CN105585558A - Double-alkoxy pyrimidine jointing 3-ethylenic-bond-oxoindole derivative and preparing method and application thereof - Google Patents
Double-alkoxy pyrimidine jointing 3-ethylenic-bond-oxoindole derivative and preparing method and application thereof Download PDFInfo
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- 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
- C07D403/06—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 carbon chain containing only aliphatic carbon atoms
Abstract
The invention discloses a double-alkoxy pyrimidine jointing 3-ethylenic-bond-oxoindole derivative. A preparing method includes the steps that different-substitution 2-indolone and different-substitution 3,5-dichloropyrimidine formaldehyde are subjected to heating reflux in an alcohols solvent under the inorganic alkaline condition, are subjected to a Knoevenagel addition-elimination reaction, and are subjected to an alcoholic-hydroxyl-group dual-substitution helium-atom reaction, and the double-alkoxy pyrimidine jointing 3-ethylenic-bond-oxoindole derivative is obtained. Skeletons include the potential biological-activity pyrimidine skeletons and the 3-ethylenic-bond-oxoindole skeletons. The double-alkoxy pyrimidine jointing 3-ethylenic-bond-oxoindole derivative is an important medical-intermediate analogue and a drug-molecule analogue, can provide compound sources for biological-activity screening, and has an important application value for drug screening and the pharmaceutical industry; according to the derivative, two tumor cell lines are subjected to tumor-growth-inhibitory activity screening, and it is proved that the derivatives have certain tumor-cell-growth-inhibitory activity, and can be expected to serve as an antineoplastic drug.
Description
Technical field
The present invention relates to pharmaceutical chemistry technical field, especially a kind of bis-alkoxy pyrimidine splicing 3-ethylene linkage Oxoindole spreads outBiology and preparation method thereof and application.
Background technology
In organic chemistry and medical chemistry, be extremely to weigh having that bio-active group is spliced in a molecular skeletonThe research field of wanting. (1) 3-ethylene linkage Oxoindole is the important heterocyclic compound of a class, because it is in each side such as agricultural chemicals and medicineThe application of face, has caused people's common concern next, and the 3-ethylene linkage Oxoindole in a lot of natural products and medicine all has veryGood biologically active. For example, SunitinibI is a kind of tyrosine kinase inhibitor, is approved for treatment kidney in 2006Cell cancer and gastrointestinal stromal tumors; The people such as Woodard have found a series of Compound I I, can be used as selectivePlasmodialCDK inhibitor; Coase such as draws to have found a series of compound III at the people, can be used as mankind's TGaseInhibitor. (2) at present listing or be about to listing medicine antitumor or viral infection resisting quite a lot of be all that pyrimidine derivates forms.For example: Zidovudine (zidovudine, AZT), ddC(dideoxycytidine) and Lamivudine (Lamivudine) etc. be that HIV is contraryTranscripting enzyme inhibitor. In view of 3-ethylene linkage Oxoindole framework compound and pyrimidine framework compound have potential biologically active.Therefore, pyrimidine skeleton is spliced on 3-ethylene linkage Oxoindole framework compound to synthetic a series of new potential how active official's energyThe pyrimidine splicing 3-ethylene linkage oxoindole derivative that group replaces, can provide compound source for bioactivity screening, to medicineScreening and pharmaceutical industry have important using value. (as shown in Figure 7).
Summary of the invention
The object of the invention is: a kind of bis-alkoxy pyrimidine splicing 3-ethylene linkage oxoindole derivative and preparation side thereof are providedMethod and application, it is the important medicine intermediate analog of a class and drug molecule analog, to drug screening and pharmaceutical industryThere is important using value, and its synthetic method is very economical easy.
The present invention is achieved in that a kind of bis-alkoxy pyrimidine splicing 3-ethylene linkage oxoindole derivative, this compoundThere is the structure of following general formula (I):
In formula, R1For alkyl; R2For alkyl or aryl or H; R3For alkyl or halogen or H.
