CN102115470A - Pyrimidine small-molecular compounds, and preparation method and application thereof - Google Patents
Pyrimidine small-molecular compounds, and preparation method and application thereof Download PDFInfo
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- CN102115470A CN102115470A CN200910247891XA CN200910247891A CN102115470A CN 102115470 A CN102115470 A CN 102115470A CN 200910247891X A CN200910247891X A CN 200910247891XA CN 200910247891 A CN200910247891 A CN 200910247891A CN 102115470 A CN102115470 A CN 102115470A
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- WJJKQURBIXUXNU-XSFVSMFZSA-N CCC(C)/N=C(/NCC(C)C)\N=C(/C)\c(cccc1)c1O Chemical compound CCC(C)/N=C(/NCC(C)C)\N=C(/C)\c(cccc1)c1O WJJKQURBIXUXNU-XSFVSMFZSA-N 0.000 description 1
- VXKHPCZFECALDJ-UHFFFAOYSA-N CCNC(C=C)=C Chemical compound CCNC(C=C)=C VXKHPCZFECALDJ-UHFFFAOYSA-N 0.000 description 1
- JORGKTGKOFOFJW-UHFFFAOYSA-N CC[n](ccc1c2)c1ccc2-c1cnc(NC(OC(C)(C)C)=O)nc1-c(cccc1)c1OCc1ccccc1 Chemical compound CC[n](ccc1c2)c1ccc2-c1cnc(NC(OC(C)(C)C)=O)nc1-c(cccc1)c1OCc1ccccc1 JORGKTGKOFOFJW-UHFFFAOYSA-N 0.000 description 1
- VONWCKHYDSLZQT-UHFFFAOYSA-N CC[n](ccc1c2)c1ccc2-c1cnc(NCC(C)C)nc1-c(cccc1)c1OCc1ccccc1 Chemical compound CC[n](ccc1c2)c1ccc2-c1cnc(NCC(C)C)nc1-c(cccc1)c1OCc1ccccc1 VONWCKHYDSLZQT-UHFFFAOYSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses novel pyrimidine small-molecular compounds, and a preparation method and application thereof. The pyrimidine compounds disclosed by the invention are represented as a general formula A. The method comprises the following steps: coupling iodochromone, which is used as a raw material, with various indolylboronic acids and azaindolylboronic acids, and condensing with amidine or guanidine compounds, thereby obtaining the pyrimidine compounds. The compounds have wide antitumor activity, and are hopeful to be prepared into new antitumor medicaments when being further optimized[General Formula A].
Description
Technical field
The present invention relates to field of medicaments, be specifically related to a kind of 2,4, the miazines micromolecular compound that 5-replaces, Preparation Method And The Use.Particularly, the present invention relates to miazines micromolecular compound, have antitumor high reactivity, can be used as antitumor drug by multi-component reaction synthetic one class new substituted.The invention still further relates to the preparation method and the application of this compounds.
Background technology
Pyrimidines is that a class has extensive bioactive material, anti-malarial for example, and anti-inflammatory, antitumor, tuberculosis, antiviral isoreactivity.Tumour is the disease that the serious harm human survival is healthy and be difficult to overcome, and its hazard rating grows with each passing day.At present, malignant tumour has become Chinese city resident first killer.The research of antitumor drug has all been stepped up in countries in the world.Compare, China's original new drug research in this respect is comparatively backward.The present invention develops novel miazines micromolecular compound, by deep structure activity study, develops the new antitumor drug of a class.In patent WO2007104254 A1, we have synthesized the new pyrimidine compounds by Suzuki coupling and condensation reaction, have found some compounds with better anti-tumor activity.Finding in the research that further introduce indoles and azaindole in the pyrimidine molecule, its anti-tumor activity improves greatly, and finding that this compounds has the effect of the microtubule polymerization of inhibition.Tubulin is the target spot of known comparatively ideal antitumor drug.And this pyrimidines suppresses cell-proliferation activity and has good dependency with inhibition microtubule polymerization data, confirms that it is tubulin that this pyrimidines has clear and definite action target spot.
Summary of the invention
One of purpose of the present invention provides a class miazines micromolecular compound, and this compounds has highly active antitumor action, and can research and develop becomes the anti-tumor drug that is used for that preparation is easy, activity is higher.
Another purpose of the present invention provides the preparation method of described miazines micromolecular compound, this method comprises with iodo chromone and indoles boric acid and the coupling of azaindole boric acid, with amidine or guanidine compound condensation, obtain miazines micromolecular compound of the present invention again.
A further object of the present invention provides the purposes of described miazines micromolecular compound in the preparation antitumor drug.
According to technical scheme of the present invention, provide a kind of miazines micromolecular compound with structure shown in the following general formula A:
Wherein, R
1For hydrogen, halogen, do not replace or C that halogen replaces
1-C
6Alkyl, do not replace or C that halogen replaces
1-C
6Alkoxyl group or nitro;
X is a hydroxyl; Unsubstituted amino; Perhaps by being selected from aryl, heteroaryl or aryl C
1-C
6The amino that the substituting group of alkyl replaces;
R
2Be hydrogen or C
1-C
6Alkyl;
R
3Be hydrogen, C
1-C
6That alkyl, unsubstituted amino or aryl replace or C
1-C
6The amino that alkyl replaces;
Z is carbon or nitrogen;
Described aryl is unsubstituted phenyl or the phenyl that replaced by substituting group, and described substituting group is selected from cyano group, halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Carbalkoxy and C
1-C
4In the haloalkyl one or more;
Described heteroaryl is to comprise 1-3 heteroatomic 5～7 yuan of heteroaryls that are selected among N, S and the O;
Described halogen is selected among fluorine, chlorine, bromine and the iodine.
