemia, bleeding, infectious fever and liver, spleen, enlargement of lymph nodes and
Skeleton pain.It is reported that the disease incidence of China each department leukaemia accounts for the 6th in various tumours.Currently, effectively treating white
The drug of blood disease is relatively limited, and prevailing price is expensive, needs that the progress that can preferably inhibit leukaemia is used for a long time, compels to be essential
Develop long-acting antileukemie drug.Leukaemia and the active association situation of Aurora A are unclear.
Summary of the invention
The purpose of the present invention is to provide a kind of pyrimidine compound and its applications.
The technical solution used in the present invention is:
A kind of pyrimidine compound, structural formula general formula are as follows:
In formula,
R1Saturated alkane base or its monosubstituted object selected from C1~C4, or salt, ester, ether for monosubstituted object；Or it is
Carboxyl or its salt and ester；
R2Saturated alkane base and its monosubstituted object selected from C1~C4.
As the further improvement of above-mentioned pyrimidine compound, R1For C1~C4 saturated alkane base monosubstituted object when, list
Substituent is its halogen substituents, hydroxyl substituent, carboxyl substituent；R2For C1~C4 saturated alkane base monosubstituted object when,
Its monosubstituted object is its halogen substituents, hydroxyl substituent, carboxyl substituent.
As the further improvement of above-mentioned pyrimidine compound, R1、R2For C1~C4 saturated alkane base when, C3 or C4's is full
It is linear saturation alkyl with alkyl.
As the further improvement of above-mentioned pyrimidine compound, R1、R2Stand alone as methyl, ethyl.
A kind of Pharmaceutical composition, the active constituent in the composition includes above-mentioned pyrimidine compound or its precursor.
Preferably, above-mentioned Pharmaceutical composition is for inhibiting Aurora A, the especially activity of Aurora A kinases.
Preferably, above-mentioned Pharmaceutical composition is for treating leukaemia, and particularly, leukaemia is for acute myeloid leukemia or slowly
Property granulocytic leukemia.
The beneficial effects of the present invention are:
Pyrimidine compound of the invention can inhibit Aurora A, the especially activity of Aurora A kinases well,
A kind of Aurora A of experiment, especially Aurora A kinase activity inhibitor can be acted on to use.
Experimental data shows that pyrimidine compound of the invention can inhibit acute myeloid leukemia and chronic grain thin well
The proliferation of born of the same parents leukaemia cell, effect are in dose-dependant.Meanwhile data show that pyrimidine compound of the invention can inhibit white
The clonality of blood disease cell.
Pyrimidine compound of the invention, synthesis step is relatively simple, and production cost is more cheap, is conducive to industrial metaplasia
It produces.
Detailed description of the invention
Fig. 1 is the vitro kinase test dose effect figure of pyrimidine compound of the present invention；
Fig. 2 is drug dose effect figure of the pyrimidine compound of the present invention to leukaemia cell inhibitory effect；
Fig. 3 is the result figure that pyrimidine compound of the present invention promotes apoptosis of leukemia；
Fig. 4 is pyrimidine compound of the present invention to leukaemia cell death related protein exercising result figure；
Fig. 5 is that pyrimidine compound of the present invention inhibits leukemic clone Forming ability result figure；
Fig. 6 is Cycle Arrest result figure of the pyrimidine compound of the present invention to leukaemia cell；
Fig. 7 is pyrimidine compound of the present invention1H NMR spectra；
Fig. 8 is pyrimidine compound of the present invention13C NMR spectra.
Specific embodiment
A kind of pyrimidine compound, structural formula general formula are as follows:
In formula,
R1Saturated alkane base or its monosubstituted object selected from C1~C4, or salt, ester, ether for monosubstituted object；Or it is
Carboxyl or its salt and ester；
R2Saturated alkane base and its monosubstituted object selected from C1~C4.
As the further improvement of above-mentioned pyrimidine compound, R1For C1~C4 saturated alkane base monosubstituted object when, list
Substituent is its halogen substituents, hydroxyl substituent, carboxyl substituent；R2For C1~C4 saturated alkane base monosubstituted object when,
Its monosubstituted object is its halogen substituents, hydroxyl substituent, carboxyl substituent.
Halogen includes fluorine, chlorine, bromine and iodine.
As the further improvement of above-mentioned pyrimidine compound, R1、R2For C1~C4 saturated alkane base when, C3 or C4's is full
It is linear saturation alkyl with alkyl.
The saturated alkane base of C1~C4 can be methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tertiary fourth
Base.
As the further improvement of above-mentioned pyrimidine compound, R1、R2Stand alone as methyl, ethyl.
The salt of above-mentioned pyrimidine compound is pharmaceutically acceptable salt, as its carboxyl reacts the salt generated with alkali.These salt
The including but not limited to salt known in the art such as sodium salt, sylvite, calcium salt, molysite.
A kind of Pharmaceutical composition, the active constituent in the composition includes above-mentioned pyrimidine compound or its precursor.
Preferably, above-mentioned Pharmaceutical composition is for inhibiting Aurora A, the especially activity of Aurora A kinases.
