CN102766068A - Halogenated salicyloyl arylamine compounds as well as preparation method and application thereof - Google Patents
Halogenated salicyloyl arylamine compounds as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to the field of pharmaceutical chemistry, in particular to halogenated salicyloyl arylamine compounds (I) for oncotherapy, a preparation method of the compounds and medicine composites containing the compounds, wherein the definitions of Ar and R are defined in the specification. Pharmacological experiments prove that the compounds provided by the invention have excellent antitumor effect.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to one type of halo salicylyl aromatic amine compounds, preparation method who is used for oncotherapy, and the pharmaceutical composition that contains them.
Background technology
The treatment of malignant tumour is a global difficult problem for a long time.In recent years; Along with the fast development of related disciplines such as oncomolecularbiology, people recognize that gradually the essence of cell carcinogenesis possibly be the cell infinite multiplication that the intracellular signal transduction pathway imbalance causes, and great change has also taken place the theory of antitumor drug research and development thereupon; (mainly act on DNA from the research of conventional cell poison type medicine; RNA and tubulin) turn to the new type antineoplastic medicine sought to the intracellular signal transduction path (referring to Peng Yao, Zhang Yixuan, Zheng Gengxin. the progress of novel protein tyrosine kinase inhibitor series antineoplastic medicament. Shenyang Pharmaceutical University's journal; 2007,24 (7): 451-456).Strong with conventional cell cytotoxic drug poor selectivity, toxic side effect, to be prone to produce characteristics such as resistance different, can reach highly selective, hypotoxic result of treatment based on the antitumor drug of signal transduction pathway in the targeted cells.With the key enzyme of some intracellular signal transduction pathway relevant with the tumour cell differentiation and proliferation as the drug screening target spot; The important directions that discovery is efficient, the new type anticancer medicine of low toxicity has become current antitumor drug research and development is (referring to Aggarwal B B; Sethi G; Baladandayuthapani V; Et al.Targeting cell signaling pathways for drug discovery:an old lock needs a new key.J.Cell.Biochem.2007,102:580-592; Zhu Yijing, Jiang Fengchao. with the conduction of regulation and control Ras signal is the antitumor drug progress of target. Acta Pharmaceutica Sinica, 2009,44 (1): 1-10; Huambo, Liu Yu. act on the angiogenesis inhibitor of VEGF signal path. pharmacy progress, 34 (6): 256-263).
In recent years; The anti-tumor activity of salicylic amide compounds has caused showing great attention to of people; Bibliographical information; The salicylic amide compounds be a kind of efficiently, EGF-R ELISA (EGFR) suppressor factor optionally, 4-(4-aminophenyl)-N-(3-chloro-phenyl-) salicylic amide, imatinib, ZD1939, lapatinibditosylate, Xarelto etc. are target spot tyrosine kinase inhibitors more than a type.Its structural formula is following:
Summary of the invention
The invention discloses one type of halo salicylyl aryl amine derivatives, pharmacological testing proves that halo salicylyl aryl amine derivatives of the present invention has good antitumor action.
Halo salicylyl aryl amine derivatives of the present invention (I) structure is following:
Wherein R randomly represents trifluoromethyl, 4-halogenophenyl or halogen;
Ar randomly represents 3-fluorophenyl, 2-pyridyl, 3-pyridyl, naphthyl, furyl, nitrogen azoles base, quinolyl.
R preferably represents trifluoromethyl or chlorine.
Ar preferably represents 3-fluorophenyl or 2-pyridyl.
Halo salicylyl aryl amine derivatives preparation method of the present invention is following:
Ar is an example for the 3-fluorophenyl:
Its pharmacy acceptable salt of compound of the present invention (I) has same effect.Hydrochloride, vitriol, phosphoric acid salt, PHENRAMINE MALEATE, fumarate, citrate, mesylate, tosilate, tartrate or the acetate of described pharmacy acceptable salt preferred formula (I) compound.
The preferred compound of the present invention's part is following:
Compound (I) or its pharmacy acceptable salt can be processed various preparations through adding pharmaceutically acceptable carrier.Be used for oral, injection etc. clinical.
The clinical used dosage of compound of the present invention (I) is 0.01mg～1000mg/ days, also can depart from this scope according to the weight of the state of an illness or the difference of formulation.