The pyrimidines of structure is preferably shown in the general formula A of the present invention:
R
1For hydrogen, halogen, do not replace or C that halogen replaces
1-C
4Alkyl, do not replace or C that halogen replaces
1-C
4Alkoxyl group or nitro;
X is a hydroxyl; Unsubstituted amino; Perhaps by being selected from phenyl that unsubstituted phenyl, substituting group replace, comprising 5～6 yuan of heteroaryls or the phenyl C of 1-3 N atom
1-C
4The amino that substituting group in the alkyl replaces, described substituting group is for being selected from cyano group, halogen radical, C
1-C
4Alkyl, C
1-C
4Alkoxyl group and C
1-C
4In the haloalkyl one or more;
R
2Be hydrogen or C
1-C
4Alkyl;
R
3Be hydrogen, C
1-C
4That alkyl, unsubstituted amino or phenyl replace or C
1-C
4The amino that alkyl replaces;
Z is carbon or nitrogen;
Described halogen is fluorine, chlorine or bromine.
The pyrimidines of structure shown in the general formula A of the present invention is more preferably: R
1Be hydrogen, 4-chlorine, 4-fluorine, 4-bromine, 4-methyl, 4-isobutyl-, 4-methoxyl group or 4-nitro; R
2Be hydrogen, methyl, ethyl, propyl group or sec.-propyl; R
3That replace for methyl, amino or phenyl or C
1～C
4The amino that alkyl replaces.
Pyrimidines shown in the general formula A of the present invention further is preferably compound shown in the table 2.
The invention provides the preparation method of the pyrimidines shown in the general formula A, this method makes halo chromone and indoles boric acid and azaindole boric acid reacting by heating under palladium catalysis and alkaline condition, add amidine or guanidine after reacting completely again, obtains corresponding product.
Particularly, the preparation method of the pyrimidines shown in the general formula A of the present invention, it comprises following method:
Method one: R in general formula A
3Be hydrogen, amino or C
1～C
6Alkyl, when X is hydroxyl,
A) formula 1 compound and aryl or heterocyclic aryl boronic acid compounds
Suzuki coupling production 2 compounds take place under palladium catalysis;
B) formula 2 compounds under alkaline condition with
Condensation production 3 compounds;
Method two: R in general formula A
3Be hydrogen, amino or C
1～C
6Alkyl, X are unsubstituted amino; Perhaps by being selected from aryl, heteroaryl or aryl C
1-C
6The substituting group of alkyl replaces when amino,
C-1) hydroxyl in formula 3 compounds and trifluoromethanesulfonic acid anhydride reactant production 4 compounds;
D-1) formula 4 compounds under palladium catalysis with R
4NH
2Buchwald-Hartiwig coupling production 5 compounds take place;
Perhaps,
Method three: R in general formula A
3That replace for phenyl or C
1-C
4The amino that alkyl replaces is when X is hydroxyl;
C-2) R
3Be NH
2Formula 3 compounds respectively with cylite (BnBr) reaction after again with Boc
2O reacts production 6 compounds under alkaline condition;
D-2) formula 6 compounds by with R
3' Y carries out alkylated reaction and slough Boc protecting group production 7 compounds with trifluoroacetic acid;
E-2) formula 7 hydrogenation of compounds are sloughed Bn protecting group production 8 compounds; Or formula 7 compounds by with R
3" Y carries out alkylated reaction production 9 compounds once more, formula 9 hydrogenation of compounds are sloughed Bn protecting group production 10 compounds;
R
1, R
2As above define with Z;
Y is a halogen;
R
3' and R
3" be C independently of one another
1～C
6Alkyl is preferably C
1～C
4Alkyl;
R
4For being selected from phenyl that unsubstituted phenyl, substituting group replace, comprising 5～6 yuan of heteroaryls or the phenyl C of 1-3 N atom
1-C
4Substituting group in the alkyl, described substituting group are served as reasons and are selected from cyano group, halogen radical, C
1-C
4Alkyl, C
1-C
4Alkoxyl group and C
1-C
4In the haloalkyl one or more.