The preparation method of bis-alkoxy pyrimidine splicing 3-ethylene linkage oxoindole derivative, phonetic by 2-indolone and 3,5-dichloroPyridine formaldehyde, under inorganic alkaline condition, for the ratio of 3:4 adds hot reflux in alcohols solvent, carries out in molar ratioReaction is eliminated in Knoevenagel addition, and the two chlorine atomic reactions that replace of alcoholic extract hydroxyl group occur simultaneously, obtains bis-alkoxy pyrimidine splicing 3-Ethylene linkage oxoindole derivative.
Described inorganic base is NaOH, KOH, Na2CO3Or K2CO3, the addition of inorganic base is Oxoindole mole50-150%。
Described alcohols solvent is methyl alcohol, ethanol, propyl alcohol, isopropyl alcohol or n-butanol.
2-indolone and 3,5-dichloro pyrimidine formolite reaction temperature are 60-100 DEG C, and the reaction time is 1-10 hour.
Reaction principle of the present invention is as follows:
In formula, R1For alkyl; R2For alkyl or aryl or H; R3For alkyl or halogen or H.
By adopting technique scheme,, under inorganic alkaline condition, press with 2-indolone and 3,5-dichloro pyrimidine formaldehydeMol ratio is that the ratio of 3:4 adds hot reflux in alcohols solvent, carries out Knoevenagel addition and eliminates reaction, and alcohol occurs simultaneouslyThe two chlorine atomic reactions that replace of hydroxyl, obtain bis-alkoxy pyrimidine splicing 3-ethylene linkage oxoindole derivative. This compounds comprisesPotential biologically active pyrimidine skeleton and Oxoindole skeleton, can provide compound source for bioactivity screening, to medicineScreening and pharmaceutical industry have important using value. And find compound energy growth inhibitory activity to tumor cell of the present invention,Can be used as antineoplastic use. Operation is simple in the present invention, and raw material is synthetic to be cheaply easy to get, can be molten at various organic alcoholsIn agent, carry out, also have good air stability, applicability is wide, has good compatibility for various substituting groups.
Brief description of the drawings
Accompanying drawing 1 and accompanying drawing 2 are the nuclear magnetic spectrogram data of the compound 3a of embodiments of the invention 1;
Accompanying drawing 3 and accompanying drawing 4 are the nuclear magnetic spectrogram data of the compound 3b of embodiments of the invention 1;
Accompanying drawing 5 and accompanying drawing 6 are the nuclear magnetic spectrogram data of the compound 3c of embodiments of the invention 1.
Accompanying drawing 7 is the monocrystalline figure of embodiments of the invention part of compounds;
Accompanying drawing 8 is the single crystal X diffraction figure of the compound 3m of embodiments of the invention 1.
Detailed description of the invention
Embodiments of the invention 1: the preparation of bis-alkoxy pyrimidine splicing 3-ethylene linkage oxoindole derivative, burn at round bottomIn bottle, first add 5mL solvent methanol (being simultaneously also as a kind of reaction substrate), then add successively 2-indolone 0.3mmol(51.6mg), 3,5-dichloro pyrimidine formaldehyde 0.4mmol(56.8mg), NaOH13.2mg(1.1eq) and, 80oIn C oil bathStirring reaction 12 hours, after TLC detection reaction is complete, reactant liquor removes solvent under reduced pressure, then direct silica gel column chromatography (300-400 orders) separate (benzinum: ethyl acetate=10:1), obtain yellow solid, i.e. compound 3a. Productive rate 96%, nuclear magnetic resonance andThe results such as high resolution mass spectrum test are as follows: fusing point: 271.2-272.6oC; The results such as nuclear magnetic resonance and high resolution mass spectrum test asUnder:1HNMR(CDCl3,400MHz)δ:3.18(s,6H),6.33(d,J=6.9Hz,1H),6.53-6.41(m,2H),6.94-6.87(m,2H),8.44(s,1H),10.66(s,1H);13CNMR(CDCl3,100MHz)δ:68.2,78.8,110.9,118.3,126.5,126.6,127.4,128.7,132.7,132.9,141.8,152.3,159.2,159.9;HRMS(ESI-TOF)m/z:Calcd.forC15H13N3NaO3[M+Na]+:306.0854;Found:306.0857.