Through test, compound of the present invention (I) can be used as antitumor drug and is applied to tumor treatment in the growth that can obviously suppress tumour cell.Be the pharmacology test and the result of part of compounds of the present invention below:
Cell cultures: this tests used non-small lung cancers cell strain A549; Hepatoma cell strain BEL-7402; Breast cancer cell line mcf-7, stomach cancer cell line SGC-7901 is the adherent growth cell strain; Adopt DMEM and the RPMI-1640 nutrient solution that contains 10% foetal calf serum (FBS) respectively, and add the culture system cultivation of penicillium mould 100IU/mL and Streptomycin sulphate 100 μ g/mL.Culture environment is 37 ℃, 5% CO
2Incubator changed a not good liquor in per 2 days, and the cell in the vegetative period of taking the logarithm experimentizes.
Measuring method and experimental result
Mtt assay is surveyed cell proliferation
With above-mentioned 4 kinds of tumour cells with 1 * 10
4The concentration in individual/hole is inoculated in 96 well culture plates, and every hole inoculum size is 100 μ L.After treating cell attachment; Be divided into given the test agent group, blank group (adding RPMI RPMI-1640 100 μ L), positive controls (the positive contrast medicine of ZD1939, lapatinibditosylate and niclosamide), solvent control group (DMSO), the final concentration of given the test agent all is respectively 0.01,0.1,1,10,100umol/L.The TV in every hole is 200 μ L.Add MTT (concentration is 5mg/mL) 20 μ L behind the effect 48h, after continuing to cultivate 4h, the centrifugal supernatant of abandoning, every hole adds the DMSO of 150 μ L, and concussion shakes up, and first a ceremonial jade-ladle, used in libation particle is fully dissolved.On enzyme-linked immunosorbent assay instrument, with wavelength 550nm, absorbancy (A is surveyed in the zeroing of reagent control group
550) value, 6 multiple holes are established in every kind of processing, repeat 3 times; Get its MV; According to the inhibiting rate of formula (1) calculation sample to growth of tumour cell, and under each concentration compound to the inhibiting rate of tumour cell, with the half-inhibition concentration (IC of each sample of SPSS computed in software
50Value).The result is as shown in table 1.The same table of compound code name in the table 1.
Calculation formula: inhibiting rate (%)=(OD
Blank-OD
Sample)/OD
Blank* 100% formula (1)
Table 1 given the test agent is to four kinds of tumor cell proliferation inhibition effects
Visible by table 1, under this experiment condition, for non-small lung cancers cell strain A549, compound S A
1～SA
3, SA
5～SA
6Suppress activity and all be better than three groups of positive control drugs, SA
4Activity is better than ZD1939 and lapatinibditosylate; For breast cancer cell line mcf-7, compound S A
1, SA
3, SA
5～SA
6Suppress activity and all be better than three groups of positive control drugs, compound S A
2, SA
4Activity is better than ZD1939 and lapatinibditosylate; For stomach cancer cell line SGC-7901, compound S A
2～SA
4, SA
6Suppress activity and all be better than three groups of positive control drugs, SA
5Activity is better than ZD1939, and is suitable with lapatinibditosylate and niclosamide; For hepatoma cell strain BEL-7402, compound S A
1～SA
6Suppress activity and all be better than three groups of positive control drugs.
Embodiment
Embodiment 1
N-4-((pyridine-2-yl) methoxyl group)-3-chloro-phenyl-)-2-hydroxyl-4-chlorobenzamide synthetic
1.1 the preparation of 2-((2-chloro-4-nitrophenoxy) methyl) pyridine
Reaction formula
In reaction flask, add 5.0g (0.03mol) 2-chloromethyl pyridine hydrochloride, 8.4g (0.06mol) salt of wormwood, 100mL DMF; Stirring at room 30min; Add 5.3g (0.03mol) 2-chloro-4-nitrophenols and 0.25g (1.5mmol) potassiumiodide successively, be warming up to 60 ℃ of reaction 16h.Add 400mL water, have a large amount of solids to separate out, suction filtration, drying gets faint yellow solid 5.5g, yield 68%, mp 149.2-149.9 ℃.