Selectively, the preparation method of the pyrimidines shown in the general formula A of the present invention, it further preferably includes following method:
Method one: R in general formula A
3Be hydrogen, amino or C
1～C
6Alkyl, when X is hydroxyl,
A) with formula 1 iodo chromone, 10%Pd/C, aryl or heterocyclic radical boronic acid compounds
Add in the flask with salt of wormwood, add acetonitrile and water again, 50 ℃ of stirrings are spent the night, and elimination Pd/C adds entry, uses ethyl acetate extraction, and dried over sodium sulfate boils off solvent, get formula 2 compounds;
B) formula 2 compounds are dissolved in N, behind N '-dimethyl formamide, add amidine or guanidine compound
Salt of wormwood, 70-80 ℃ of stirring adds entry, uses ethyl acetate extraction, and dried over sodium sulfate boils off solvent, and column chromatography (sherwood oil and eluent ethyl acetate) purifying promptly gets formula 3 compounds;
Method two: R in general formula A
3Be hydrogen, amino or C
1～C
6Alkyl, X are unsubstituted amino; Perhaps aryl, heteroaryl or aryl C
1-C
6Alkyl replaces when amino,
C-1) formula 3 compounds and DMAP (4-Dimethylamino pyridine) are added in the flask, add the methylene dichloride dissolving again, drip trifluoromethanesulfanhydride anhydride in-78 ℃, room temperature reaction 10 hours adds entry, uses ethyl acetate extraction, dried over sodium sulfate, boil off solvent, column chromatography (sherwood oil and eluent ethyl acetate) purifying promptly gets formula 4 compounds;
D-1) with formula 4 compounds, Pd
2(dba)
3(three (dibenzalacetones), two palladiums), BINAP ((±)-2,2 '-two-(diphenyl phosphine)-1,1 '-dinaphthalene), R
4NH
2Add in the flask with cesium carbonate, add toluene again, 120 ℃ of stirrings are spent the night, and add entry, use ethyl acetate extraction, and dried over sodium sulfate boils off solvent, and column chromatography (sherwood oil and eluent ethyl acetate) purifying promptly gets formula 5 compounds;
Perhaps,
Method three: R in general formula A
3That replace for phenyl or C
1-C
4The amino that alkyl replaces is when X is hydroxyl;
C-2) formula 3 compounds and salt of wormwood are added in the flask, add ethanol and cylite again, backflow is spent the night, and adds entry, uses ethyl acetate extraction, and dried over sodium sulfate boils off solvent, behind column chromatography (sherwood oil and the eluent ethyl acetate) purifying, adds Boc
2O and sodium bicarbonate add THF, reflux 4 hours, add entry, use ethyl acetate extraction, and dried over sodium sulfate boils off solvent, and column chromatography (sherwood oil and eluent ethyl acetate) purifying gets formula 6 compounds;
D-2) formula 6 compounds are dissolved among the THF, add NaH, add R after half an hour
3`Y reacted 2 hours, added entry, use ethyl acetate extraction, dried over sodium sulfate boils off solvent, behind column chromatography (sherwood oil and the eluent ethyl acetate) purifying, add trifluoroacetic acid reaction 1 hour, add the sodium hydrogen carbonate solution cancellation, use ethyl acetate extraction, dried over sodium sulfate, boil off solvent, column chromatography (sherwood oil and eluent ethyl acetate) purifying gets formula 7 compounds;
E-2) formula 7 compounds are dissolved in methyl alcohol, add 10%Pd/C,, reacted 6 hours in 40 ℃ of logical hydrogen hydrogenations.Elimination Pd/C boils off solvent, and column chromatography (sherwood oil and eluent ethyl acetate) purifying gets formula 8 compounds; Or
Formula 7 compounds are dissolved among the THF, add NaH, add R after half an hour
3``Y reacted 2 hours, added entry, used ethyl acetate extraction, and dried over sodium sulfate boils off solvent, and column chromatography (sherwood oil and eluent ethyl acetate) purifying gets formula 9 compounds;
Formula 9 compounds are dissolved in methyl alcohol, add 10%Pd/C,, reacted 6 hours in 40 ℃ of logical hydrogen hydrogenations.Elimination Pd/C boils off solvent, and column chromatography (sherwood oil and eluent ethyl acetate) purifying gets formula 10 compounds.To those skilled in the art, reaction conditions that is adopted among the above-mentioned preparation method and reagent etc. all are selections of this area routine, can suitably adjust according to employed reactant and the reaction of carrying out.
Embodiment
Preparation embodiment further specifies the present invention below, but does not limit the present invention.
The preparation of embodiment 1:3a
0.2mmol 3-iodine chromone (1a) is dissolved in the 3ml acetonitrile: in the water (4: 1) (volume ratio), add 0.4mmol salt of wormwood again, 0.22mmol 5-indoles boric acid, 10mg 10%Pd/C stirs under 50 ℃ and spends the night.Elimination Pd/C adds entry, uses ethyl acetate extraction, and dried over sodium sulfate boils off solvent and gets compound 2a; Compound 2a is dissolved in 2ml DMF, adds 0.3mmol guanidine and 0.4mmol salt of wormwood again, 70-80 ℃ of stirring after reacting completely, adds ethyl acetate and water, and organic phase washes with water, anhydrous sodium sulfate drying.Solvent evaporated, purification by silica gel column chromatography (sherwood oil and ethyl acetate are towards post), solvent evaporated gets solid 3a (30mg, yield 50%).
1H-NMR(300MHz，CD
3OD)δ：8.28(1H，s)，7.40(1H，d，J＝1.4Hz)，7.29(1H，d，J＝8.2Hz)，7.23(1H，d，J＝3.3Hz)，7.10(1H，td，J＝7.7，1.6Hz)，6.97(1H，dd，J＝8.0，1.5Hz)，6.81-6.87(2H，m)，6.38-6.45(2H，m).
The preparation of embodiment 2:3b
Concrete operations just are changed to 1-methyl-5-indoles boric acid with 5-indoles boric acid with the preparation of 3a, get compound 3b at last.
1H-NMR(300MHz，CDCl
3)δ：8.40(1H，s)，7.55(1H，s)，7.27(1H，d，J＝7.7Hz)，7.52-7.57(3H，m)，7.265(2H，d，J＝8.9Hz)，7.08-7.19(2H，m)，6.93-7.02(3H，m)，6.50(1H，d，J＝3.3Hz)，6.37(1H，t，J＝7.5Hz)，5.10(2H，br)，3.82(3H，s).
The preparation of embodiment 3:3c
Concrete operations just are changed to 1-ethyl-5-indoles boric acid with 5-indoles boric acid with the preparation of 3a, get compound 3c at last.