The preparation method of compound 3b-3p is with compound 3a, and rate of charge is identical with compound 3a, can obtain compound 3b-3p, anti-Product yield and reaction time is in table 1, but what need emphasize is that compound of the present invention is not limited to the represented content of table 1.
The present embodiment is prepared compound 3b: yellow solid, productive rate 92%, fusing point: 195.1-196.9oC; Nuclear magnetic resonanceAs follows with results such as high resolution mass spectrum tests:1HNMR(CDCl3,400MHz)δ:3.54(s,6H),7.66(d,J=9.3Hz,1H),7.87(s,1H),8.05(m,1H),8.39(d,J=1.4Hz,1H),8.71-8.75(m,4H),8.86-8.88(m,2H),10.45(s,1H);13CNMR(CDCl3,100MHz)δ:54.5,99.3,108.9,120.8,122.5,124.3,124.5,126.8,128.0,128.7,129.6,130.0,134.1,143.4,157.6,167.2;HRMS(ESI-TOF)m/z:Calcd.forC21H17N3NaO3[M+Na]+:382.1167;Found:382.1168.
The present embodiment is prepared compound 3c: yellow solid, productive rate 94%, fusing point: 156.4-157.9oC. Nuclear magnetic resonance and heightDifferentiate the results such as mass spectrometric measurement as follows:1HNMR(CDCl3,400MHz)δ:2.50(s,6H),4.01(s,2H),6.74(d,J=8.8Hz,1H),6.99-6.91(m,2H),7.43-7.33(m,2H),7.56-7.49(m,4H),7.67(s,1H),9.42(s,1H);13CNMR(CDCl3,100MHz)δ:42.1,51.8,88.9,97.0,106.7,107.7,109.2,109.6,112.2,113.2,113.4,114.2,120.0,125.0,137.2,144.9,145.1,159.6;HRMS(ESI-TOF)m/z:Calcd.forC22H19N3NaO3[M+Na]+:396.1324;Found:396.1326.
The present embodiment is prepared compound 3d: yellow solid, productive rate 91%, fusing point: 183.0-184.7oC. Nuclear magnetic resonance and heightDifferentiate the results such as mass spectrometric measurement as follows:1HNMR(CDCl3,400MHz)δ:3.93(s,3H),4.78(s,3H),5.46(s,6H),7.77(s,1H),8.04(d,J=6.9Hz,1H),8.27-8.16(m,1H),8.40(s,1H),9.54(s,1H);13CNMR(CDCl3,100MHz)δ:20.6,25.9,54.4,99.4,108.2,120.8,122.8,124.8,129.3,130.2,130.5,141.7,157.5,167.1;HRMS(ESI-TOF)m/z:Calcd.forC17H17N3NaO3[M+Na]+:334.1167;Found:334.1169.
The present embodiment is prepared compound 3e: yellow solid, productive rate 90%, fusing point: 141.7-142.4oC. Nuclear magnetic resonance and heightDifferentiate the results such as mass spectrometric measurement as follows:1HNMR(DMSO-d6,400MHz)δ:2.17(s,3H),3.97(s,3H),4.95(s,2H),6.63(s,1H),6.85(d,J=7.2Hz,1H),7.05(d,J=7.2Hz,1H),7.26-7.28(m,1H),7.32-7.35(m,3H),7.43(s,1H),8.64(s,1H);13CNMR(DMSO-d6,100MHz)δ:20.6,42.7,54.4,99.4,108.8,120.9,123.4,125.0,127.3,127.4,128.6,128.9,130.1,130.7,136.6,140.6,157.5,166.9,167.2;HRMS(ESI-TOF)m/z:Calcd.forC23H21N3NaO3[M+Na]+:410.1480;Found:410.1484.