1.2 4-((pyridine-2-yl) methoxyl group)-3-chloroaniline is synthetic
Reaction formula
Reactions step
With 4.5g (17mmol) 2-(2-chloro-4-nitrophenoxy) methyl) pyridine, 3.8g (68mmol) reduced iron powder, 5.4g (102mmol) ammonium chloride and 80mL volume(tric)fraction be that 90% ethanol water adds in the reaction flask back flow reaction 12h.Suction filtration, concentrated filtrate is dissolved in the gained solid in the methylene dichloride to doing, and uses water washing, gets organic layer.It is slightly acidic that water layer is surveyed pH, uses Na
2CO
3The aqueous solution is regulated pH to 8-9, uses dichloromethane extraction, merges organic layer, anhydrous sodium sulfate drying, and the filtering siccative, concentrating under reduced pressure filtrating gets pale yellow powder 3.0g, yield 75%, mp 90.9-91.8 ℃.
1.3 N-4-((pyridine-2-yl) methoxyl group)-3-chloro-phenyl-)-2-hydroxyl-4-chlorobenzamide synthetic
Reaction formula
Reactions step
3.0g (13mmol) 4-((pyridine-2-yl) methoxyl group)-3-chloroaniline, 2.1g (12mmol) 4-chloro-salicylic acid, 30mL chlorobenzene are added in the reaction flask; Be stirred to dissolving fully under 80 ℃; Be warming up to 135 ℃ of back flow reaction, slowly drip 0.8g (6mmol) PCl when waiting to reflux
3, keep refluxing and continue to react 9 hours.Suction filtration cools off and separates out solid while hot, and suction filtration is used acetone recrystallization, gets N-4 ((pyridine-2-yl) methoxyl group)-3-chloro-phenyl-)-2-hydroxyl-4-chlorobenzamide pearl crystal, yield is 36.0%, m.p.220.8-221.5 ℃.
1H-NMR(DMSO-d
6，400Hz)δ:11.92(s,1H,NH),10.34(s,1H,-OH),8.60(d,J=4.8Hz,1H,Py-H),7.94(m,2H,ArH),7.88(dd,J＝7.8,1.5Hz,1H,Py-H),7.58~7.54(m,2H,Py-H),7.39~7.35(m,1H,ArH),7.26(d,J＝9.0Hz,1H,ArH),7.05~7.02(m,2H,ArH),5.28(s,2H,CH
2);
13C-NMR(DMSO-d
6，100MHz)δ:165.5,159.0,156.2,150.0,149.0,137.4,137.1,132.1,130.6,123.0,122.6,121.4,121.1,120.8,119.2,116.9,116.8,114.4,71.1;IR(KBr,cm
-1)υ:3341.9,3075.1,1662.4,1600.1,1545.69,1502.3,1443.5,1411.3,1280.1,1215.7,1063.9,913.4;ESI-Mass?forC
19H
14Cl
2N
2O
3:m/z(M
+-H)386.89
Embodiment 2
N-4 ((pyridine-2-yl) methoxyl group)-3-chloro-phenyl-)-2-hydroxyl-5-chlorobenzamide synthetic
Press 1.3 methods operation among the embodiment 1, get N-4 ((pyridine-2-yl) methoxyl group)-3-chloro-phenyl-)-2 hydroxyls-5-chlorobenzamide off-white color crystal, yield is 40.0%, m.p.218.6-219.9 ℃.
1H-NMR(DMSO,400MHz)δ:11.82(s,1H,NH),10.39(s,1H,OH),8.61(d,J＝4.4Hz,1H,Py-H),7.96(t,J＝1.6Hz,2H,Ar-H),7.90(t,J＝7.6Hz,1H,Py-H),7.59(d,J＝8.4Hz,2H,ArH),7.48(dd,J＝8.8,1.6Hz,1H,ArH),7.38(t,J＝6.0Hz,1H,Py-H),7.27(d,J＝9.2Hz,1H,ArH),7.03(d,J＝8.8Hz,1H,ArH),5.29(s,2H,Py-CH
2-O);
13C-NMR(DMSO,100MHz)δ:165.0,157.0,156.2,150.1,149.1,137.0,133.1,132.0,129.1,128.2,123.0,122.7,122.6,121.4,121.1,120.7,119.1,114.3,71.1;IR(KBr,cm
-1)υ:3320.5,3075.2,2545.7,1661.0,1601.0,1545.1,1501.1,1446.4,1413.1,1375.0,1275.4,1217.9,1152.6,1106.1,1064.9,1008.0,801.9,761.7;ESI-Mass?for?C
19H
14Cl
2N
2O
3:m/z(M
+-H)387.42.