1H-NMR(300MHz，CDCl
3)δ：8.41(1H，s)，7.557(1H，d，J＝1.1Hz)，7.29(1H，d，J＝8.4Hz)，7.11-7.19(2H，m)，6.94-7.02(3H，m)，6.51(1H，d，J＝3.4Hz)，6.38(1H，t，J＝8.0Hz)，5.13(2H，br)，4.19(2H，q，J＝7.33Hz)，1.49(3H，t，J＝7.3Hz)。
The preparation of embodiment 4:3d
Concrete operations just are changed to ethanamidine with guanidine with the preparation of 3c, get compound 3d at last.
1H-NMR(300MHz，CDCl
3)δ：8.70(1H，s)，7.62(1H，d，J＝1.3Hz)，7.34(1H，d，J＝8.3Hz)，7.14-7.22(2H，m)，6.99-7.07(3H，m)，6.54(1H，d，J＝3.2Hz)，6.39(1H，t，J＝7.5Hz)，4.20(2H，q，J＝7.4Hz)，2.82(3H，s).1.50(3H，t，J＝7.3Hz)。
The preparation of embodiment 5:3e
Concrete operations just are changed to ethanamidine with guanidine with the preparation of 3a, and 5-indoles boric acid is changed to 1-sec.-propyl-5-indoles boric acid, get compound 3e at last.
1H-NMR(300MHz，CDCl
3)δ：8.41(1H，s)，7.56(1H，d，J＝1.6Hz)，7.31(1H，d，J＝8.4Hz)，7.28(1H，d，J＝3.2Hz)，7.15(1H，td，J＝7.8，1.3Hz)，，6.93-7.04(3H，m)，6.53(1H，d，J＝2.9Hz)6.39(1H，td，J＝7.5，1.4Hz)，5.11(2H，br)，4.62-4.73(1H，m).1.55(6H，d，J＝6.4Hz)。
The preparation of embodiment 6:3f
Concrete operations just are changed to 1-ethyl-5-indoline boric acid with 5-indoles boric acid with the preparation of 3a, get compound 3f at last.
1H-NMR(300MHz，CDCl
3)δ：8.32(1H，s)，7.14-7.21(1H，m)，7.11(1H，dd，J＝8.0，1.7Hz)，6.94-7.01(1H，m)，6.51(1H，td，J＝7.7，1.1Hz)，6.45(1H，d，J＝8.6Hz)，5.05(2H，br)，3.38(2H，t，J＝8.2Hz)，3.16(2H，q，J＝7.13Hz)，2.93(2H，t，J＝8.3Hz)，1.21(3H，t，J＝7.3Hz)。
The preparation of embodiment 7:3g
Concrete operations just are changed to 1-ethyl-7-azepine-5-indoles boric acid with 5-indoles boric acid with the preparation of 3a, get compound 3g at last.
1H-NMR(300MHz，CDCl
3)δ：8.38(1H，s)，8.15(1H，d，J＝1.8Hz)，7.76(1H，d，J＝1.9Hz)，7.29(1H，d，J＝3.6Hz)，7.16(1H，t，J＝7.7Hz)，6.98(1H，d，J＝8.3Hz)，6.90(1H，d，J＝7.9Hz)，6.37-6.45(2H，m)，5.21(2H，br)，4.35(2H，q，J＝7.3Hz)，1.50(3H，t，J＝7.3Hz)。
The preparation of embodiment 8:3h
Concrete operations just are changed to 1-ethyl-4-indoles boric acid with 5-indoles boric acid with the preparation of 3a, get compound 3h at last.
1H-NMR(300MHz，CDCl
3)δ：8.47(1H，s)，7.34(1H，d，J＝8.3Hz)，7.20(1H，t，J＝7.6Hz)，7.05-7.13(2H，m)，6.86-6.97(3H，m)，6.27(1H，t，J＝7.5Hz)，6.17(1H，d，J＝3.1Hz)，5.16(2H，br)，4.19(2H，q，J＝7.2Hz)，1.48(3H，t，J＝7.3Hz)。
The preparation of embodiment 9:3i
Concrete operations just are changed to 1-ethyl-6-indoles boric acid with 5-indoles boric acid with the preparation of 3a, get compound 3i at last.
1H-NMR(300MHz，DMSO-d6)δ：10.86(1H，s)，8.32(1H，s)，7.39(1H，d，J＝8.2Hz)，7.31(1H，d，J＝2.8Hz)，7.26(1H，s)，7.09(1H，t，J＝7.3Hz)，6.98(1H，d，J＝7.9Hz)，6.85(2H，br)，6.80(1H，d，J＝7.8Hz)，6.75(1H，d，J＝7.9Hz)，6.55(1H，t，J＝7.5Hz)，6.34(1H，d，J＝3.0Hz)，4.06(2H，q，J＝7.0Hz)，1.19(3H，t，J＝7.1Hz)。
The preparation of embodiment 10:3k
Concrete operations just are changed to 1b with 1a with the preparation of 3a, and 5-indoles boric acid is changed to 1-ethyl-5-indoles boric acid, get compound 3k at last.
1H-NMR(300MHz，CDCl
3)δ：12.30(1H，s)，8.43(1H，s)，7.53(1H，d，J＝1.9Hz)，7.32(1H，d，J＝8.6Hz)，7.18(1H，J＝2.8Hz)，6.83-6.98(3H，m)，6.69(1H，dd，J＝4.4，2.6Hz)，6.50(1H，dd，J＝3.1，0.8Hz)，5.13(2H，br)，4.19(2H，q，J＝7.27Hz)，1.49(3H，t，J＝7.4Hz)。
The preparation of embodiment 11:31
Concrete operations just are changed to 1c with 1a with the preparation of 3a, and 5-indoles boric acid is changed to 1-ethyl-5-indoles boric acid, get compound 31 at last.
