CN107286101B - 1-aryl aldoxime uracil and its preparation method - Google Patents

1-aryl aldoxime uracil and its preparation method Download PDF

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CN107286101B
CN107286101B CN201710622318.7A CN201710622318A CN107286101B CN 107286101 B CN107286101 B CN 107286101B CN 201710622318 A CN201710622318 A CN 201710622318A CN 107286101 B CN107286101 B CN 107286101B
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uracil
aldoxime
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CN107286101A (en
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金毅
林军
赵舒悦
蒋昆明
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Yunnan University YNU
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    • C07—ORGANIC CHEMISTRY
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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    • C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
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Abstract

A1-aryl aldoxime uracil and a preparation method thereof relate to the field of medicines, in particular to a 1-aryl aldoxime uracil which can inhibit the growth activity of tumor cells and has obvious inhibition thymidine phosphorylase and anti-tumor activity and a preparation method thereof. The 1-aryl aldoxime uracil of the present invention is characterized in that the compound has the following structure I:
Figure DDA0001361991290000011
wherein R is1Is methyl or hydrogen, R2Is chlorine, iodine, carboxyl or hydrogen, Ar is alkyl phenyl, halogenated phenyl, alkoxy phenyl, thienyl or furyl. The 1-aryl aldoxime uracil and the preparation method thereof show high activity of inhibiting the growth of tumor cells, have the functions of obviously inhibiting thymidine phosphorylase and resisting tumor activity, have simple and convenient preparation process and high feasibility, are convenient for large-scale production, and are beneficial to reducing the production cost.

Description

1-aryl aldoxime uracil and its preparation method
Technical Field
The invention relates to the field of medicines, in particular to 1-aryl aldoxime uracil which can inhibit the growth activity of tumor cells and has obvious inhibition thymidine phosphorylase and anti-tumor activity, and a preparation method thereof.
Background
Angiogenesis plays a very important role in the process of tumor growth and metastasis. Thymidine Phosphorylase (TP), an enzyme involved in thymidine homeostasis and metabolism, is considered to be angiogenesis-dependent because its endothelial cells have a tropism that stimulates endothelial cell migration. The main functions of the enzyme are to reversibly phosphorylate thymidine to thymine and 2-deoxyribose-1-phosphate and to activate 5-fluorouracil and precursors. Thymidine phosphorylase can recognize not only thymidine but also deoxyuridine and pyrimidine nucleoside derivatives. Human thymidine phosphorylase corresponds to an angiogenic protein, an endothelial cell platelet-derived growth factor, based on gene sequence comparison. Thymidine phosphorylase and endothelial cell platelet derived growth factor are inseparable linked to gastric, renal, uterine, leiomyoma, breast, colon and lung cancers.
Endothelial cell migration is an important step in angiogenesis, and thymidine phosphorylase catalytic activity is important in endothelial cell migration, so many thymidine phosphorylases and their analogues of various crystal structures have been described in the years. Recently, a series of thymidine phosphorylase inhibitors, either basic or non-basic, have been synthesized and published and have potential anti-thymidine phosphorylase activity as well as anti-neoangiogenesis. Physically, the most effective thymidine phosphorylase inhibitors are uracil derivatives, which are expected to bind to sites on thymidine to achieve an inhibitory effect. The most effective inhibitor at present is 5-chloro-6- [1- (2-aminopyrrole) methyl ] uracil phosphate (TPI), the IC50 of which reaches 35nM, and the inhibitor shows good inhibitory activity. At the same time, a series of abasic TP inhibitors have been synthesized and tested, and the mechanisms of action of some of these compounds are predicted, and they achieve inhibition through interaction with the allosteric binding site of TP, unlike general substrate site binding. However, the long-term clinical use of the same TP inhibitor may have side effects such as toxic drug resistance. To solve this problem a new series of TP inhibitors should be further investigated.
Amidoximes are important organic compounds having an amidooxime structure, and are often used as starting materials for synthesizing heterocycles and related intermediates for wide applications in pharmaceuticals, antitumor agents, antibacterial agents, anti-inflammatory agents, and the like. The terminal groups of the amidoxime and the aminopyrrole of TPI share similarities, so we designed the molecule of interest. In addition to uracil units, the novel amidoxime structures have C-N, N-OH, N-H, C-O and various substituents, which may bind to the active site and thus achieve inhibitory activity.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides 1-aryl aldoxime uracil which can inhibit the growth activity of tumor cells and has obvious inhibition thymidine phosphorylase and anti-tumor activity, and a preparation method thereof.