Preferably, above-mentioned Pharmaceutical composition is for treating leukaemia, and particularly, leukaemia is for acute myeloid leukemia or slowly
Property granulocytic leukemia.
Below by taking the synthesis of compound AKI7w as an example, the synthetic method of pyrimidine compound of the present invention is further illustrated.
Intermediate 1(2,6-dichloro-N-(5-methyl-1H- pyrazol-3-yl) pyrimidin-4-amine)
Synthesis
1) weigh 2,4,6- trichloropyrimidines (1.83 g, 10 mmol) and 3- amino-5-methylpyrazole (0.97 g, 10
Mmol it) is dissolved in 100 mL dehydrated alcohols, is added triethylamine (2.7 mL, 20 mmol), be stirred to react 12 h at 0 DEG C；
2) after stopping reaction, 150 mL water is added into reaction solution, a large amount of white solid is precipitated immediately.It filters, Gu
Body is successively washed with 50 mL ice water and 20 mL ice methanol, obtains intermediate 1(1.82 g, yield 75% after dry).
The characterize data of intermediate 1 is as follows:
1H NMR (400 MHz, DMSO-d 6 ) δ: 12.19 (s, 1H), 10.61 (s, 1H), 7.72-6.78
(m, 1H), 6.29-5.80 (m, 1H), 2.22 (s, 3H); 13C NMR (100 MHz, DMSO-d 6 ) δ: 161.1,
158.5, 147.0, 139.1, 102.8, 95.5, 10.5 ppm。
Intermediate 2(4- ((4-chloro-6- ((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-
Yl) amino) benzonitrile) synthesis
1) intermediate 1(488.2 mg, 2.0 mmol are weighed), p-aminophenyl formonitrile HCN (283.5 mg, 2.6 mmol), to first
Benzene sulfonic acid monohydrate (304.4 mg, 0.8 mmol), is dissolved in 20 mL n-butanols, 15 h of back flow reaction at 140 DEG C；
2) after stopping reaction, 5 mL is added and are saturated NaHCO3Solution, adjusts pH value of solution=7-8, and methylene chloride extraction is organic
Mutually through saturated common salt water washing, anhydrous Na2SO4Dry, vacuum distillation removes solvent, and methanol trituration obtains intermediate 2(281.5 mg,
Yield 43.2%).
The characterize data of intermediate 2 is as follows:
1H NMR (400 MHz, DMSO-d 6) δ: 12.12 (s, 1H), 10.07 (s, 1H), 10.00 (s,
1H), 7.99 (d, J = 6.5 Hz, 2H), 7.72 (d, J = 8.5 Hz, 2H), 6.26 (s, 2H), 2.25
(s, 3H); 13C NMR (100 MHz, DMSO-d 6) δ: 160.7, 158.4, 147.7, 144.6, 133.4,
132.9, 119.5, 118.6, 113.4, 110.5, 102.6, 96.3, 10.7 ppm. HRMS (ESI-TOF): m/z
calcd. for C15H13ClN7, [M+H]+: 326.0915, found: 326.0894。
Compound AKI7w(4- ((4- ((5-methyl-1H-pyrazol-3-yl)amino)-6-(4-
Methylpiperazin-1-yl) pyrimidin-2-yl) amino) benzonitrile) and synthesis
Weigh intermediate 2(163 mg, 0.5 mmol) withNMethyl piperazine (0.55 mL, 5 mmol), is dissolved in the 1 of 3mL,
In 4- dioxane, 1 h of microwave reaction at 180 DEG C, vacuum distillation removes solvent, and column chromatographic purifying obtains compound AKI7w
(110 mg, yield 56.7%).
The characterize data of compound AKI7w is as follows:
1H NMR (400 MHz, DMSO-d 6) δ: 11.86 (s, 1H), 9.25 (s, 1H), 9.02 (s,
1H), 7.96 (s, 2H), 7.64 (d, J = 7.8 Hz, 2H), 6.22 (s, 1H), 6.04 (s, 1H), 3.49
(s, 4H), 2.39 (s, 4H), 2.22 (s, 3H), 2.20 (s, 3H); 13C NMR (100 MHz, DMSO-d 6)
δ: 163.3, 160.4, 158.1, 145.9, 132.7, 119.8, 118.0, 101.0, 95.1, 77.9, 54.2,
45.7, 43.8, 10.7 ppm. HRMS (ESI-TOF): m/z calcd. for C20H22N9, [M-H]-:
388.2004, found: 388.2009.Its1H and13C NMR spectra difference is as shown in FIG. 7 and 8.
Compound activity experiment:
Experiment 1: AKI7w pairs of pyrimidine compound is detected according to " Caliper Mobility Shift Assay " method
The influence of Aurora-A kinase activity.Compound is diluted since 10 μM with 3 times, totally 10 concentration.