1H-NMR(300MHz，CDCl
3)δ：12.23(1H，s)，8.41(1H，s)，7.56(1H，d，J＝1.2Hz)，7.33(1H，d，J＝8.6Hz)，7.15(1H，J＝2.8Hz)，7.01(1H，dd，J＝8.1，1.5
Hz)，6.88(1H，d，J＝9.1Hz)，6.74(1H，dd，J＝8.8，3.1Hz)，6.50(1H，dd，J＝9.0，3.1Hz)，5.10(2H，br)，4.19(2H，q，J＝7.26Hz)，2.83(3H，s)，1.44(3H，t，J＝7.4Hz)。
The preparation of embodiment 12:3m
Concrete operations just are changed to 1e with 1a with the preparation of 3a, and 5-indoles boric acid is changed to 1-ethyl-5-indoles boric acid, get compound 3m at last.
1H-NMR(300MHz，CDCl
3)δ：8.3(1H，s)，7.56(1H，d，J＝1.0Hz)，7.31(1H，d，J＝8.4Hz)，7.18(1H，J＝3.0Hz)，6.99(1H，dd，J＝8.5，1.6Hz)，6.92(1H，d，J＝9.2Hz)，6.74(1H，dd，J＝8.8，3.1Hz)，6.51(1H，d，J＝2.9Hz)，6.47(1H，d，J＝2.5Hz)，5.95(1H，dd，J＝9.0，2.5Hz)，5.04(2H，br)，4.20(2H，q，J＝7.37Hz)，3.74(3H，s)，1.50(3H，t，J＝7.3Hz)。
The preparation of embodiment 13:8a
30mmol 3c and 60mmol salt of wormwood are added in the flask, add 400ml ethanol and 60mmol cylite again, backflow is spent the night, add entry, use ethyl acetate extraction, dried over sodium sulfate, boil off solvent, behind column chromatography (sherwood oil and the eluent ethyl acetate) purifying, add 36mmol Boc
2O and 45mmol sodium bicarbonate add 300ml THF, reflux 4 hours, add entry, use ethyl acetate extraction, and dried over sodium sulfate boils off solvent, and column chromatography (sherwood oil and eluent ethyl acetate) purifying gets 6c (12.5g, 80%).
0.2mmol 6c is dissolved among the 4ml THF, adds 0.3mmol NaH, add 0.3mmol MeI after half an hour, reacted 2 hours, and added entry, use ethyl acetate extraction, dried over sodium sulfate boils off solvent, behind column chromatography (sherwood oil and the eluent ethyl acetate) purifying, add 1ml trifluoroacetic acid reaction 1 hour, add sodium hydrogen carbonate solution, use ethyl acetate extraction, dried over sodium sulfate, boil off solvent, column chromatography (sherwood oil and eluent ethyl acetate) purifying gets 7a (52mg, 60%).
7a (50mg) is dissolved in 3ml methyl alcohol, adds 10mg 10%Pd/C,, reacted 6 hours in 40 ℃ of logical hydrogen hydrogenations.Elimination Pd/C boils off solvent, and column chromatography (sherwood oil and eluent ethyl acetate) purifying gets 8a.
1H-NMR(300MHz，CDCl
3)δ：8.43(1H，d，J＝2.4Hz)，8.40(1H，s)，8.00(1H，d，J＝1.6Hz)，7.32(1H，d，J＝8.6Hz)，7.15(1H，td，J＝8.1，1.6Hz)，7.09(1H，dd，J＝8.5，1.7Hz)，6.98(1H，dd，J＝8.4，1.0Hz)，6.89(1H，dd，J＝8.2，1.3Hz)，6.36(1H，td，J＝7.6，1.1Hz)，5.30(1H，br)，4.28(2H，q，J＝7.3Hz)，3.11(3H，d，J＝5.3Hz)，1.60(3H，t，J＝7.3Hz)。
The preparation of embodiment 14:8b
Concrete operations just change methyl iodide into iodoethane with the preparation of 8a, get compound 8b at last.
1H-NMR(300MHz，CDCl
3)δ：8.44(1H，d，J＝1.8Hz)，8.39(1H，s)，8.00(1H，d，J＝1.6Hz)，7.26-7.35(2H，m)，7.06-7.18(2H，m)，6.98(1H，d，J＝8.3Hz)，6.89(1H，d，J＝8.1Hz)，6.36(1H，td，J＝7.6，1.2Hz)，5.36(1H，br)，4.28(2H，q，J＝7.4Hz)，3.47-3.58(2H，m)，1.59(3H，t，J＝7.4Hz)，1.33(3H，t，J＝7.1Hz)。
The preparation of embodiment 15:10c
0.1mmol 7b is dissolved among the 2ml THF, adds 0.15mmol NaH, add 0.2mmol EtI after half an hour, reacted 2 hours, add entry, use ethyl acetate extraction, dried over sodium sulfate, boil off solvent, get 9c (43mg, 90%) behind column chromatography (sherwood oil and the eluent ethyl acetate) purifying.
9c (40mg) is dissolved in 3ml methyl alcohol, adds 10mg 10%Pd/C,, reacted 6 hours in 40 ℃ of logical hydrogen hydrogenations.Elimination Pd/C boils off solvent, and column chromatography (sherwood oil and eluent ethyl acetate) purifying gets 10c.
