CN104693189A - Pyrimidine compound and preparation method and application thereof - Google Patents
Pyrimidine compound and preparation method and application thereof Download PDFInfo
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- CN104693189A CN104693189A CN201510007559.1A CN201510007559A CN104693189A CN 104693189 A CN104693189 A CN 104693189A CN 201510007559 A CN201510007559 A CN 201510007559A CN 104693189 A CN104693189 A CN 104693189A
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Abstract
The invention discloses a pyrimidine compound and a synthesis method and application thereof. The pyrimidine compound has the structural general formula represented by a formula shown in descriptions. The pyrimidine compound disclosed by the invention can be used for excellently inhibiting the activity of Aurora kinase, can be used as an Aurora kinase activity inhibitor for experiments, and is expected to be developed into drugs for treating leukemia. According to the pyrimidine compound disclosed by the invention, synthesis steps are relatively simple, and the production cost is relatively low, so that industrial production is facilitated.
Description
Technical field
The present invention relates to a kind of new compound and its preparation method and application.
Background technology
Aurora A is the serine/threonine kinase that a class has important regulating and controlling effect in cell growth cycle, participates in regulating spindle body formation, centrosome maturation, karyomit(e) differentiation and division of cytoplasm process, has keying action to the genomic stability of maintenance.Research finds, the overexpression of Aurora A easily causes cell mitogen abnormal, closely related with the formation of tumour.Aurora A overexpression in many cancer cells (as lung cancer, mammary cancer, the rectum cancer, thyroid carcinoma, carcinoma of the pancreas), suppresses the activity of Aurora A can cause the gathering of tumour cell polyploid, promotes apoptosis, blocks cell proliferation.Aurora A is just expressed and activates in mitotic division, and they are invalid for the cell of non-proliferative, and in human body most of Normocellular rate of propagation unhappy.Therefore Aurora A inhibitor belongs to anti-tumor drugs targeting, compared with other non-specific cell cytotoxic drug, will have larger advantage.
According to the difference of aminoacid sequence, mankind's Aurora A is divided into Aurora A, Aurora B and Aurora C tri-kinds of hypotypes.These three kinds of hypotypes have very conservative C-and hold catalytic domain and N-to hold variable region, namely have the ATP-binding site (C-holds catalytic domain) of very high homology, but have larger difference on the amino acid length and sequence of N-end.
Aurora A kinase gene orientates 20q13 as, and proteins encoded is containing 403 amino acid, and molecular weight is 46KD.Aurora A kinases participates in the regulation and control of the processes such as centrosome maturation, mitotic division startup and the bipolar formation of spindle body.In various kinds of cell strain, the overexpression of Aurora A gene can cause the multipolarization of spindle body, causes chromosome segregation abnormal, produces chromosome aneuploid cell.Otherwise, suppress the expression of Aurora A kinase protein can suppress the formation of normal bipolar spindle body, cause the single polarization of cell spindle, and then the Arrested Cell cycle, cause apoptosis.Existing result of study shows that Aurora A is regulating the polarity of spindle body and playing a crucial role in assembling, the mutant protein that inherent Aurora A albumen or overexpression non-activity are eliminated in immunity all causes tubulin retard motion, finally causes the spindle body maintaining chromosome stabilityX destructurized.
The normal high expression level of mRNA of Aurora A is in the tumor tissues of the epithelial cell origins such as the poor mammary gland of prognosis and intestines.At the solid tumor at many positions, as in mammary cancer, cancer of the stomach, liver cancer, the esophageal carcinoma, lung cancer, carcinoma of the pancreas, ovarian cancer and bladder cancer, all find the gene amplification of Aurora A, sudden change or albumen high expression level.The classification of the amplification of Aurora A, high expression level or Mutation and tumour cell, by stages, aggressive and prognosis be closely connected.In the cell of Aurora A high expression level, can be observed the amplification of centrosome, the formation of chromosome aneuploid and Normocellular cancer transform; On soft agar culture plate, cell forms colony, and transplanting cells in nude mouse can tumorigenesis, confirms that the unconventionality expression of Aurora A is tumorigenic major reason further.Research shows that the expression of Aurora A and the resistance of chemotherapeutics exist important relation.In ovarian cancer cell, Aurora A process LAN apoptosis capable of inhibiting cell; Aurora A disappearance can increase the susceptibility of cell to cis-platinum; In squamous cell carcinoma of esophagus, the process LAN of Aurora A can resist the apoptosis of cisplatin induction; In prostate cancer cell, suppress Aurora A can work in coordination with chemotherapeutics killing tumor cell, the kinase whose unconventionality expression of prompting Aurora A may be cause that drug susceptibility is clinically low, one of the reason of weak curative effect.