The result of experiment 1 is as shown in Figure 1.The experimental results showed that compound AKI7w can dose-dependant with the raising of concentration
Inhibit Aurora A kinase activity, IC50For 8.0 nM, show that the inhibitor can inhibit Aurora-A kinases in very low dose
Activity, inhibitory effect is splendid and has targeting specific.The IC that compound AKI7w inhibits Aurora B activity50It is 48.7
NM shows that compound AKI7w can also effectively inhibit Aurora B kinase activity.
Experiment 2: pyrimidine compound AKI7w is dissolved in DMSO(100 mM) as storage liquid, when experiment, is diluted with PBS,
It is added in culture solution.Cell is incubated at respectively in 96 orifice plates, and the compound AKI7w that various concentration is respectively adopted handles each leukaemia
MTT, 37 DEG C of culture 4h are added after cell 48h, detect OD value with 490 nm, abscissa is the concentration of compound in each figure, indulges and sits
It is designated as cell relative survival rate.
The result of experiment 2 is as shown in Figure 2.As shown in Figure 2 a, AKI7w(concentration is 0 μM, 0.075 μM, 0.15 μM, 0.3
μM, 0.6 μM, 1.2 μM) there is dose-dependent inhibiting effect to the proliferation of HL-60 cell；As shown in Figure 2 b, AKI7w
(concentration be 0 μM, 0.075 μM, 0.15 μM, 0.3 μM, 0.6 μM, 1.2 μM) to the proliferation of K562 cell have dosage according to
Rely the inhibiting effect of property；As shown in Figure 2 c, AKI7w(concentration is 0 μM, 0.075 μM, 0.15 μM, 0.3 μM, 0.6 μM, 1.2
μM) there is dose-dependent inhibiting effect to the proliferation of KBM5 cell.The experimental results showed that can inhibit acute myeloid white by AKI7w
Blood disease and the proliferation of chronic myeloid leukemia cell are simultaneously acted in dose-dependant.
Experiment 3: leukaemia cell is handled using the pyrimidine compound AKI7w solution of various concentration.After testing 48h
Collect cell, AnnexinV/PI dyeing, flow cytomery apoptotic cell group.
The result of experiment 3 is as shown in Figure 3.The experimental results showed that in leukaemia cell KBM5, in shown concentration range
AKI7w can promote Apoptosis, show as early apoptosis (AnnexinV+/PI-) and late apoptic (AnnexinV+/PI+) it is thin
Born of the same parents' number obviously increases.
Experiment 4: the synthesized AKI7w of various concentration is handled into leukaemia cell, cell is collected after 48h, uses
The expression of Western blot detection Cleaved Caspase3 and Cleaved PARP.GAPDH is as internal reference.Specific steps
To collect the cell Jing Guo drug-treated, abundant lytic cell；With 4 DEG C of 14000 turns of centrifugation 15min, supernatant is taken.Protein content
Measurement uses Bradford albuminimetry.It takes 40 μ g of protein sample, carries out protein delivery to NC after SDS-PAGE electrophoresis
Film, it is rear to carry out antibody incubation and chemiluminescence development.
The result of experiment 4 is as shown in Figure 4.The experimental results showed that AKI7w has the function of significantly promoting Apoptosis, table
Now it is incremented by for the expression of Cleaved Caspase3 and Cleaved PARP with compound effects increasing concen-trations.KBM5 cell exists
There is the expression of apparent Cleaved Caspase3 and Cleaved PARP when being 0.15 μM in activity.Show the compound
The effect for killing leukaemia cell is related to activation apoptotic signal access.
The experiment that experiment 5: pyrimidine compound AKI7w inhibits leukemic clone to be formed.Leukaemia cell is incubated at
In methylcellulose, and carry out the pyrimidine compound AKI7w processing of various concentration.After 10d, microscopically observation calculates clone's shape
At the case where.
The result of experiment 5 is as shown in Figure 5.The experimental results showed that in leukaemia cell KBM5,0.3 μM and 0.6 μM
AKI7w can completely inhibit the clonality of leukaemia cell, as a result further prompt the compound to have and inhibit leukaemia
The function of stem cells self-renewal.
Experiment 6: taking the pyrimidine compound AKI7w of various concentration to handle leukaemia cell respectively, collects after 48h thin
Born of the same parents, are dyed after 70% ethyl alcohol is fixed with 50 μ g/mL PI, carry out cell cycle detection using flow cytometer.
The result of experiment 6 is as shown in Figure 6.The experimental results showed that AKI7w is in shown concentration model in leukaemia cell KBM5
Enclose it is interior can obviously cause G2/M cell-cycle arrest, and there is polyploid phenomenon, show AKI7w by inhibiting Aurora-A
Cell cycle has an impact, and then inhibits cell Proliferation, causes apoptosis.
Claims (1)
1. application of the compound in preparation treatment leukemia medicament, which is characterized in that compound has the following structure:
In formula,
R1For methyl；
R2For methyl,
The application is the drug for the self-renewing that preparation inhibits leukemic stem cells.
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Non-Patent Citations (1)
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| Design,synthesis and bioevaluation of N-trisubstituted pyrimidine;Yu Luo et al.;《European Journal of Medicinal Chemistry》;20140312;第78卷;第65-71页 |
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