The 1-aryl aldoxime uracil of the present invention is characterized in that the compound has the following structure I:
Figure BDA0001361991280000021
wherein R is1Is methyl or hydrogen, R2Is chlorine, iodine, carboxyl or hydrogen, Ar is alkyl phenyl, halogenated phenyl, alkoxy phenyl, thienyl or furyl.
The 1-aryl aldoxime uracil is any one of the following twenty-four:
Figure BDA0001361991280000022
Figure BDA0001361991280000031
a preparation method of 1-aryl aldoxime uracil is characterized in that the synthesis reaction formula of the preparation method is as follows:
Figure BDA0001361991280000032
the preparation method comprises the following specific steps:
(1) dissolving aromatic aldehyde in methanol, stirring at normal temperature, adding hydroxylamine hydrochloride and potassium carbonate into the methanol after the aromatic aldehyde is completely dissolved, reacting for 2-5h, extracting reaction liquid after the reaction is completely finished, washing with saturated sodium bicarbonate solution, drying with anhydrous sodium sulfate, and distilling under reduced pressure to recover the methanol to obtain the aromatic aldoxime.
(2) Dissolving aromatic aldoxime in N, N-dimethylformamide, stirring at normal temperature, adding NCS (N-butylsuccinimide) after the aromatic aldoxime is completely dissolved, stirring at normal temperature for 2-6h, extracting after complete reaction, washing by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, and removing the solvent by reduced pressure distillation to obtain o-chloro aromatic aldoxime;
(3) dissolving o-chloro aromatic aldoxime, substituted uracil and alkali in organic solvent 1, stirring at normal temperature for 2-4h, extracting and washing after complete reaction, adding 3-carboxybenzaldehyde, stirring at normal temperature for 6h, separating out white solid, filtering, washing, drying with anhydrous sodium sulfate, and performing column chromatography separation or recrystallization to obtain the 1-aromatic aldoxime uracil.
In the step (3), the organic solvent 1 is a mixture of any two or more of methanol, ethanol, isopropanol, ethyl acetate, toluene, tetrahydrofuran, toluene, dichloromethane, chloroform, 1, 4-dioxane, N-dimethylformamide and dimethyl sulfoxide.
In the step (3), the alkali is one or a mixture of more of lithium hydroxide, sodium hydroxide, potassium carbonate, cesium carbonate, potassium phosphate, cesium fluoride and triethylamine.
The 1-aryl aldoxime uracil disclosed by the invention is characterized in that the compound is used as an inhibitor of thymidine phosphorylase, has the activity of inhibiting the thymidine phosphorylase and is used for treating gastric cancer, renal cancer, uterine cancer, leiomyoma, breast cancer, colon cancer or lung cancer.
The 1-aryl aldoxime uracil and the preparation method thereof show high activity of inhibiting the growth of tumor cells, have the functions of obviously inhibiting thymidine phosphorylase and resisting tumor activity, have simple and convenient preparation process and high feasibility, are convenient for large-scale production, and are beneficial to reducing the production cost.
Detailed Description
Example 1: a1-aryl aldoxime uracil having the following structure I:
Figure BDA0001361991280000041
wherein R1 is methyl or hydrogen, R2 is chlorine, iodine, carboxyl or hydrogen, Ar is alkylphenyl, halophenyl, alkoxyphenyl, thienyl or furyl.
The structural formula of the 1-aryl aldoxime uracil is as follows:
Figure BDA0001361991280000051
the preparation method of the 1-aryl aldoxime uracil comprises the following synthetic reaction formula:
Figure BDA0001361991280000052
R1＝CH3，H R2＝Cl，I，COOH，H
Figure BDA0001361991280000053
the preparation method comprises the following specific steps:
(1) dissolving 0.02mol of aromatic aldehyde in 25mL of methanol, stirring at normal temperature, adding 0.02mol of hydroxylamine hydrochloride and 0.022mol of potassium carbonate into the methanol after the aromatic aldehyde is completely dissolved, reacting for 3 hours, extracting a reaction solution after the reaction is completely finished, washing with a saturated sodium bicarbonate solution, drying with anhydrous sodium sulfate, and distilling under reduced pressure to recover the methanol to obtain the aromatic aldoxime.
(2) Dissolving 0.02mol of aromatic aldoxime in 25mL of N, N-dimethylformamide, stirring at normal temperature, adding 0.022mol of NCS after the aromatic aldoxime is completely dissolved, stirring at normal temperature for 4 hours, extracting after complete reaction, washing by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, and removing the solvent by reduced pressure distillation to obtain o-chloro aromatic aldoxime;
(3) dissolving 2.4mmol of o-chloro aromatic aldoxime, 2mmol of substituted uracil and 2.4mmol of sodium hydroxide in a mixed solvent of 10mLN, N-dimethylformamide and 10mL of methanol, stirring at normal temperature for 2-4h, after the reaction is completed, extracting and washing, adding 3-carboxybenzaldehyde, stirring at normal temperature for 6h, separating out a white solid, filtering, washing, drying with anhydrous sodium sulfate, and performing column chromatography separation or recrystallization to obtain the 1-aryl aldoxime uracil.