Based on Aurora kinase families in normal cell division the central role that rises, along with illustrating this kinase active site crystalline structure, the top manufacturer in the world of some cancer therapy drugs, as Merck, AstraZenecas etc. are devoted to the design and research of small molecules Aurora A inhibitor one after another, and the small molecules Aurora A inhibitor reported comprises ZM447439, Hesperadin and VX-680 etc.In vitro tests finds that they have anti-tumor activity, and this may be anti-cancer agent R&D direction extremely likely.The targeted therapy of Aurora A micromolecular inhibitor has been tried out in clinical treatment with the advantage that its selective Qiang ﹑ toxicity is low, demonstrates the curative effect that this novel targets is superior, becomes new focus in the research of Aurora A is occurred in cancer, treating.At present, Aurora inhibitor MLN8054, MLN8237 (Alisertib), PHA-739358, AMG 900, SNS-314 etc. is in clinical I, II or III phase and studies, and needs to become high efficiency anti-tumor medicine of new generation.
Leukemia is a class hemopoietic stem cell malignant clone disease.Clonal leukemia cell breeds accumulation in a large number because of mechanism such as proliferation out of control, dysdifferentiation, apoptosis are obstructed in marrow and other hemopoietic tissues, and infiltrates its hetero-organization and organ, and normal hematopoiesis is suppressed simultaneously.Clinical visible anaemia in various degree, hemorrhage, infectious fever and liver, spleen, lymphadenectasis and skeleton pain.It is reported, the leukemic sickness rate in China each department accounts for the 6th in various tumour.At present, effectively the leukemic medicine for the treatment of is comparatively limited, and prevailing price is expensive, needs life-time service can better suppress leukemic progress, in the urgent need to developing long-acting antileukemie medicine.Leukemia it be unclear that with the situation that associates of Aurora A activity.
Summary of the invention
The object of the present invention is to provide a kind of pyrimidine compound and application thereof.
The technical solution used in the present invention is:
A kind of pyrimidine compound, its structural formula general formula is as follows:
In formula,
R
1be selected from the saturated alkane base of C1 ~ C4, or its monosubstituted thing, or be salt, ester, the ether of monosubstituted thing; Or be carboxyl, or its salt and ester;
R
2be selected from the saturated alkane base of C1 ~ C4 and monosubstituted thing thereof.
As the further improvement of above-mentioned pyrimidine compound, R
1during the monosubstituted thing of the saturated alkane base for C1 ~ C4, its monosubstituted thing is its halogen substituents, hydroxyl substituent, carboxyl substituted thing; R
2during the monosubstituted thing of the saturated alkane base for C1 ~ C4, its monosubstituted thing is its halogen substituents, hydroxyl substituent, carboxyl substituted thing.
As the further improvement of above-mentioned pyrimidine compound, R
1, R
2during saturated alkane base for C1 ~ C4, the saturated alkane base of C3 or C4 is straight chain saturated alkane base.
As the further improvement of above-mentioned pyrimidine compound, R
1, R
2independent is methyl, ethyl.
A kind of medicinal compositions, the activeconstituents in described composition comprises above-mentioned pyrimidine compound, or its precursor.
Preferably, above-mentioned medicinal compositions for suppressing Aurora A, the particularly kinase whose activity of Aurora A.
Preferably, above-mentioned medicinal compositions is used for the treatment of leukemia, and especially, leukemia is acute myeloid leukemia or chronic myelocytic leukemia.
The invention has the beneficial effects as follows:
Pyrimidine compound of the present invention, can suppress Aurora A well, particularly the kinase whose activity of Aurora A, can act on a kind of Aurora A of testing, and particularly Aurora A kinase activity inhibitor uses.