The present embodiment is prepared compound 3f: yellow solid, productive rate 86%, fusing point: 156.4-157.9oC. Nuclear magnetic resonance and high scoreDistinguish that the results such as mass spectrometric measurement are as follows:1HNMR(CDCl3,400MHz)δ:2.57(s,3H),3.57(s,3H),3.98(s,6H),6.70(d,J=7.8Hz,1H),6.77-6.80(m,1H),6.98(d,J=7.8Hz,1H),7.55(s,1H),8.49(s,1H);13CNMR(CDCl3,100MHz)δ:19.2,29.6,54.3,100.4,119.4,121.5,122.3,122.4,123.8,129.4,133.3,141.9,157.0,167.6,168.7;HRMS(ESI-TOF)m/z:Calcd.forC17H17N3NaO3[M+Na]+:334.1167;Found:334.1170.
The present embodiment is prepared compound 3g: yellow solid, productive rate 92%, fusing point: 215.0-216.7oC. Nuclear magnetic resonance and heightDifferentiate the results such as mass spectrometric measurement as follows:1HNMR(CDCl3,400MHz)δ:3.31(s,3H),3.96(s,6H),5.23(s,2H),6.73(d,J=6.0Hz,1H),6.88-6.85(m,1H),6.99(s,1H),7.16(s,2H),7.29-7.24(s,1H),7.38-7.35(m,2H),7.44(s,1H),8.64(s,1H);13CNMR(CDCl3,100MHz)δ:18.2,44.3,54.5,99.4,119.4,121.6,122.0,122.3,123.7,125.4,127.0,128.8,133.7,138.2,140.9,157.5,167.2;HRMS(ESI-TOF)m/z:Calcd.forC23H21N3NaO3[M+Na]+:410.1480;Found:410.1484.
The present embodiment is prepared compound 3h: yellow solid, productive rate 82%, fusing point: 217.7-218.2oC. Nuclear magnetic resonance and heightDifferentiate the results such as mass spectrometric measurement as follows:1HNMR(CDCl3,400MHz)δ:3.31(s,3H),3.97(s,6H),6.76-6.73(m,1H),7.08-7.06(m,1H),7.42-7.38(m,1H),7.45(s,1H),8.65(s,1H);13CNMR(CDCl3,100MHz)δ:26.1,54.5,99.1,110.0,122.2,123.9,125.0,125.7,128.0,129.3,142.6,157.9,167.2;HRMS(ESI-TOF)m/z:Calcd.forC16H14ClN3NaO3[M+Na]+:354.0621;Found:354.0627.
The present embodiment is prepared compound 3i: yellow solid, productive rate 91%, fusing point: 135.4-136.1oC. Nuclear magnetic resonance and heightDifferentiate the results such as mass spectrometric measurement as follows:1HNMR(CDCl3,400MHz)δ:2.87(s,6H),4.19(s,2H),6.53(s,1H),6.83(d,J=8.7Hz,1H),7.28-7.16(m,6H),7.53(s,1H),8.98(s,1H);13CNMR(CDCl3,100MHz)δ:44.3,54.6,99.1,114.2,123.4,123.5,123.9,125.8,126.0,127.0,127.3,128.6,131.8,137.8,138.4,157.9,167.2;HRMS(ESI-TOF)m/z:Calcd.forC22H18ClN3NaO3[M+Na]+:430.0934;Found:430.0934.
The present embodiment is prepared compound 3j: yellow solid, productive rate 87%, fusing point: 172.7-173.4oC. Nuclear magnetic resonance and heightDifferentiate the results such as mass spectrometric measurement as follows:1HNMR(CDCl3,400MHz)δ:3.97(s,6H),5.34(s,2H),6.88-6.84(m,1H),7.01-6.93(m,1H),7.21-7.18(m,2H),7.28-7.24(m,2H),7.36-7.32(m,2H),7.55(s,1H),8.65(s,1H);13CNMR(CDCl3,100MHz)δ:44.3,54.6,99.1,114.2,123.4,123.5,123.9,125.8,126.0,127.0,127.3,128.5,128.6,131.8,137.8,138.4,157.9,167.2;HRMS(ESI-TOF)m/z:Calcd.forC22H18ClN3NaO3[M+Na]+:430.0934;Found:430.0938.