(Z) -1- (phenyl) (hydroxyimino) methyl) -6-methylpyrimidine-2, 4- (1H,3H) -dione (Compound 1).
A white solid; m.p.245-246 ℃; IR (KBr, v)max,cm-1):3451,2918,1731,1658,1459,1367,1085,947,813,693,462；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.35(s,1H,NH),11.48(s,1H,OH),7.63-7.61(m,J＝2.0Hz,2H,ArH),7.48-7.46(t,J＝7.0Hz,3H,ArH),5.72(s,1H,CH),1.89(s,3H,CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm):163.4,152.5,149.8,143.2,132.0,130.7,129.6,125.5,101.5,18.3；HRMS(ESI-TOF,[M+Na]+):m/z calcd for C12H11N3O3,268.0693；found,268.0687。
1. In vitro anti-tumor experiments:
the positive reference compounds used were 7-deazaxanthine (7DX) and 5-chloro-6- [1- (2-aminopyrrole) methyl ] uracil phosphate (TPI).
TABLE 1 Thymidine phosphorylase inhibitory Activity at the cellular level in vitro
Figure BDA0001361991280000061
Pharmacological results show that the 1-aryl aldoxime uracil compounds are high-activity tumor growth inhibitors and have strong activity of inhibiting thymidine phosphorylase, especially IC of compounds 4, 5,6, 7 and 1250The value reaches 0.12-9.7 mu M, and the high inhibitory activity is shown.
2. Experiments with cytotoxins
The reference compound used was cycloheximide.
Compounds 4, 5,6 and 12 with good inhibitory activity to thymidine phosphorylase were selected and evaluated for cytotoxicity and growth inhibitory activity on mouse fibroblast cell lines. All active compounds were found to be non-toxic within a concentration of 50. mu.M.
Example 2: 1-aryl aldoxime uracil with the structural formula
Figure BDA0001361991280000071
(Z) -1- ((2-fluorophenyl) (hydroxyimino) methyl) -6-methylpyrimidine-2, 4- (1H,3H) -dione (Compound 2).
A white solid; m.p.248-249 ℃; IR (KBr, v)max,cm-1):3440,2919,1695,1432,1302,1179,989,811,512；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.57(s,1H,NH),11.50(s,1H,OH),7.52-7.47(m,J＝7.6Hz,3H,ArH),7.46-7.33(m,1H,ArH),5.73(s,1H,CH),1.89(s,3H,CH3)；13CNMR(150MHz,DMSO-d6)(δ,ppm):163.4,162.1,152.3,149.8,142.5(d,3JC–F＝3Hz),134.6(d,3JC–F＝7.5Hz),131.7(d,3JC–F＝7.5Hz),121.7(d,3JC–F＝1.5Hz),117.6(d,2JC–F＝21Hz),112.3(d,2JC–F＝24Hz),101.8,18.3；HRMS(ESI-TOF,[M+H]+):m/z calcd for C12H10FN3O3,264.0779；found,264.0776。
Example 3: 1-aryl aldoxime uracil with the structural formula
Figure BDA0001361991280000072
(Z) -1- ((4-fluorophenyl) (hydroxyimino) methyl) -6-methylpyrimidine-2, 4- (1H,3H) -dione (Compound 3).
A white solid; m.p.234-235 ℃; IR (KBr, v max, cm-1):3419,2921,1706,1513,1459,1159,841,605,538; 1H NMR (500MHz, DMSO-d6) (δ, ppm):12.36(s,1H, NH),11.48(s,1H, OH),7.70-7.67(m, J ═ 8.5Hz,2H, ArH),7.31-7.28((m, J ═ 7Hz,2H, ArH),5.72(s,1H, CH),1.89(s,3H, CH 3);13C NMR(125MHz,DMSO-d6)(δ,ppm):163.4,162.7,152.4,149.8,142.5,128.7(d,3JC–F＝2.5Hz),128.0(d,3JC–F＝8.8Hz),116.7,116.5,101.6,18.3；HRMS(ESI-TOF,[M+H]+):m/z calcd for C12H10FN3O3,264.0779；found,264.0776。
example 4: 1-aryl aldoxime uracil with the structural formula
Figure BDA0001361991280000081
(Z) -1- ((4-chlorophenyl) (hydroxyimino) methyl) -6-methylpyrimidine-2, 4- (1H,3H) -dione (Compound 4).