1H-NMR(300MHz，CDCl
3)δ：8.43(1H，s)，7.56(1H，d，J＝1.7Hz)，7.29(1H，d，J＝8.5Hz)，7.10-7.18(2H，m)，6.94-7.03(3H，m)，6.51(1H，dd，J＝3.0，0.7Hz)，6.36(1H，td，J＝7.6，1.2Hz)，4.19(2H，q，J＝7.3Hz)，3.69(4H，q，J＝7.1Hz)，1.50(3H，t，J＝7.3Hz)，1.30(6H，t，J＝7.1Hz)。
The preparation of embodiment 16:8d
Concrete operations just change methyl iodide into isobutyl bromide with the preparation of 8a, get compound 8d at last.
1H-NMR(300MHz，CDCl
3)δ：8.43(1H，d，J＝1.8Hz)，8.39(1H，s)，8.00(1H，d，J＝1.3Hz)，7.26-7.35(2H，m)，7.06-7.19(2H，m)，6.98(1H，d，J＝8.4Hz)，6.89(1H，d，J＝8.2Hz)，6.36(1H，t，J＝7.6Hz)，5.36(1H，br)，4.29(2H，q，J＝7.5Hz)，3.31(2H，t，J＝10.1Hz)，1.57-1.63(4H，m)，1.04(6H，d，J＝6.8Hz)。
The preparation of embodiment 17:5a
32mmol 3d and 96mmol DMAP (4-Dimethylamino pyridine) are added in the flask, add the dissolving of 300ml methylene dichloride again, in-78 ℃ of dropping 38mmol trifluoromethanesulfanhydride anhydrides, room temperature reaction 10 hours adds entry, use ethyl acetate extraction, dried over sodium sulfate boils off solvent, column chromatography (sherwood oil and eluent ethyl acetate) purifying, promptly get product 4d (14g, 95%).
With 0.2mmol 4d, 9.1mg Pd
2(dba)
3, 9.3mg BINAP, 0.24mmol aniline and 0.28mmol cesium carbonate add in the flask, add 3ml toluene again, 120 ℃ of stirrings are spent the night, add entry, use ethyl acetate extraction, dried over sodium sulfate, boil off solvent, column chromatography (sherwood oil and eluent ethyl acetate) purifying promptly gets product 5a (64mg, 80%).
1H-NMR(300MHz，CDCl
3)δ：8.76(1H，s)，7.85(1H，br)，7.35(1H，d，J＝8.2Hz)，7.06-7.25(6H，m)，6.92-6.97(3H，m)，6.87(1H，t，J＝7.3Hz)，6.66(1H，t，J＝7.7Hz)，6.48(1H，d，J＝3.1Hz)，4.15(2H，q，J＝7.3Hz)，2.86(3H，s)，1.46(3H，t，J＝7.3Hz)。
The preparation of embodiment 18:5b
Concrete operations just change aniline into adjacent cyano-aniline with the preparation of 5a, get compound 5b at last.
1H-NMR(300MHz，CDCl
3)δ：8.87(1H，br)，8.78(1H，s)，7.42-7.53(3H，m)，7.06-7.25(6H，m)，7.09-7.26(7H，m)，6.89(1H，d，J＝8.5Hz)，6.75-6.83(2H，m)，6.46(1H，d，J＝2.2Hz)，4.14(2H，q，J＝7.0Hz)，2.94(3H，s)，1.46(3H，t，J＝7.2Hz)。
The preparation of embodiment 19:5c
Concrete operations just change aniline into adjacent fluoroaniline with the preparation of 5b, get compound 5c at last.
1H-NMR(300MHz，CDCl
3)δ：8.77(1H，s)，8.44(1H，br)，7.54(1H，d，J＝1.7Hz)，7.41(1H，d，J＝8.1Hz)，7.01-7.28(6H，m)，6.74-6.83(1H，m)，6.67(1H，t，J＝7.3Hz)，6.47(1H，d，J＝3.1Hz)，4.14(2H，q，J＝7.3Hz)，2.88(3H，s)，1.46(3H，t，J＝7.3Hz)。
The preparation of embodiment 20:5d
Concrete operations just change aniline into m-fluoroaniline with the preparation of 5a, get compound 5d at last.
1H-NMR(300MHz，CDCl
3)δ：8.76(1H，s)，7.71(1H，br)，7.54(1H，d，J＝1.7Hz)，7.49(1H，d，J＝1.7Hz)，7.35(1H，d，J＝7.7Hz)，7.04-7.24(5H，m)，6.91(1H，dd，J＝8.6，1.5Hz)，6.77(1H，td，J＝7.5，1.1Hz)，6.43-6.63(4H，m)，4.14(2H，q，J＝7.3Hz)，2.86(3H，s)，1.46(3H，t，J＝7.3Hz)。
The preparation of embodiment 21:5e
Concrete operations just change aniline into para-fluoroaniline with the preparation of 5a, get compound 5e at last.
1H-NMR(300MHz，CDCl
3)δ：8.76(1H，s)，7.71(1H，br)，7.57(1H，s)，7.53(1H，s)，7.09-7.26(5H，m)，6.81-6.97(5H，m)，7.04-7.24(5H，m)，6.66(1H，t，J＝7.1Hz)，6.46(1H，d，J＝3.2Hz)，4.15(2H，q，J＝7.2Hz)，2.86(3H，s)，1.46(3H，t，J＝7.3Hz)。
The preparation of embodiment 22:5f
Concrete operations just change aniline into P-nethoxyaniline with the preparation of 5a, get compound 5f at last.