The present embodiment is prepared compound 3k: yellow solid, productive rate 96%, fusing point: 235.0-236.9oC. Nuclear magnetic resonance and heightDifferentiate the results such as mass spectrometric measurement as follows:1HNMR(CDCl3,400MHz)δ:3.27(s,3H),4.01(s,6H),6.60-6.57(m,1H),6.74-6.70(m,1H),7.00-6.95(m,1H),7.65(s,1H),8.52(s,1H);13CNMR(CDCl3,100MHz)δ:26.2,54.5,100,0,107.9,108.1,112.1,112.3,115.4,115.6,122.9,125.6,129.1,140.2,157.5,159.7,167.7;HRMS(ESI-TOF)m/z:Calcd.forC16H14FN3NaO3[M+Na]+:338.0916;Found:338.0918.
The present embodiment is prepared compound 3l: yellow solid, productive rate 84%, fusing point: 223.2-224.5oC. Nuclear magnetic resonance and heightDifferentiate the results such as mass spectrometric measurement as follows:1HNMR(CDCl3,400MHz)δ:4.02(s,6H),4.98(s,2H),6.62-6.58(m,2H),6.85(d,J=2.5Hz,1H),7.26(s,1H),7.37-7.31(m,4H),7.22(s,1H),8.52(s,1H);13CNMR(CDCl3,100MHz)δ:43.9,54.5,100.0,108.9,109.0,112.1,112.4,115.3,115.6,123.0,126.0,127.2,127.4,127.6,128.7,128.8,135.8,139.3,157.5,159.9,167.7;HRMS(ESI-TOF)m/z:Calcd.forC22H18FN3NaO3[M+Na]+:414.1229;Found:414.1227.
The present embodiment is prepared compound 3m: yellow solid, productive rate 95%, fusing point: 223.7-224.8oC. Nuclear magnetic resonance and heightDifferentiate the results such as mass spectrometric measurement as follows:1HNMR(CDCl3,400MHz)δ:3.26(s,3H),4.02(s,6H),6.70(d,J=8.2Hz,1H),6.95(s,1H),7.38(d,J=8.1Hz,1H),7.66(s,1H),8.53(s,1H);13CNMR(CDCl3,100MHz)δ:26.2,54.5,100.0,109.1,114.3,123.5,125.8,127.8,128.2,131.7,143.0,157.6,166.2,167.7;HRMS(ESI-TOF)m/z:Calcd.forC16H14BrN3NaO3[M+Na]+:398.0116;Found:398.0118.
The present embodiment is prepared compound 3n: yellow solid, productive rate 94%, fusing point: 142.3-143.7oC. Nuclear magnetic resonance and high scoreDistinguish that the results such as mass spectrometric measurement are as follows:1HNMR(CDCl3,400MHz)δ:3.27(s,3H),4.01(s,6H),6.58-6.60(m,1H),6.71-6.74(m,1H),6.97-6.98(m,1H),7.65(s,1H),8.52(s,1H);13CNMR(CDCl3,100MHz)δ:26.2,54.5,100.0,108.0,112.3,115.5(d,JCF=19.5Hz),122.8(d,JCF=7.1Hz),125.6,129.1,140.2,157.5,158.6(d,JCF=217.8Hz),167.7;HRMS(ESI-TOF)m/z:Calcd.forC18H18FN3NaO3[M+Na]+:366.1229;Found:366.1227.
The present embodiment is prepared compound 3o: yellow solid, productive rate 94%, fusing point: 162.1-163.7oC. Nuclear magnetic resonance and high scoreDistinguish that the results such as mass spectrometric measurement are as follows:1HNMR(CDCl3,400MHz)δ:1.23-1.26(m,10H),2.57(s,3H),3.57(s,3H),4.41-4.46(m,4H),6.76-6.80(m,2H),6.95-6.98(m,1H),7.56(s,1H),8.44(s,1H);13CNMR(CDCl3,100MHz)δ:14.4,19.2,29.6,29.7,63.2,100.2,119.1,121.3,122.5,122.8,124.3,129.2,133.1,141.7,156.9,167.4,168.9;HRMS(ESI-TOF)m/z:Calcd.forC19H21N3O3[M+Na]+:339.1582;Found:339.1585.