A white solid; m.p.249-250 deg.c; IR (KBr, v max, cm)-1):3445,2922,1673,1493,1312,1093,942,836,705,504；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.50(s,1H,NH),11.51(s,1H,OH),7.66-7.64(d,J＝8.6Hz,2H,ArH),7.53-7.52(d,J＝8.6Hz,2H,ArH),5.73(s,1H,CH),1.89(s,3H,CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm):163.4,152.4,149.8,142.5,135.3,131.0,129.6,127.4,101.7,18.3；HRMS(ESI-TOF,[M+H]+):m/z calcd for C12H10ClN3O3,280.0483；found,264.0480。
Example 5: 1-aryl aldoxime uracil with the structural formula
Figure BDA0001361991280000082
(Z) -1- ((hydroxyimino) (p-tolyl) methyl) -6-methylpyrimidine-2, 4- (1H,3H) -dione (Compound 5).
A white solid; m.p.256-257 ℃; IR (KBr, v)max,cm-1):3431,3287,2854,1671,1612,1408,1303,1185,941,823,706,531；1H NMR(500MHz,DMSO-d6)(δ,ppm):12.17(s,1H,NH),11.42(s,1H,OH),7.51-7.49(d,J＝8.5Hz,2H,ArH),7.28-7.26(d,J＝8Hz,2H,ArH),5.70(s,1H,CH),2.34(s,3H,CH3),1.88(s,3H,CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm):163.4,152.6,149.8,143.2,140.5,130.1,129.5,125.5,101.4,21.3,18.3；HRMS(ESI-TOF,[M+Na]+):m/zcalcd for C13H13N3O3,282.0849；found,282.0845。
Example 6: 1-aryl aldoxime uracil with the structural formula
Figure BDA0001361991280000091
(Z) -1- ((4-ethylphenyl) (hydroxyimino) methyl) -6-methylpyrimidine-2, 4- (1H,3H) -dione (Compound 6).
A white solid; m.p.256-257 ℃; IR (KBr, v)max,cm-1):3444,3242,2964,1720,1656,1462,1370,1154,1020,950,849,526；1H NMR(500MHz,DMSO-d6)(δ,ppm):12.18(s,1H,NH),11.42(s,1H,OH),7.53-7.52(d,J＝8Hz,2H,ArH),7.31-7.29(d,J＝8Hz,2H,ArH),5.70(s,1H,CH),2.65-2.64(m,2H,CH2),1.89(s,3H,CH3),1.21-1.18(m,3H,CH3)；13C NMR(125MHz,DMSO-d6)(δ,ppm):163.4,152.6,149.8,146.7,143.2,129.6,128.9,125.6,101.4,28.4,18.3,15.8；HRMS(ESI-TOF,[M+H]+):m/z calcd for C14H15N3O3,274.1186；found,274.1182。
Example 7: 1-aryl aldoxime uracil with the structural formula
Figure BDA0001361991280000092
(Z) -1- ((4-bromophenyl) (hydroxyimino) methyl) -6-methylpyrimidine-2, 4- (1H,3H) -dione (Compound 7).
A white solid; m.p.261-262 ℃; IR (KBr, v)max,cm-1):3426,1697,1672,1409,1310,1182,999,848,772,511；1H NMR(500MHz,DMSO-d6)(δ,ppm):12.51(s,1H,NH),11.51(s,1H,OH),7.72-7.70(m,J＝8.5Hz,2H,ArH),7.63-7.62(d,J＝8.5Hz,2H,ArH),5.76(s,1H,CH),1.94(s,3H,CH3)；13C NMR(125MHz,DMSO-d6)(δ,ppm):163.4,152.4,149.8,142.6,132.5,131.7,127.6,124.1,101.7,18.3；HRMS(ESI-TOF,[M+H]+):m/z calcd for C12H10BrN3O3,323.9984；found,323.9978。
Example 8: 1-aryl aldoxime uracil with the structural formula
Figure BDA0001361991280000101
(Z) -1- ((hydroxyimino) (3-methoxyphenyl) methyl) -6-methylpyrimidine-2, 4- (1H,3H) -dione (Compound 8).