Experimental data shows, and pyrimidine compound of the present invention can suppress the propagation of acute myeloid leukemia and chronic myeloid leukemia cell well, and its effect is dose-dependant.Meanwhile, data presentation pyrimidine compound of the present invention can suppress the clonality of leukemia cell.
Pyrimidine compound of the present invention, synthesis step is comparatively simple, and production cost is comparatively cheap, is conducive to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the vitro kinase test dose effect figure of pyrimidine compound of the present invention;
Fig. 2 is the drug dose effect figure of pyrimidine compound of the present invention to leukemia cell inhibitory effect;
Fig. 3 is the result figure that pyrimidine compound of the present invention promotes apoptosis of leukemia;
Fig. 4 is that pyrimidine compound of the present invention is to leukemia cell death related protein exercising result figure;
Fig. 5 is that pyrimidine compound of the present invention suppresses leukemic clone Forming ability result figure;
Fig. 6 is the Cycle Arrest result figure of pyrimidine compound of the present invention to leukemia cell;
Fig. 7 is pyrimidine compound of the present invention
1h NMR spectrogram;
Fig. 8 is pyrimidine compound of the present invention
13c NMR spectrogram.
Embodiment
A kind of pyrimidine compound, its structural formula general formula is as follows:
In formula,
R
1be selected from the saturated alkane base of C1 ~ C4, or its monosubstituted thing, or be salt, ester, the ether of monosubstituted thing; Or be carboxyl, or its salt and ester;
R
2be selected from the saturated alkane base of C1 ~ C4 and monosubstituted thing thereof.
As the further improvement of above-mentioned pyrimidine compound, R
1during the monosubstituted thing of the saturated alkane base for C1 ~ C4, its monosubstituted thing is its halogen substituents, hydroxyl substituent, carboxyl substituted thing; R
2during the monosubstituted thing of the saturated alkane base for C1 ~ C4, its monosubstituted thing is its halogen substituents, hydroxyl substituent, carboxyl substituted thing.
Halogen comprises fluorine, chlorine, bromine and iodine.
As the further improvement of above-mentioned pyrimidine compound, R
1, R
2during saturated alkane base for C1 ~ C4, the saturated alkane base of C3 or C4 is straight chain saturated alkane base.
The saturated alkane base of C1 ~ C4 can be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl.
As the further improvement of above-mentioned pyrimidine compound, R
1, R
2independent is methyl, ethyl.
The salt of above-mentioned pyrimidine compound is pharmacy acceptable salt, as the salt that its carboxyl and alkali reaction generate.These salt include but not limited to the salt known in the art such as sodium salt, sylvite, calcium salt, molysite.
A kind of medicinal compositions, the activeconstituents in described composition comprises above-mentioned pyrimidine compound, or its precursor.
Preferably, above-mentioned medicinal compositions for suppressing Aurora A, the particularly kinase whose activity of Aurora A.
Preferably, above-mentioned medicinal compositions is used for the treatment of leukemia, and especially, leukemia is acute myeloid leukemia or chronic myelocytic leukemia.
Below with
compd A KI7wsynthesize example, further illustrate the synthetic method of pyrimidine compound of the present invention.
intermediate 1(2,6-
dichloro-
n-(5-methyl-1
h-pyrazol-3-yl) pyrimidin-4-amine) synthesis
1) take 2,4,6-trichloropyrimidine (1.83 g, 10 mmol) and 3-amino-5-methylpyrazole (0.97 g, 10 mmol) is dissolved in 100 mL dehydrated alcohols, add triethylamine (2.7 mL, 20 mmol), stirring reaction 12 h at 0 DEG C;
2), after stopped reaction, in reaction soln, add 150 mL water, separate out a large amount of white solids immediately.Suction filtration, solid uses 50 mL frozen water and 20 mL ice methanol wash successively, obtains intermediate after drying
1(1.82 g, productive rate 75%).
Intermediate
1characterization data 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-1
h-pyrazol-3-yl) amino) pyrimidin-2-yl) amino) benzonitrile) and synthesis
1) intermediate is taken
1(488.2 mg, 2.0 mmol), p-aminophenyl formonitrile HCN
(283.5 mg, 2.6 mmol), tosic acid monohydrate (304.4 mg, 0.8 mmol), is dissolved in 20 mL propyl carbinols, back flow reaction 15 h at 140 DEG C;
2), after stopped reaction, the saturated NaHCO of 5 mL is added
3solution, regulator solution pH=7-8, dichloromethane extraction, organic phase through saturated common salt water washing, anhydrous Na
2sO
4drying, underpressure distillation is except desolventizing, and methanol trituration obtains intermediate
2(281.5 mg, productive rate 43.2%).