Embodiment 3
N-4-((pyridine-2-yl) methoxyl group)-3-chloro-phenyl-)-2-hydroxyl-4-trifluoromethyl benzamide synthetic
Reactions step
Press 1.3 methods operation among the embodiment 1, get N-4-((pyridine-2-yl) methoxyl group)-3-chloro-phenyl-)-2-hydroxyl-4-trifluoromethyl benzamide white crystal, yield is 36.0%, m.p.223.7-224.9 ℃.
1H-NMR(DMSO,400MHz)δ:11.82(s,1H,NH),10.44(s,1H,OH),8.60(d,J=4.2Hz,1H,Py-H),8.00(d,J=8.0Hz,1H,Py-H),7.96(d,J=2.0Hz,1H,ArH),7.88(t,J=6.8Hz,1H,Py-H),7.58(d,J=7.6Hz,2H,ArH),7.38~7.36(m,1H,Py-H),7.30~7.25(m,3H,ArH),5.29(s,2H,OCH
2);
13C-NMR(DMSO,100MHz)δ:164.7,157.3,156.2,150.0,149.0,137.1,132.3,132.2,130.5,125.3,123.2,123.0,122.2,121.4,121.2,120.5,115.3,114.4,113.4,71.1;IR(KBr,cm
-1)υ:3348.4,3075.8,1665.0,1597.0,1543.2,1502.8,1422.4,1290.2,1157.5,1128.1,1065.4,1036.0,925.9,855.8,750.9;ESI-Mass?for?C
20H
14ClF
3N
2O
3:m/z(M
+-H)421.28.
Embodiment 4
N-4 ((pyridin-3-yl) methoxyl group)-3-chloro-phenyl-)-2-hydroxyl-5-chlorobenzamide synthetic
4.1 the preparation of 3-((2-chloro-4-nitrophenoxy) methyl) pyridine
Reaction formula
Reactions step
In reaction flask, add 5.0g (0.03mol) 3-chloromethyl pyridine hydrochloride, 8.4g (0.06mol) salt of wormwood, 100mL DMF; Stirring at room 30min; Add 5.3g (0.03mol) 2-chloro-4-nitrophenols and 0.25g (1.5mmol) potassiumiodide successively, be warming up to 60 ℃ of reaction 15h.Add 400mL water, have a large amount of solids to separate out, suction filtration, drying gets faint yellow solid 5.0g, yield 63%, mp 142.2-143.5 ℃.
4.2 4-((pyridin-3-yl) methoxyl group)-3-chloroaniline is synthetic
Reaction formula
Reactions step
With 4.5g (17mmol) 3-((2-chloro-4-nitrophenoxy) methyl) pyridine, 3.8g (68mmol) reduced iron powder, 5.4g (102mmol) ammonium chloride and 80mL volume(tric)fraction is that 90% ethanol water adds in the reaction flask back flow reaction 13h.Suction filtration, concentrated filtrate is dissolved in the gained solid in the methylene dichloride to doing, and uses water washing, gets organic layer.It is slightly acidic that water layer is surveyed pH, uses Na
2CO
3The aqueous solution is regulated pH to 8-9, uses dichloromethane extraction, merges organic layer, anhydrous sodium sulfate drying, and the filtering siccative, concentrating under reduced pressure filtrating gets pale yellow powder 2.7g, yield 67.5%, mp 88.7-89.9 ℃.
4.3 N-4-((pyridin-3-yl) methoxyl group)-3-chloro-phenyl-)-2-hydroxyl-5-chlorobenzamide synthetic
Reaction formula
Reactions step
3.0g (13mmol) 4-((pyridin-3-yl) methoxyl group)-3-chloroaniline, 2.0g (12mmol) 5-chloro-salicylic acid, 30mL chlorobenzene are added in the reaction flask; Be stirred to dissolving fully under 80 ℃; Be warming up to 135 ℃ of back flow reaction, slowly drip 0.8g (6mmol) PCl when waiting to reflux
3, keep refluxing and continue to react 8 hours.Suction filtration cools off and separates out solid while hot, and suction filtration is used acetone recrystallization, gets white solid 2.3g, yield 50%, mp 242.4-243.9 ℃.