The present embodiment is prepared compound 3p: yellow solid, productive rate 86%, fusing point: 148.0-149.9oC. Nuclear magnetic resonance and high scoreDistinguish that the results such as mass spectrometric measurement are as follows:1HNMR(CDCl3,400MHz)δ:0.82-0.86(m,6H),1.62-1.67(m,4H),4.33-4.37(m,4H),6.88-6.93(m,3H),7.17-7.21(m,1H),7.60(s,1H),8.46(s,1H),9.12(s,1H);13CNMR(CDCl3,100MHz)δ:10.2,22.1,69.0,100.1,109.8,121.5,122.6,124.9,125.0,129.4,129.9,141.4,157.1,167.5,170.2;HRMS(ESI-TOF)m/z:Calcd.forC19H21N3NaO3[M+Na]+:362.1480;Found:362.1484.
The present embodiment is prepared compound 3q: yellow solid, productive rate 66%, fusing point: 157.1-158.7oC. Nuclear magnetic resonance and heightDifferentiate the results such as mass spectrometric measurement as follows:1HNMR(CDCl3,400MHz)δ:0.84(s,6H),1.30-1.25(m,4H),1.63-1.57(m,4H),4.41-4.37(m,4H),6.93-6.87(m,3H),7.21-7.17(m,1H),7.58(s,1H),8.46(s,1H),8.88(s,1H);13CNMR(CDCl3,100MHz)δ:13.7,19.0,29.7,30.8,67.3,100.2,109.7,121.6,122.7,124.9,125.0,129.4,129.9,141.3,157.1,167.6,170.1;HRMS(ESI-TOF)m/z:Calcd.forC21H25N3NaO3[M+Na]+:390.1793;Found:390.1797.
Formula of the present invention (1) compound has important biologically active, human lung carcinoma cell (A549) and human leukemia cell(K562) cell toxicity test of totally two strain tumour cells shows: the bis-alkoxy pyrimidine splicing of the structure shown in this type of formula (1)3-ethylene linkage oxoindole derivative is inhibited to growth of tumour cell, likely develops into new anti-curing oncoma medicineThing. But what need emphasize is that compound of the present invention is not limited to human lung carcinoma cell (A549) and human leukemia cell (K562) representsCytotoxicity.
Pharmacology embodiment 1: compound 3a, 3b, 3e, 3j, 3l, 3m, the cytotoxicity of 3n to A549 cell, but needWhat emphasize is that compound of the present invention is not limited to compound 3a, 3b, 3e, 3j, 3l, 3m, the cell of 3n to A549 cellToxicity.
A549(Non-small cell lung carcinoma lung cancer) use DMEM medium culture, in culture medium, contain 10% hyclone, 100The penicillin of U/mL and 100U/mL streptomysin. Cell joins in 96 holes with the concentration of 4000 cells in every hole, contains 5% at 37 DEG CCO2In the incubator of humid air, cultivate 24 hours.