1H-NMR(300MHz，CDCl
3)δ：8.77(1H，s)，7.65(1H，br)，7.57(1H，s)，7.24(1H，d，J＝9.2Hz)，7.15(1H，d，J＝3.0Hz)，7.02-7.10(3H，m)，6.98(1H，dd，J＝8.5，1.5Hz)，6.92(2H，d，J＝9.1Hz)，6.80(2H，d，J＝8.7Hz)，6.53-6.59(1H，m)，6.48(1H，d，J＝2.9Hz)，4.15(2H，q，J＝7.4Hz)，3.78(3H，s)，2.86(3H，s)，1.47(3H，t，J＝7.1Hz)。
The preparation of embodiment 23:5g
Concrete operations just change aniline to monomethylaniline into the preparation of 5a, get compound 5g at last.
1H-NMR(300MHz，CDCl
3)δ：8.77(1H，s)，7.82(1H，br)，7.56(1H，s)，7.21-7.29(2H，m)，6.94-7.16(6H，m)，6.89(2H，d，J＝8.1Hz)，6.61(1H，t，J＝7.3Hz)，6.48(1H，d，J＝2.8Hz)，4.15(2H，q，J＝7.3Hz)，2.86(3H，s)，2.29(3H，s)，1.47(3H，t，J＝7.3Hz)。
The anti tumor activity in vitro screening of compound
Top synthetic part of compounds has been carried out antitumor activity in vitro.Compound anti tumor activity in vitro classical sulphonyl rhodamine B (Sulforhodamine B, SRB) method.
Tumour cell is cultivated with RPMI 1640 or DMEM substratum (Gibco), includes 10% foetal calf serum, and culture condition is 37 ℃, 5% (volume percent) CO
2According to tumor cell type, inoculate 0.4-1.0 * 10 respectively
4Cells/well is in the 96-orifice plate, after 24 hours, with the compound treatment of gradient concentration.After the compound treatment 72 hours, discard nutrient solution, with the cold Tricholroacetic Acid fixed cell of 10% (volume ratio).Use sulphonyl rhodamine B (Sulforhodamine B, SRB) solution-dyed then.Flush away with Tris dissolving and protein bound SRB, under 520nm wavelength is measured OD value with microplate reader not in conjunction with behind the SRB, calculates inhibitory rate of cell growth with following formula:
Inhibiting rate=(OD value
Control wells-OD value
Dosing holes)/OD value
Control wells* 100%
According to each concentration inhibiting rate, adopt Logit method calculation of half inhibitory concentration IC
50The results are shown in Table 1 and table 2.
Table 1 compound 3c is to the influence of the tumor cell proliferation of multiple vitro culture
As can be seen from Table 1, compound 3c has good antitumor activity, at most clone IC
50All reach tens nM levels, and all be better than the positive control drug colchicine, reach the activity suitable with vinorelbine in most clone activity.Importantly, 3c has the tumour cell KBV200 of multidrug resistance to high expression level P-170 glycoprotein, still has good active, and no tangible cross-resistance between this compounds and the traditional cytotoxic drug is described.
Table 2 part of compounds is to the influence of the human liver cancer cell BEL-7402 propagation of vitro culture
As can be seen from Table 2, nearly all compound suppresses the effect that human liver cancer cell BEL-7402 increases to all having, and wherein compound 3b, 3c, 3d, 3e, 3k, 3m, 3n, 3p, 3r and 8a have very high inhibition activity, its IC
50All reach tens nM levels.The compound of listing in the last table is the typical case's representative in the application's the compound, and this makes becomes possibility by its activity of knowing the compound of other structural similitudies by inference.
Claims (6)
1. miazines micromolecular compound with structure shown in the following general formula A:
Wherein, R
1For hydrogen, halogen, do not replace or C that halogen replaces
1-C
6Alkyl, do not replace or C that halogen replaces
1-C
6Alkoxyl group or nitro;
X is a hydroxyl; Unsubstituted amino; Perhaps by being selected from aryl, heteroaryl or aryl C
1-C
6The amino that the substituting group of alkyl replaces;
R
2Be hydrogen or C
1-C
6Alkyl;
R
3Be hydrogen, C
1-C
6That alkyl, unsubstituted amino or aryl replace or C
1-C
6The amino that alkyl replaces;
Z is carbon or nitrogen;
Described aryl is unsubstituted phenyl or the phenyl that replaced by substituting group, and described substituting group is selected from cyano group, halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
4Carbalkoxy and C
1-C
4In the haloalkyl one or more;
Described heteroaryl is to comprise 1-3 heteroatomic 5～7 yuan of heteroaryls that are selected among N, S and the O;
Described halogen is selected among fluorine, chlorine, bromine and the iodine.
2. miazines micromolecular compound as claimed in claim 1, wherein, R
1For hydrogen, halogen, do not replace or C that halogen replaces
1-C
4Alkyl, do not replace or C that halogen replaces
1-C
4Alkoxyl group or nitro;
X is a hydroxyl; Unsubstituted amino; Perhaps by being selected from phenyl that unsubstituted phenyl, substituting group replace, comprising 5～6 yuan of heteroaryls or the phenyl C of 1-3 N atom
1-C
4The amino that substituting group in the alkyl replaces, described substituting group is for being selected from cyano group, halogen radical, C
1-C
4Alkyl, C
1-C
4Alkoxyl group and C
1-C
4In the haloalkyl one or more;
R
2Be hydrogen or C
1-C
4Alkyl;
R
3Be hydrogen, C
1-C
4That alkyl, unsubstituted amino or phenyl replace or C
1-C
4The amino that alkyl replaces;
Z is carbon or nitrogen;
Described halogen is fluorine, chlorine or bromine.