1H-NMR(DMSO,300MHz)δ:11.79(s,1H,NH),10.41(s,1H,OH),8.75(d,J=1.2Hz,1H,Py-H),8.63(dd,J=4.8,1.42Hz,1H,Py-H),8.02(d,J＝8.0Hz,1H,Py-H),7.94(d,J＝2.8Hz,1H,Py-H),7.91(d,J＝2.4Hz,1H,ArH),7.62(dd,J=8.8,2.4Hz,1H,ArH),7.61~7.57(m,1H,ArH),7.49(dd,J=8.8,2.8Hz,1H,ArH),7.32(d,J=8.8Hz,1H,ArH),7.04(d,J=8.8Hz,1H,ArH),5.29(s,2H,Py-OCH
2);
13C-NMR(DMSO,100MHz)δ:165.0,156.9,150.0,148.4,148.0,136.5,133.1,132.7,132.2,128.2,124.0,122.7,122.5,121.4,120.7,119.3,119.1,114.7,68.0;IR(KBr,cm
-1)υ:3439.8,1664.2,1604.8,1548.0,1501.5,1413.2,1274.3,1220.6,803.8;ESI-Mass?for?C
19H
14Cl
2N
2O
3:m/z(M
+-H)386.92.
Embodiment 5
N-4 ((pyridin-3-yl) methoxyl group)-3-chloro-phenyl-)-2-hydroxyl-4-chlorobenzamide synthetic
Reaction formula
Reactions step
Press 4.3 methods operation among the embodiment 4, get N-4 ((pyridin-3-yl) methoxyl group)-3-chloro-phenyl-)-2-hydroxyl-4-chlorobenzamide white crystal, yield is 35.0%, m.p.239.6-241.4 ℃.
1H-NMR(DMSO,400MHz)δ:8.77(s,1H,Py-H),8.64(d,J＝4.0Hz,1H,Py-H),8.34(d,J＝2.8Hz,1H,Py-H),8.29(dd,J＝9.2,2.8Hz,1H,Py-H),8.00(d,J＝8.0Hz,1H,ArH),7.80(d,J＝8.4Hz,1H,ArH),7.56~7.51(m,2H,ArH),7.06(d,J＝2.0Hz,1H,ArH),6.99(dd,J＝8.4,2.0Hz,1H,ArH),5.46(s,2H,Py-CH
2-O);
13C-NMR(DMSO,100MHz)δ:171.1,161.7,158.6,149.0,148.4,141.0,139.5,136.4,131.8.0,131.6,125.4,124.5,124.0,122.1,119.4,116.8,113.8,112.3,68.7;IR(KBr,cm
-1)υ:3083.4,2931.6,1673.9,1583.9,1519.8,1486.5,1358.2,1278.9,1215.0,1124.3,1009.2,904.3,855.4,794.4,737.6;ESIMass?for?C
19H
14Cl
2N
2O
3:m/z(M
+-H)386.86.
Embodiment 6
N-4 ((pyridin-3-yl) methoxyl group)-3-chloro-phenyl-)-2-hydroxyl-4-trifluoromethyl benzamide synthetic
Reaction formula
Reactions step
Press 4.3 methods operation among the embodiment 4, get N-4 ((pyridin-3-yl) methoxyl group)-3-chloro-phenyl-)-2 hydroxyl 4-trifluoromethyl benzamide pearl crystal, yield is 35.0%, m.p.242.7-244.4 ℃.
1H-NMR(DMSO,400MHz)δ:11.50(s,1H,NH),10.44(s,1H,OH),8.71(d,J=1.6Hz,1H,Py-H),8.59(dd,J=4.8,1.6Hz,1H,Py-H),8.00(d,J=8.0Hz,1H,Py-H),7.94(m,2H,ArH),7.63(dd,J=8.8,2.4Hz,1H,ArH),7.49~7.46(m,1H,ArH),7.32~7.29(m,3H,Py-H，ArH),5.27(s,2H,OCH
2);
13C-NMR(DMSO,100MHz)δ:164.7,157.3,149.9,149.1,148.7,135.7,132.7,132.4,132.3,130.5,124.9,123.7,123.2,122.2,121.4,120.4,115.3,114.7,113.4,68.1;IR(KBr,cm
-1)υ:3064.2,2866.7,2583.3,1594.1,1502.9,1439.3,1379.3,1334.0,1291.8,1230.0,1066.7,921.2,743.1,702.3;ESI-Mass?for?C
20H
14ClF
3N
2O
3:m/z(M
+-H)421.00.