Improvement mtt assay for the mensuration of cell survival rate. Cell is through after 24 hours hatch, respectively by the compound of newly joining3a, 3b, 3e, 3j, 3l, 3m, the dimethyl sulphoxide solution of 3n joins in each hole with concentration gradient, makes compound in holeUltimate density is respectively 5 μ mol/L, 10 μ mol/L, 20 μ mol/L, 40 μ mol/L and 80 μ mol/L. After 48 hours,Every hole adds 10 μ LMTT(5mg/mL) phosphate buffer, then continue 37oC cultivated after 4 hours, centrifugal 5 pointsClock is removed unconverted MTT, adds 150 μ L dimethyl sulfoxide (DMSO)s in every hole. With the MTT crystal formazan of dissolving and reducing(formazan), measure OD value with ELIASA at 490nm wavelength. Wherein compound 3a-3q is to PC-3 cell 503nhibiting concentrationIC50Obtained by spss software (19 version) analysis. The IC of compound 3a to A549 tumour cell50Be 43.1 μ mol/L; Chemical combinationThe IC of thing 3b to A549 tumour cell50Be 26.8 μ mol/L; The IC of compound 3e to A549 tumour cell50Be 30.5 μ mol/L; The IC of compound 3j to A549 tumour cell50Be 57.5 μ mol/L; The IC of compound 3l to A549 tumour cell50Be 45.4μ mol/L; The IC of compound 3m to A549 tumour cell50Be 35.3 μ mol/L; Compound 3n is to A549 tumour cellIC50Be 19.0 μ mol/L; The IC of compound 3p to A549 tumour cell50Be 46.4 μ mol/L; And it is positive in cis-platinum pairThe IC of A549 tumour cell50Be 26.9 μ mol/L.
Experiment conclusion: A549 cell is that test compounds refers to Cytotoxic effective tool and the evaluation of tumour cellMark. This experiment shows that the bis-alkoxy pyrimidine splicing 3-ethylene linkage oxoindole derivative shown in this type of formula (1) is to A549 cell toolThere is stronger cytotoxicity, likely develop into the new medicine with antitumor action.
Pharmacology embodiment 2: the cytotoxicity of compound 3a-3q to K562 cell, but what need emphasize is chemical combination of the present inventionThing is not limited to compound 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, the cytotoxicity of 3p to A549 cell.
K562(people's chronic myelogenous leukemia cell) use RPMI-1640 medium culture, in culture medium, contain 10% tire ox bloodClearly, the penicillin of 100U/mL and 100U/mL streptomysin. Cell joins in 96 holes with the concentration of 5000 cells in every hole,37 DEG C containing 5%CO2In the incubator of humid air, cultivate 24 hours.
Improvement mtt assay for the mensuration of cell survival rate. Concrete grammar is as pharmacology embodiment 1. Compound 3a is to K562 tumourThe IC of cell50Be 9.1 μ mol/L; The IC of compound 3b to K562 tumour cell50Be 5.8 μ mol/L; Compound 3c is to K562The IC of tumour cell50Be 51.5 μ mol/L; The IC of compound 3d to K562 tumour cell50Be 41.3 μ mol/L; Compound 3eTo the IC of K562 tumour cell50Be 6.3 μ mol/L; The IC of compound 3f to K562 tumour cell50Be 45.9 μ mol/L; ChangeThe IC of compound 3g to K562 tumour cell50Be 40.8 μ mol/L; The IC of compound 3h to K562 tumour cell50Be 9.5 μMol/L; The IC of compound 3i to K562 tumour cell50Be 31.7 μ mol/L; The IC of compound 3j to K562 tumour cell50For5.2 μ mol/L; The IC of compound 3p to K562 tumour cell50Be 17.2 μ mol/L; And positive control cis-platinum is to K562 tumourThe IC of cell50Be 22.6 μ mol/L.
Experiment conclusion: K562 cell is that test compounds refers to Cytotoxic effective tool and the evaluation of tumour cellMark. This experiment shows that the bis-alkoxy pyrimidine splicing 3-ethylene linkage oxoindole derivative shown in this type of formula (1) is to K562 cell toolThere is stronger cytotoxicity, likely develop into the new medicine with antitumor action.
From above pharmacology embodiment, we can find out that these compounds all show necessarily this two strains tumour cellCytotoxicity. But what need emphasize is that compound of the present invention is not limited to human lung carcinoma cell (A549) and human leukemia cell(K562) cytotoxicity representing. Visible these compounds have exploitation becomes the potentiality of antineoplastic, is worth continuing deeplyResearch is gone down.
Claims (6)
1. a bis-alkoxy pyrimidine splicing 3-ethylene linkage oxoindole derivative, is characterized in that: this compound has as general formulaStructure shown in (I):
In formula, R1For alkyl; R2For alkyl or aryl or H; R3For alkyl or halogen or H.