Intermediate
2characterization data 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/zcalcd. for C
15H
13ClN
7, [M+H]
+: 326.0915, found: 326.0894。
compd A KI7w(4-((4-((5-methyl-1
h-pyrazol-3-yl) amino)-6-(4-methylpiperazin-1-yl) pyrimidin-2-yl) amino) benzonitrile) and synthesis
Take intermediate
2(163 mg, 0.5 mmol) with
n-methylpiperazine (0.55 mL, 5 mmol), is dissolved in the Isosorbide-5-Nitrae-dioxane of 3mL, microwave reaction 1 h at 180 DEG C, and underpressure distillation is except desolventizing, and column chromatography purification obtains compound
aKI7w(110 mg, productive rate 56.7%).
Compound
aKI7wcharacterization data 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/zcalcd. for C
20H
22N
9, [M-H]
-: 388.2004, found: 388.2009。Its
1h and
13c NMR spectrogram respectively as shown in FIG. 7 and 8.
compound activity is tested:
Experiment 1: detect pyrimidine compound according to " Caliper Mobility Shift Assay " method
aKI7won the impact of Aurora-A kinase activity.Compound, from 10 μMs, dilutes with 3 times, totally 10 concentration.
The result of experiment 1 as shown in Figure 1.Experimental result shows the raising along with concentration, compound
aKI7waurora A kinase activity can be suppressed, its IC by dose-dependant
50be 8.0 nM, show that this inhibitor can suppress Aurora-A kinase activity at very low dose, inhibition is splendid and have targeting specific.Compound
aKI7wto the IC that Aurora B activity suppresses
50be 48.7 nM, show compound
aKI7walso Aurora B kinase activity can effectively be suppressed.
Experiment 2: pyrimidine compound
aKI7wbe dissolved in DMSO(100 mM) as storing liquid, diluting with PBS during experiment, being added in nutrient solution.Cell is incubated in 96 orifice plates respectively, adopts the compound of different concns respectively
aKI7wadd MTT after processing each leukemia cell 48h, cultivate 4h for 37 DEG C, detect OD value with 490 nm, in each figure, X-coordinate is the concentration of compound, and ordinate zou is cell relative survival rate.
The result of experiment 2 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 μMs) has the restraining effect of dose-dependently to the propagation of HL-60 cell; As shown in Figure 2 b,
aKI7w(concentration is 0 μM, 0.075 μM, 0.15 μM, 0.3 μM, 0.6 μM, 1.2 μMs) has the restraining effect of dose-dependently to the propagation of K562 cell; 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 μMs) has the restraining effect of dose-dependently to the propagation of KBM5 cell.Experimental result shows
aKI7wcan suppress acute myeloid leukemia and chronic myeloid leukemia cell propagation and in dose-dependant effect.
Experiment 3: the pyrimidine compound adopting different concns
aKI7wsolution processes leukemia cell.Collecting cell after experiment 48h, AnnexinV/PI dyes, flow cytomery apoptotic cell group.
The result of experiment 3 as shown in Figure 3.Experimental result shows in leukemia cell KBM5, in shown concentration range
aKI7wcan apoptosis be promoted, show as early apoptosis (AnnexinV
+/ PI
-) and late apoptic (AnnexinV
+/ PI
+) cell count obviously increase.
Experiment 4: by the AKI7w process leukemia cell synthesized by different concns, collecting cell after 48h, adopts Western blot to detect the expression of Cleaved Caspase3 and Cleaved PARP.GAPDH is as internal reference.Concrete steps are collect the cell through drug treating, abundant lysing cell; Leave heart 15min with 4 DEG C 14000, get supernatant.Determining the protein quantity adopts Bradford albuminimetry.Get protein sample 40 μ g, to carry out after SDS-PAGE electrophoresis by protein delivery to NC film, after carry out antibody incubation and chemoluminescence development.