Embodiment 7
Synthesizing of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-2-hydroxyl-4-chlorobenzamide
Reaction formula
Reactions step
3.3g (13mmol) 3-chloro-4-((3-fluorophenyl) methoxyl group) aniline, 2.0g (12mmol) 4-chloro-salicylic acid, 30mL chlorobenzene are added in the reaction flask; Be stirred to dissolving fully under 80 ℃; Be warming up to 135 ℃ of back flow reaction, slowly drip 0.8g (6mmol) PCl when waiting to reflux
3, keep refluxing and continue to react 8 hours.Suction filtration cools off and separates out solid while hot, and suction filtration is used acetone recrystallization, gets white solid 2.4g, yield 52.0%, mp 218.7-220.3 ℃.
1H-NMR(DMSO,400MHz)δ:12.08(s,1H,NH),10.35(s,1H,OH),7.95(t,J＝8.4Hz,2H,ArH),7.60(d,J＝8.8Hz,1H,ArH),7.49~7.44(m,1H,ArH),7.33(t,J＝6.8Hz,2H,ArH),7.25(d,J＝9.2Hz,1H,ArH),7.20(t,J＝8.8Hz,1H,ArH),7.06(s,1H,ArH),7.05(d,J＝8.8Hz,1H,ArH),5.24(s,2H,-CH
2-O);
13C-NMR(DMSO,100MHz)δ:165.5,162.2,159.1,150.0,139.6,137.5,132.1,130.6,123.2,122.6,121.3,120.7,119.2,116.8,114.7,114.5,114.4,114.1,113.9,69.4;IR(KBr,cm
-1)υ:3319.5,2924.2,1619.7,1560.5,1501.5,1453.6,1423.2,1378.4,1332.5,1288.8,1257.9,1227.5,1136.3,1063.7,1018.3,929.3,857.4,814.1,779.6,754.2,710.3,677.8;ESI-Mass?for?C
20H
14Cl
2FNO
3:m/z(M
+-H)404.62.
Embodiment 8
Synthesizing of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-2-hydroxyl-5-chlorobenzamide
Reaction formula
Reactions step
Press the operation of embodiment 7 methods, get N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-2-hydroxyl-5-chlorobenzamide white crystal, yield is 57.0%, m.p.215.6-216.9 ℃.
1H-NMR(DMSO-d
6,400MHz)δ:11.78(s,1H,NH),10.39(s,1H,OH),7.92(dd,J=11.6,2.5Hz,2H,ArH),7.58(dd,J=8.8,2.5Hz,1H,ArH),7.51~7.42(m,2H,Ar?H),7.31(t,J=7.8Hz,2H,ArH),7.25(d,J=9.0Hz,1H,ArH),7.18(t,J=8.8Hz,1H,ArH),7.01(d,J=8.8Hz,1H,ArH),5.24(s,2H,OCH
2),
13C-NMR(DMSO-d
6，100MHz)δ:165.0,162.2,156.9,150.0,139.6,133.1,132.0,130.6,128.2,123.3,122.6,121.3,120.7,119.3,119.1,114.8,114.5,114.1,113.8,69.4;IR(KBr,cm
-1)υ:3313.5,3069.7,1624.3,1550.8,1502.4,1419.6,1384.5,1290.1,1223.2,817.5,680.7;ESI-Mass?for?C
20H
14ClFNO
3:m/z(M
+-H)404.62
Embodiment 9
Synthesizing of N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-2-hydroxyl-4-trifluoro yl-benzamide
Reaction formula
Reactions step
Press the operation of embodiment 7 methods, get N-(4-(3-fluorine benzyloxy)-3-chloro-phenyl-)-2-hydroxyl-4-trifluoro yl-benzamide white crystal, yield is 50.0%, m.p.219.7-220.9 ℃.