2. a preparation method for bis-alkoxy pyrimidine splicing 3-ethylene linkage oxoindole derivative as claimed in claim 1, itsBe characterised in that: under inorganic alkaline condition, be that the ratio of 3:4 is at alcohol by 2-indolone and 3,5-dichloro pyrimidine formaldehyde in molar ratioIn kind solvent, add hot reflux, carry out Knoevenagel addition and eliminate reaction, the two chlorine atomic reactions that replace of alcoholic extract hydroxyl group occur simultaneously,Obtain bis-alkoxy pyrimidine splicing 3-ethylene linkage oxoindole derivative.
3. the preparation method of bis-alkoxy pyrimidine splicing 3-ethylene linkage oxoindole derivative according to claim 2, its spyLevy and be: described inorganic base is NaOH, KOH, Na2CO3Or K2CO3, the addition of inorganic base is Oxoindole mole50-150%。
4. the preparation method of bis-alkoxy pyrimidine splicing 3-ethylene linkage oxoindole derivative according to claim 2, its spyLevy and be: described alcohols solvent is methyl alcohol, ethanol, propyl alcohol, isopropyl alcohol or n-butanol.
5. the preparation method of bis-alkoxy pyrimidine splicing 3-ethylene linkage oxoindole derivative according to claim 2, its spyLevy and be: 2-indolone and 3,5-dichloro pyrimidine formolite reaction temperature are 60-100 DEG C, and the reaction time is 1-10 hour.
6. a bis-alkoxy pyrimidine splicing 3-ethylene linkage oxoindole derivative as claimed in claim 1 is at the anti-curing oncoma of preparationApplication in disease medicament.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111533700A (en) * | 2020-05-20 | 2020-08-14 | 天津科技大学 | 5-substituted uracil derivative and preparation method and application thereof |
| CN114213396A (en) * | 2022-01-27 | 2022-03-22 | 深圳市乐土生物医药有限公司 | Indole-2-ketone compound and preparation method and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998050356A1 (en) * | 1997-05-07 | 1998-11-12 | Sugen, Inc. | 2-indolinone derivatives as modulators of protein kinase activity |
| CN1356872A (en) * | 1998-12-31 | 2002-07-03 | 苏根公司 | 3-heteroarylidenyl-2-indolinone compounds for modulating protein kinase activity and for use in cancer chemotherapy |
| US20070167488A1 (en) * | 2003-12-16 | 2007-07-19 | Leo Pharma A/S | Novel therapeutic use |
| US20100081678A1 (en) * | 2008-09-30 | 2010-04-01 | Vanderbilt University | Indole compounds and their use as radiation sensitizing agents and chemotherapeutic agents |
-
2015
- 2015-12-15 CN CN201510929100.7A patent/CN105585558A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998050356A1 (en) * | 1997-05-07 | 1998-11-12 | Sugen, Inc. | 2-indolinone derivatives as modulators of protein kinase activity |
| CN1356872A (en) * | 1998-12-31 | 2002-07-03 | 苏根公司 | 3-heteroarylidenyl-2-indolinone compounds for modulating protein kinase activity and for use in cancer chemotherapy |
| US20070167488A1 (en) * | 2003-12-16 | 2007-07-19 | Leo Pharma A/S | Novel therapeutic use |
| US20100081678A1 (en) * | 2008-09-30 | 2010-04-01 | Vanderbilt University | Indole compounds and their use as radiation sensitizing agents and chemotherapeutic agents |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111533700A (en) * | 2020-05-20 | 2020-08-14 | 天津科技大学 | 5-substituted uracil derivative and preparation method and application thereof |
| CN111533700B (en) * | 2020-05-20 | 2023-03-28 | 天津科技大学 | 5-substituted uracil derivative and preparation method and application thereof |
| CN114213396A (en) * | 2022-01-27 | 2022-03-22 | 深圳市乐土生物医药有限公司 | Indole-2-ketone compound and preparation method and application thereof |
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