3. miazines micromolecular compound as claimed in claim 2, wherein, R
1Be hydrogen, 4-chlorine, 4-fluorine, 4-bromine, 4-methyl, 4-isobutyl-, 4-methoxyl group or 4-nitro; R
2Be hydrogen, methyl, ethyl, propyl group or sec.-propyl; R
3That replace for methyl, amino or phenyl or C
1～C
4The amino that alkyl replaces.
4. miazines micromolecular compound as claimed in claim 2, wherein said compound is
5. the preparation method of miazines micromolecular compound as claimed in claim 1, it comprises following method:
Method one: R in general formula A
3Be hydrogen, amino or C
1～C
6Alkyl, when X is hydroxyl,
A) formula 1 compound and aryl or heterocyclic aryl boronic acid compounds
Suzuki coupling production 2 compounds take place under palladium catalysis;
B) formula 2 compounds under alkaline condition with
Condensation production 3 compounds;
Method two: R in general formula A
3Be hydrogen, amino or C
1～C
6Alkyl, X are unsubstituted amino; Perhaps by being selected from aryl, heteroaryl or aryl C
1-C
6The substituting group of alkyl replaces when amino,
C-1) hydroxyl in formula 3 compounds and trifluoromethanesulfonic acid anhydride reactant production 4 compounds;
D-1) formula 4 compounds under palladium catalysis with R
4NH
2Buchwald-Hartiwig coupling production 5 compounds take place;
Perhaps,
Method three: R in general formula A
3That replace for phenyl or C
1-C
4The amino that alkyl replaces is when X is hydroxyl;
C-2) R
3Be NH
2Formula 3 compounds and cylite reaction after again with Boc
2O reacts production 6 compounds under alkaline condition;
D-2) formula 6 compounds by with R
3' Y carries out alkylated reaction and slough Boc protecting group production 7 compounds with trifluoroacetic acid;
E-2) formula 7 hydrogenation of compounds are sloughed Bn protecting group production 8 compounds; Or formula 7 compounds by with R
3" Y carries out alkylated reaction production 9 compounds once more, formula 9 hydrogenation of compounds are sloughed Bn protecting group production 10 compounds;
R
1, R
2With Z such as claim 1 definition;
Y is a halogen;
R
3' and R
3" be C independently of one another
1～C
6Alkyl;
R
4For being selected from phenyl that unsubstituted phenyl, substituting group replace, comprising 5～6 yuan of heteroaryls or the phenyl C of 1-3 N atom
1-C
4Substituting group in the alkyl, described substituting group are served as reasons and are selected from cyano group, halogen radical, C
1-C
4Alkyl, C
1-C
4Alkoxyl group and C
1-C
4In the haloalkyl one or more.
6. the application of miazines micromolecular compound according to claim 1 in the preparation antitumor drug.
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| CN103086980A (en) * | 2011-11-07 | 2013-05-08 | 北京清美联创干细胞科技有限公司 | Pyrimidine compound for efficiently promoting stem cell proliferation and use thereof |
| CN104341386A (en) * | 2013-07-23 | 2015-02-11 | 中国科学院上海药物研究所 | Aryl heterocycle micromolecule compounds, derivatives thereof, and preparing methods and uses of the compounds and the derivatives |
| CN105523986A (en) * | 2015-12-30 | 2016-04-27 | 江汉大学 | Synthetic method of efflux pump inhibitor N-hydrogen-2-arylindol and derivatives thereof |
| CN110563701A (en) * | 2019-08-06 | 2019-12-13 | 浙江工业大学 | N-2-pyrimidine-2-azido-3- (2,2,6, 6-tetramethylpiperidinyloxy) indoline and preparation and application thereof |
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| CN101033224A (en) * | 2006-03-10 | 2007-09-12 | 中国科学院上海药物研究所 | Novel pyrimidines small molecular compound, its preparation method and use |
| CN101370788A (en) * | 2006-01-11 | 2009-02-18 | 阿斯利康(瑞典)有限公司 | Morpholino pyrimidine derivatives and their use in therapy |
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| CN101370788A (en) * | 2006-01-11 | 2009-02-18 | 阿斯利康(瑞典)有限公司 | Morpholino pyrimidine derivatives and their use in therapy |
| CN101033224A (en) * | 2006-03-10 | 2007-09-12 | 中国科学院上海药物研究所 | Novel pyrimidines small molecular compound, its preparation method and use |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103086980A (en) * | 2011-11-07 | 2013-05-08 | 北京清美联创干细胞科技有限公司 | Pyrimidine compound for efficiently promoting stem cell proliferation and use thereof |
| CN104341386A (en) * | 2013-07-23 | 2015-02-11 | 中国科学院上海药物研究所 | Aryl heterocycle micromolecule compounds, derivatives thereof, and preparing methods and uses of the compounds and the derivatives |
| CN105523986A (en) * | 2015-12-30 | 2016-04-27 | 江汉大学 | Synthetic method of efflux pump inhibitor N-hydrogen-2-arylindol and derivatives thereof |
| CN110563701A (en) * | 2019-08-06 | 2019-12-13 | 浙江工业大学 | N-2-pyrimidine-2-azido-3- (2,2,6, 6-tetramethylpiperidinyloxy) indoline and preparation and application thereof |
| CN110563701B (en) * | 2019-08-06 | 2022-09-16 | 浙江工业大学 | N-2-pyrimidine-2-azido-3- (2,2,6, 6-tetramethylpiperidinyloxy) indoline and preparation and application thereof |
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