1H-NMR(DMSO,400MHz)δ:11.72(s,1H,NH),10.45(s,1H,OH),7.99(d,J=8.0Hz,1H,ArH),7.93(d,J=2.4Hz,1H,ArH),7.59(dd,J=8.8,2.4Hz,1H,ArH),7.43~7.49(m,1H,ArH),7.33(d,J=7.6Hz,2H,ArH),7.28(s,2H,ArH),7.26(d,J=8.8Hz,1H,ArH),7.20~7.15(m,1H,ArH),5.24(s,2H,CH
2);
13C-NMR(DMSO,100MHz)δ:164.7,162.2,157.4,149.9,139.6,132.3,130.6,130.5,123.3,123.2,122.2,121.3,120.4,115.2,114.8,114.6,114.1,113.8,113.4,69.4;IR(KBr,cm
-1)υ:3320.2,3116.0,1627.7,1564.8,1503.5,1431.8,1389.7,1332.2,1291.5,1265.8,1228.3,1181.2,1125.2,1068.8,810.5;ESI-Mass?forC
21H
14ClF
4NO
3:m/z(M
+-H)438.18.
Claims (5)
1. the compound of general formula (I) or its pharmacy acceptable salt:
Wherein R randomly represents trifluoromethyl, 4-halogenophenyl or halogen;
Ar randomly represents 3-fluorophenyl, 2-pyridyl, 3-pyridyl, naphthyl, furyl, nitrogen azoles base or quinolyl.
2. the compound of claim 1 or its pharmacy acceptable salt, wherein R represents trifluoromethyl or chlorine.
3. the compound of claim 1 or its pharmacy acceptable salt, wherein Ar represents 3-fluorophenyl or 2-pyridyl.
4. pharmaceutical composition wherein contains in the claim 1 to 3 each compound or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
5. each compound or its pharmacy acceptable salt are used to prepare the purposes of antitumor drug in the claim 1 to 3.
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| CN103304513A (en) * | 2013-06-28 | 2013-09-18 | 安徽中医学院 | One-class 1,2-benzothiazine compound as well as preparation method and application thereof |
| CN103980153A (en) * | 2014-05-30 | 2014-08-13 | 西安交通大学 | Biphenyl amide compound with antitumor activity as well as preparation method and application thereof |
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| CN102249945A (en) * | 2010-05-21 | 2011-11-23 | 复旦大学 | Salicyloyl anilines compound as well as preparation method and application thereof |
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| CN102249945A (en) * | 2010-05-21 | 2011-11-23 | 复旦大学 | Salicyloyl anilines compound as well as preparation method and application thereof |
| CN102010348A (en) * | 2010-11-12 | 2011-04-13 | 李家明 | Salicylamide ester type derivative and preparation method and application thereof |
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| CN103304513A (en) * | 2013-06-28 | 2013-09-18 | 安徽中医学院 | One-class 1,2-benzothiazine compound as well as preparation method and application thereof |
| CN103980153A (en) * | 2014-05-30 | 2014-08-13 | 西安交通大学 | Biphenyl amide compound with antitumor activity as well as preparation method and application thereof |
| CN103980153B (en) * | 2014-05-30 | 2016-01-20 | 西安交通大学 | Dibenzoyl amine compound with anti-tumor activity and its preparation method and application |
| KR20210033275A (en) * | 2019-09-18 | 2021-03-26 | 한국과학기술연구원 | Novel heteroaryl amide derivatives as MAO-B inhibitors and pharmaceutical compositions for preventing, ameliorating or treating neurodegenerative diseases comprising the same |
| KR102247779B1 (en) * | 2019-09-18 | 2021-05-04 | 한국과학기술연구원 | Novel heteroaryl amide derivatives as MAO-B inhibitors and pharmaceutical compositions for preventing, ameliorating or treating neurodegenerative diseases comprising the same |
| CN110818618A (en) * | 2019-11-26 | 2020-02-21 | 山东铂源药业有限公司 | Synthetic method of pyrroltinib intermediate 2- [ (2-chloro-4-nitrophenoxy) methyl ] pyridine |
| WO2021244559A1 (en) * | 2020-06-04 | 2021-12-09 | 广州市朝利良生物科技有限公司 | Small molecular compound and use thereof in preparing anti-tumor metastasis drugs |
| CN115536579A (en) * | 2022-10-28 | 2022-12-30 | 江苏海洋大学 | Tyrosine kinase inhibitor and preparation method and application thereof |
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