A white solid; m.p.256-257 ℃; IR (KBr, v)max,cm-1):3427,3200,2922,1717,1659,1459,1385,1310,1236,1018,815,704；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.37(s,1H,NH),11.47(s,1H,OH),7.38-7.37(m,J＝8Hz,1H,ArH),7.16-7.14(m,J＝2Hz,3H,ArH),5.72-5.71(d,1H,CH),3.80(s,3H,CH3),1.89(s,3H,CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm):163.4,160.1,152.5,149.8,143.1,133.5,130.8,118.0,116.4,110.5,101.5,55.7,18.3；HRMS(ESI-TOF,[M+H]+):m/z calcd for C13H13N3O4,276.0984；found,276.0978.
Example 9: 1-aryl aldoxime uracil with the structural formula
Figure BDA0001361991280000102
(Z) -1- ((4-ethylphenyl) (hydroxyimino) methyl) -6-methylpyrimidine-2, 4- (1H,3H) -dione (Compound 9).
A white solid; m.p.243-244 ℃; IR (KBr, v)max,cm-1):3436,2920,1730,1669,1608,1450,1367,1181,1033,944,813,523；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.05(s,1H,NH),11.43(s,1H,OH),7.55-7.54(d,J＝8.8Hz,2H,ArH),7.01-7.00(d,J＝8.8Hz,2H,ArH),5.69(s,1H,CH),3.80(s,3H,CH3),1.88(s,3H,CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm):163.4,161.3,152.6,149.8,143.0,127.1,124.5,115.0,101.4,55.8,18.3；HRMS(ESI-TOF,[M+H]+):m/z calcd for C13H13N3O4,276.0984；found,276.0982。
Example 10: 1-aryl aldoxime uracil with the structural formula
Figure BDA0001361991280000111
(Z) -1- ((hydroxyimino) (m-tolyl) methyl) -6-methylpyrimidine-2, 4- (1H,3H) -dione (Compound 10).
A white solid; m.p.246-247 ℃; IR (KBr, v)max,cm-1):3443,2920,1655,1480,1315,1022,923,802,711,507；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.27(s,1H,NH),11.44(s,1H,OH),7.43(s,1H,ArH),7.41-7.40(d,J＝7.9Hz,1H,ArH),7.36-7.33(t,J＝7.7Hz,1H,ArH),7.30-7.29(d,J＝7.5Hz,1H,ArH),5.71(s,1H,CH),2.35(s,3H,CH3),1.89(s,3H,CH3)；13CNMR(150MHz,DMSO-d6)(δ,ppm):163.4,152.6,149.8,143.3,138.9,132.1,131.4,129.4,125.8,122.8,101.5,21.4,18.4；HRMS(ESI-TOF,[M+Na]+):m/z calcd for C13H13N3O3,282.0849；found,282.0844。
Example 11: 1-aryl aldoxime uracil with the structural formula
Figure BDA0001361991280000112
(Z) -1- ((3-fluorophenyl) (hydroxyimino) methyl) -6-methylpyrimidine-2, 4- (1H,3H) -dione (Compound 11).
A white solid; m.p.255-256 ℃; IR (KBr, v)max,cm-1):3439,3155,2766,1712,1616,1432,1296,1082,955,818,745,514；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.49(s,1H,NH),11.41(s,1H,OH),7.45-7.42(m,J＝7.7Hz,3H,ArH),7.39-7.38(m,J＝7.3Hz,1H,ArH),7.28-7.26(t,J＝8Hz,1H,ArH)5.65(s,1H,CH),1.81(s,3H,CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm):163.4,162.1,152.3,149.8,142.5,134.7,131.8(d,3JC–F＝7.5Hz),121.7,117.6(d,2JC–F＝21Hz),112.3(d,2JC–F＝24Hz),101.8,18.3；HRMS(ESI-TOF,[M+H]+):m/z calcd forC12H10FN3O3,264.0779；found,264.0776。
Example 12: 1-aryl aldoxime uracil with the structural formula
Figure BDA0001361991280000121
(Z) -1- ((3, 4-dichlorophenyl) (hydroxyimino) methyl) -6-methylpyrimidine-2, 4- (1H,3H) -dione (Compound 12).
A white solid; m.p.244-245 ℃; IR (KBr, v)max,cm-1):3428,2901,1755,1928,1367,1128,1025,892,655,543；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.70(s,1H,NH),11.51(s,1H,OH),7.89(s,1H,ArH),7.74-7.73(d,J＝8.5Hz,1H,ArH),7.66-7.65(d,J＝8.5Hz,1H,ArH),5.73(s,1H,CH),2.35(s,3H,CH3),1.90(s,3H,CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm):163.4,152.2,149.9,141.8,133.3,132.9,132.5,131.8,127.2,125.8,102.0,18.3；HRMS(ESI-TOF,[M+H]+):m/z calcd for C12H9Cl2N3O3,314.0094；found,314.0088。
Example 13: 1-aryl aldoxime uracil with the structural formula
Figure BDA0001361991280000122
(Z) -1- ((hydroxyimino) (thienyl) methyl) -6-methylpyrimidine-2, 4- (1H,3H) -dione (Compound 13).