The result of experiment 4 as shown in Figure 4.Experimental result shows
aKI7whave and significantly promote apoptotic effect, the expression showing as Cleaved Caspase3 and Cleaved PARP increases progressively with compound effects increasing concen-trations.The expression of obvious Cleaved Caspase3 and Cleaved PARP is there is in KBM5 cell when activity is 0.15 μM.Show the effect that this compound kills and wounds leukemia cell relevant to activation apoptotic signal path.
Experiment 5: pyrimidine compound
aKI7wsuppress the experiment that leukemic clone is formed.Leukemia cell is incubated in methylcellulose gum, and carries out the pyrimidine compound of different concns
aKI7wprocess.After 10d, basis of microscopic observation calculates the situation of Clone formation.
The result of experiment 5 as shown in Figure 5.Experimental result shows in leukemia cell KBM5,0.3 μM and 0.6 μM
aKI7wcan suppress the clonality of leukemia cell completely, result points out this compound to have the function suppressing leukemic stem cells self further.
Experiment 6: the pyrimidine compound getting different concns respectively
aKI7wleukemia cell is processed, collecting cell after 48h, dye with 50 μ g/mL PI after 70% ethanol is fixing, adopt flow cytometer to carry out cell cycle detection.
The result of experiment 6 as shown in Figure 6.Experimental result shows in leukemia cell KBM5,
aKI7win shown concentration range, all can obviously cause G2/M cell-cycle arrest, and occur polyploid phenomenon, show
aKI7wby suppressing Aurora-A cell cycle to have an impact, and then antiproliferative effect, cause apoptosis.
Claims (10)
1. a pyrimidine compound, its structural formula general formula is as follows:
In formula,
R
1be selected from the saturated alkane base of C1 ~ C4, or its monosubstituted thing, or be salt, ester, the ether of monosubstituted thing; Or be carboxyl, or its salt and ester;
R
2be selected from the saturated alkane base of C1 ~ C4 and monosubstituted thing thereof.
2. pyrimidine compound according to claim 1, is characterized in that: R
1during the monosubstituted thing of the saturated alkane base for C1 ~ C4, its monosubstituted thing is its halogen substituents, hydroxyl substituent, carboxyl substituted thing; R
2during the monosubstituted thing of the saturated alkane base for C1 ~ C4, its monosubstituted thing is its halogen substituents, hydroxyl substituent, carboxyl substituted thing.
3. pyrimidine compound according to claim 1 and 2, is characterized in that: R
1, R
2during saturated alkane base for C1 ~ C4, the saturated alkane base of C3 or C4 is straight chain saturated alkane base.
4. pyrimidine compound according to claim 1, is characterized in that: R
1, R
2independent is methyl, ethyl.
5. a medicinal compositions, the activeconstituents in described composition comprises the pyrimidine compound described in Claims 1 to 4 any one, or the precursor of pyrimidine compound described in claim 1.
6. medicinal compositions according to claim 5, is characterized in that: described medicinal compositions is for suppressing the activity of Aurora A.
7. medicinal compositions according to claim 6, is characterized in that: described Aurora A is Aurora A kinases.
8. medicinal compositions according to claim 5, is characterized in that: described medicinal compositions is used for the treatment of leukemia.
9. pyrimidine compound described in claim 1 is as the application for the treatment of leukemia medicament.
10. application according to claim 9, is characterized in that: described leukemia is acute myeloid leukemia or chronic myelocytic leukemia.
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|---|---|---|---|---|
| CN108276390A (en) * | 2017-06-12 | 2018-07-13 | 中山大学附属第三医院 | A kind of pyrimidine derivatives of reversing tumor cells resistance and its application |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103059002A (en) * | 2012-12-31 | 2013-04-24 | 中山大学 | Pyrimidine derivative with Aurora kinase inhibitory activity and preparation method and application thereof |
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2015
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| CN103059002A (en) * | 2012-12-31 | 2013-04-24 | 中山大学 | Pyrimidine derivative with Aurora kinase inhibitory activity and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| YU LUO ET AL.: "Design,synthesis and bioevaluation of N-trisubstituted pyrimidine", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (1)
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|---|---|---|---|---|
| CN108276390A (en) * | 2017-06-12 | 2018-07-13 | 中山大学附属第三医院 | A kind of pyrimidine derivatives of reversing tumor cells resistance and its application |
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