CN104163772A - Substituted diaryl ester compound, and preparation method and application thereof - Google Patents

Substituted diaryl ester compound, and preparation method and application thereof Download PDF

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CN104163772A
CN104163772A CN201410232271.XA CN201410232271A CN104163772A CN 104163772 A CN104163772 A CN 104163772A CN 201410232271 A CN201410232271 A CN 201410232271A CN 104163772 A CN104163772 A CN 104163772A
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replace
substituted
compound
aryl
nmr
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李福男
李善花
王利娟
杨少梅
侯瑾
黄志宁
郑满意
姜吉利
陈秋月
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Xiamen University
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Xiamen University
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Abstract

The invention discloses a substituted diaryl ether compound. The structural formula of the compound is shown in the specification. In the structural formula, Z is -CH- or -N-; W is -CH-or -N-; Y is -O-, -CH2-, -NH- or -NRy-; R1 is one of hydrogen, halogen, NO2, CN, CF3, ORa, CORa, COORa, SO2Ra, SO2NRaRb, NRaRb, NRaCORb, a non-substituted/substituted C1-C4 alkyl group, a non-substituted/substituted aryl group and a non-substituted/substituted heterocyclic group; R2 is hydrogen, a non-substituted/substituted C1-C4 alkyl group, or halogen; and R is one of a non-substituted/substituted C1-C12 alkyl group, a non-substituted/substituted C3-C12 cycloalkyl group, a non-substituted/substituted C2-C12 alkenyl group, a non-substituted/substituted aryl group, substituted alkylamine, and a non-substituted/substituted heterocyclic group. The substituted diaryl ether compound can obviously inhibit the malignant proliferation phenotype of cancer cells, promotes the expression of cell apoptosis factor proteins, and provides a new potential anticancer drug.