A yellow solid; m.p.234-235 ℃; IR (KBr, v)max,cm-1):3452,2901,1822,1652,1331,839,524；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.08(s,1H,NH),11.43(s,1H,OH),7.82-7.81(m,1H,CH),7.67-7.65(m,1H,CH),7.42-7.41(m,1H,CH),5.69(s,1H,CH),1.90(s,3H,CH3)；13CNMR(150MHz,DMSO-d6)(δ,ppm):163.5,152.3,149.7,140.6,134.7,128.7,126.3,124.9,101.5,18.3。
Example 14: 1-aryl aldoxime uracil with the structural formula
Figure BDA0001361991280000123
(E) -1- ((hydroxyimino) (p-tolyl) methyl) -5-iodopyrimidine-2, 4- (1H,3H) -dione (compound 14).
A white solid; m.p.241-242 ℃; IR (KBr, v)max,cm-1):3438,3189,3049,2892,1720,1652,1408,1283,1140,1018,950,826,605,492；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.14(s,1H,NH),11.90(s,1H,OH),8.10(s,1H,CH),7.51-7.49(d,J＝8.2Hz,2H,ArH),7.25-7.24(d,J＝8.1Hz,2H,ArH),2.33(s,3H,CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm):161.5,149.1,148.4,143.8,140.4,129.8,128.9,126.0,70.3,21.4；HRMS(ESI-TOF,[M+H]+):m/z calcd forC12H10IN3O3,371.9840；found,371.9838。
Example 15: 1-aryl aldoxime uracil with the structural formula
Figure BDA0001361991280000131
(E) -1- ((4-ethylphenyl) (hydroxyimino) methyl) -5-iodopyrimidine-2, 4- (1H,3H) -dione (compound 15).
A white solid; m.p.238-240 ℃; IR (KBr, v)max,cm-1):3417,3187,3047,2965,2881,1720,1651,1603,1411,1285,1140,1014,949,841,606,530；1H NMR(500MHz,DMSO-d6)(δ,ppm):12.15(s,1H,NH),11.92(s,1H,OH),8.10(s,1H,CH),7.54-7.52(d,J＝7.5Hz,2H,ArH),7.28-7.27(d,J＝7.5Hz,2H,ArH),2.65-2.61(m,2H,CH2),1.19-1.16(t,3H,CH3)；13C NMR(125MHz,DMSO-d6)(δ,ppm):161.5,149.2,148.4,146.7,143.8,129.2,128.7,126.1,70.3,28.5,15.9；HRMS(ESI-TOF,[M+Na]+):m/z calcd for C12H11IN3O3,407.9821；found,407.9816。
Example 16: 1-aryl aldoxime uracil with the structural formula
Figure BDA0001361991280000132
(E) -1- ((2-fluorophenyl) (hydroxyimino) methyl) -5-iodopyrimidine-2, 4- (1H,3H) -dione (compound 16).
A white solid; m.p.249-250 deg.c; IR (KBr, v)max,cm-1):3441,3052,2882,1724,1652,1601,1410,1306,1283,1139,1014,948,846,611,542；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.48(s,1H,NH),11.91(s,1H,OH),8.11(s,1H,CH),7.49-7.48(m,J＝2.4Hz,3H,ArH),7.33-7.30(m,J＝2.4Hz,1H,ArH)；13C NMR(150MHz,DMSO-d6)(δ,ppm):163.6,162.0,161.5,149.2,148.1,143.1(d,3JC–F＝3Hz),134.3(d,3JC–F＝9Hz),131.4(d,3JC–F＝9Hz),122.3,117.5(d,2JC–F＝22.5Hz),112.9(d,2JC–F＝24Hz),70.7；HRMS(ESI-TOF,[M-H]-):m/z calcd forC11H7FIN3O3,373.9438；found,373.9442。
Example 17: 1-aryl aldoxime uracil with the structural formula
Figure BDA0001361991280000141
(E) -1- ((4-chlorophenyl) (hydroxyimino) methyl) -5-iodopyrimidine-2, 4- (1H,3H) -dione (compound 17).
A white solid; m.p.225-226 ℃; IR (KBr, v)max,cm-1):3440,3190,3048,2924,1727,1651,1601,1410,1307,1287,1095,948,832,770,511；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.41(s,1H,NH),11.94(s,1H,OH),8.11(s,1H,CH),7.66-7.65(d,J＝8.6Hz,2H,ArH),7.50-7.49(m,J＝1.8Hz,2H,ArH)；13C NMR(150MHz,DMSO-d6)(δ,ppm):161.5,149.2,148.2,143.1,135.2,130.7,129.3,127.9,70.7；HRMS(ESI-TOF,[M+H]+):m/z calcd for C11H7ClIN3O3,391.9299；found,391.9294。
Example 18: 1-aryl aldoxime uracil with the structural formula
Figure BDA0001361991280000142
(E) -1- ((4-fluorophenyl) (hydroxyimino) methyl) -5-iodopyrimidine-2, 4- (1H,3H) -dione (compound 18).
A white solid; m.p.242-243 ℃; IR (KBr, v)max,cm-1):3440,3199,3052,2905,1728,1655,1600,1444,1305,1285,1214,1023,842,794,678,550；1H NMR(500MHz,DMSO-d6)(δ,ppm):12.29(s,1H,NH),11.92(s,1H,OH),8.12(s,1H,CH),7.70-7.68(m,J＝8.5Hz,2H,ArH),7.29-7.26(m,J＝9Hz,2H,ArH)；13C NMR(125MHz,DMSO-d6)(δ,ppm):164.5,162.8,161.5,149.2,148.3,143.1,128.5(t,2JC–F＝22.5Hz),115.8(d,2JC–F＝17.5Hz),70.5；HRMS(ESI-TOF,[M-H]-):m/z calcd for C11H7FIN3O3,373.9438；found,373.9444。
Example 19: 1-aryl aldoxime uracil with the structural formula
Figure BDA0001361991280000151
(E) -1- ((hydroxyimino) (4-methoxyphenyl) methyl) -5-iodopyrimidine-2, 4- (1H,3H) -dione (compound 19).
A yellow solid; m.p.245-246 ℃; IR (KBr, v)max,cm-1):3189,3050,2894,1722,1655,1521,1415,1345,1285,1178,1013,948,836,638,542；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.00(s,1H,NH),11.89(s,1H,OH),8.08(s,1H,CH),7.56-7.54(d,J＝8.8Hz,2H,ArH),6.99-6.98(d,J＝8.9Hz,2H,ArH),3.79(s,3H,CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm):161.5,161.3,149.1,148.4,143.6,127.7,124.1,114.7,70.2,55.9；HRMS(ESI-TOF,[M+H]+):m/z calcdfor C11H10IN3O4,387.9789；found,387.9787。
Example 20: 1-aryl aldoxime uracil with the structural formula
Figure BDA0001361991280000152
(E) -1- ((hydroxyimino) (phenyl) methyl) -5-iodopyrimidine-2, 4- (1H,3H) -dione (compound 20).
A white solid; m.p.253-254 ℃; IR (KBr, v)max,cm-1):3443,3087,3051,2916,1722,1649,1439,1285,1015,949,781,610；1H NMR(500MHz,DMSO-d6)(δ,ppm):12.28(s,1H,NH),11.93(s,1H,OH),8.13(s,1H,CH),7.62-7.61(d,2H,ArH),7.48-7.42(m,2H,ArH)；13C NMR(125MHz,DMSO-d6)(δ,ppm):161.5,149.2,148.4,143.8,131.7,130.6,129.3,126.1,70.5；HRMS(ESI-TOF,[M+Na]+):m/z calcd for C11H8IN3O3,379.9308；found,379.9504。
Example 21: 1-aryl aldoxime uracil with the structural formula
Figure BDA0001361991280000161
(E) -1- ((hydroxyimino) (3-methoxyphenyl) methyl) -5-iodopyrimidine-2, 4- (1H,3H) -dione (compound 21).
A yellow solid; m.p.255-256 ℃; IR (KBr, v)max,cm-1):3478,3072,2894,1738,1608,1434,1218,1138,1044,940,756,636,549；1H NMR(600MHz,DMSO-d6)(δ,ppm):12.31(s,1H,NH),11.92(s,1H,OH),8.11(s,1H,CH),7.36-7.35(t,1H,ArH),7.16-7.14(m,2H,ArH),7.07-7.05(t,1H,ArH),3.79(s,3H,CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm):161.9,151.7,149.2,148.3,143.7,133.1,130.5,118.6,116.3,111.2,55.8；HRMS(ESI-TOF,[M-H]-):m/zcalcd for C12H10IN3O4,385.9638；found,385.9645。
Example 22: 1-aryl aldoxime uracil with the structural formula
Figure BDA0001361991280000162
(E) -5-chloro-3- ((hydroxyimino) (p-tolyl) methyl) -4-methylpyridine-2, 6(1H,3H) -dione (compound 22).
A white solid;1H NMR(600MHz,DMSO-d6)(δ,ppm):12.32(s,1H,NH),11.05(s,1H,OH),7.60-7.58(d,J＝8.2Hz,2H,ArH),7.27-7.26(d,J＝8.1Hz,2H,ArH),2.38-2.33(m,3H,CH3),2.20-2.19(d,3H,CH3)；13C NMR(150MHz,DMSO-d6)(δ,ppm):159.3,148.9,148.3,143.2,140.7,130.3,130.1,129.0,126.5,125.7,107.6,21.4,16.8.l。
example 23: 1-aryl aldoxime uracil with the structural formula
Figure BDA0001361991280000163
(E) -5- ((hydroxyimino) (p-tolyl) methyl) -2, 6-dione-1, 2,5, 6-tetrahydropyridine-3-carboxylic acid (compound 23).
A white solid;1H NMR(600MHz,DMSO-d6)(δ,ppm):15.12(s,1H,COOH),12.32(s,1H,NH),11.05(s,1H,OH),8.13(s,1H,CH),7.72-7.70(d,2H,ArH),7.26-7.25(d,2H,ArH),2.57(s,3H,CH3)。
example 24: 1-aryl aldoxime uracil with the structural formula
Figure BDA0001361991280000171
(E) -5-fluoro-3- ((hydroxyimino) (p-tolyl) methyl) pyridine-2, 6- (1H,3H) -dione (compound 24).
A white solid;1H NMR(600MHz,DMSO-d6)(δ,ppm):11.01(s,1H,NH),10.23(s,1H,OH),7.56(s,1H,CH),7.28-7.27(m,2H,ArH),7.71-7.70(m,2H,ArH),2.57(s,3H,CH3)。

Claims (6)

1. a 1-aryl aldoxime uracil which is characterized in that it has the following structure I:
Figure FDA0002287645380000011
wherein R is1Is methyl or hydrogen, R2Is chlorine, iodine, carboxyl or hydrogen, Ar is alkyl phenyl, halogenated phenyl, alkoxy phenyl, thienyl or furyl.
2. A 1-arylaldoxime uracil according to claim 1 which is any one of the twenty-one following compounds:
Figure FDA0002287645380000012
Figure FDA0002287645380000021
3. a preparation method of 1-aryl aldoxime uracil is characterized in that the synthesis reaction formula of the preparation method is as follows:
Figure FDA0002287645380000022
the preparation method comprises the following specific steps:
(1) dissolving aromatic aldehyde in methanol, stirring at normal temperature, adding hydroxylamine hydrochloride and potassium carbonate into the methanol after the aromatic aldehyde is completely dissolved, reacting for 2-5h, extracting reaction liquid after the reaction is completely finished, washing with saturated sodium bicarbonate solution, drying with anhydrous sodium sulfate, and distilling under reduced pressure to recover the methanol to obtain the aromatic aldoxime.
(2) Dissolving aromatic aldoxime in N, N-dimethylformamide, stirring at normal temperature, adding NCS (N-butylsuccinimide) after the aromatic aldoxime is completely dissolved, stirring at normal temperature for 2-6h, extracting after complete reaction, washing by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, and removing the solvent by reduced pressure distillation to obtain o-chloro aromatic aldoxime;
(3) dissolving o-chloro aromatic aldoxime, substituted uracil and alkali in organic solvent 1, stirring at normal temperature for 2-4h, extracting and washing after complete reaction, adding 3-carboxybenzaldehyde, stirring at normal temperature for 6h, separating out white solid, filtering, washing, drying with anhydrous sodium sulfate, and performing column chromatography separation or recrystallization to obtain the 1-aromatic aldoxime uracil.
4. The method according to claim 3, wherein the organic solvent 1 in the step (3) is a mixture of two or more of methanol, ethanol, isopropanol, ethyl acetate, toluene, tetrahydrofuran, dichloromethane, chloroform, 1, 4-dioxane, N-dimethylformamide, and dimethylsulfoxide.
5. The method for preparing 1-arylaldoxime uracil as claimed in claim 3, wherein in the step (3), the base is one or more of lithium hydroxide, sodium hydroxide, potassium carbonate, cesium carbonate, potassium phosphate, cesium fluoride and triethylamine.
6. A 1-arylaldoxime uracil as claimed in claim 1 which is active as an inhibitor of thymidine phosphorylase and has activity in inhibiting thymidine phosphorylase for the treatment of gastric, renal, uterine, leiomyoma, breast, colon or lung cancer.
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