Description

A kind of replacement two aryl oxide compounds and preparation method thereof and application
Technical field
The invention belongs to chemicals field, be specifically related to a kind of replace two aryl oxide compounds and preparation method thereof and application.
Background technology
Malignant tumour is common disease, the frequently-occurring disease of serious threat human health, is the great scientific research task in the field of medical science of countries in the world, there is no at present satisfied prophylactico-therapeutic measures.The annual whole world approximately has 7,000,000 people to die from cancer, accounts for 1/4th of total death toll.In the three large therapies (operation, chemotherapy and radiation) of malignant tumour, chemotherapy is still the important method of clinical treatment.Anti-malignant-tumor agent is little to cancer cells and human normal cell's selectivity difference, thereby untoward reaction in application process extensively and serious.In addition, easily producing resistance is also one of problem in therapeutic process.In recent years, along with the further understanding of the molecular level mechanism of generation to cancer of molecular biology, immunology, cytokinetic development and people, development, the research and development of antitumor drug are from the research of traditional cytotoxic drug targeted drug that to transfer to the signal path of Tumor-assaciated be target spot.
1973, first professor Folkman has proposed tumor angiogenesis factor (tumor angiogenesis factor, TFA) after, confirm in tumour patient body, there is multiple angiogenesis factor, its VEGF (vascular endothelial growth factor, VEGF) is a kind of angiogenesis factor (Biochem Biophys Res Commun such as Kraizer Y the strongest in body, 2001,287:209-215).VEGF and acceptor thereof (vascular endothelial growth factor receptor, VEGFR) in liver cancer tissue, compared with normal hepatic tissue was high expression level, and with growth, transfer, the recurrence of liver cancer and treat closely related (the Am J Physiol such as Suzuki H, 1999,276).Therefore, the many target spots receptor tyrosine kinase inhibitors taking VEGF/VEGFR as target spot becomes the important topic of cancer therapy drug research.
2005, by a kind of multiple receptor tyrosine kinases inhibitor Xarelto (being shown below) of the common development of Bayer A.G and U.S.'s Aironix (ONYX) company, treatment by U.S. FDA approval for terminal cancer, this is nearly first new drug of approved treatment terminal cancer during the last ten years, and cancer therapy aspect has late obtained major progress.But Xarelto is often higher with the incidence of the light moderate untoward reaction such as fash, diarrhoea and stomatocace, also there is the serious adverse reaction (Lin Lin etc., Journal of Clinical Oncology, 2009,14 (4): 366-368) of myocardial infarction.
(the Acta Pharm Sin such as Yang Zhao, 2011,46:1093-1097) the structure of modification based on bioisostere, replace urea with thiocarbamide, the substituting group changing on A ring obtains a series of derivatives (being shown below), its to the inhibition activity of kidney 760-O, liver cancer HepG2, lung cancer A549, mammary cancer MDA-MB-435, prostate cancer PC3 and six kinds of tumour cells of colon cancer cell HT-29 higher than Xarelto, between on the end phenyl ring of compound 1b, sulfoamido is introduced in position, and its inhibition activity to 6 kinds of tumour cells will be optimized compound 1a.
It is many that the structure of Xarelto has transformation site, optimize the large advantage in space, taking Xarelto as lead compound, carry out structure of modification for specific target spot, by the combination of virtual screening and active screening, the compound that independent research is similar to pharmacological action to Xarelto structure, has certain reference function to the research and development of antitumor drug.
Summary of the invention
The object of the present invention is to provide a kind of two aryl oxide compounds that replace.
Another object of the present invention is to provide the preparation method of above-claimed cpd.
A further object of the present invention is to provide the application of above-claimed cpd.
Concrete technical scheme of the present invention is as follows:
A kind of two aryl oxide compounds that replace, its structure is as follows:
Z is-CH-or-N-;
W is-CH-or-N-;
Y is-O-,-CH 2-,-NH-or-NR y-;
R 1for hydrogen, halogen, NO 2, CN, CF 3, OR a, COR a, COOR a, SO 2r a, SO 2nR ar b, NR ar b, NR acOR b, do not replace replace C 1-C 4alkyl, do not replace replace aryl or do not replace replace heterocyclic group in one, wherein, above-mentioned do not replace replace C 1-C 4alkyl is preferably methyl, ethyl, propyl group, sec.-propyl or the tertiary butyl, above-mentioned do not replace the aryl that replaces comprise the compound of single or multiple rings, also comprise and contain polynuclear compound independent or aryl that merge, preferred aryl contains 6 to about 10 carboatomic ring atoms, particularly preferred aryl comprise do not replace replace phenyl, do not replace replace naphthyl, above-mentioned do not replace replace heterocyclic group comprise contain 1 to 3 independence or merge ring and from 5 fragrant heterocyclic radicals to about 10 annular atomses, preferred fragrant heterocyclic radical contains one, two or three are selected from N, the heteroatoms of O or S, for example comprise: furyl, imidazolyl, thiazolyl, isothiazolyl, quinolyl (comprising isoquinolyl), pyridyl, thienyl, pyrryl, indyl, triazolyl, benzimidazolyl-, benzofuryl, benzothienyl, benzothiazolyl.
R 2for hydrogen, do not replace replace C 1-C 4alkyl or halogen; Wherein, above-mentioned do not replace replace C 1-C 4alkyl is preferably methyl, ethyl, propyl group, sec.-propyl or the tertiary butyl.
R be do not replace replace C 1-C 12alkyl, do not replace replace C 3-C 12cycloalkyl, do not replace replace C 2-C 12thiazolinyl, do not replace replace aryl, substituted alkylamine or do not replace replace heterocyclic group in one, wherein, above-mentioned do not replace replace C 1-C 12alkyl preferably has the alkyl of 1,2,3 or 4 carbon atom, more preferably methyl, ethyl, propyl group, sec.-propyl or the tertiary butyl, above-mentioned do not replace replace C 3-C 12cycloalkyl be preferably pentamethylene base, cyclohexyl, cyclopropane base or tetramethylene base, above-mentioned do not replace the aryl that replaces comprise the compound of single or multiple rings, also comprise and contain polynuclear compound independent or aryl that merge, preferred aryl contains 6 to about 10 carboatomic ring atoms, particularly preferred aryl comprise do not replace replace phenyl, do not replace replace naphthyl, above-mentioned do not replace replace heterocyclic group comprise contain 1 to 3 independence or merge ring and from 5 fragrant heterocyclic radicals to about 10 annular atomses, preferred fragrant heterocyclic radical contains one, two or three are selected from N, the heteroatoms of O or S, for example comprise: furyl, imidazolyl, thiazolyl, isothiazolyl, quinolyl (comprising isoquinolyl), pyridyl, thienyl, pyrryl, indyl, triazolyl, benzimidazolyl-, benzofuryl, benzothienyl, benzothiazolyl.
Preferably, described R afor hydrogen, do not replace replace C 1-C 4alkyl, do not replace replace C 2-C 4thiazolinyl, do not replace replace aryl or do not replace replace heterocyclic group in one, wherein, above-mentioned do not replace replace C 1-C 4alkyl is preferably methyl, ethyl, propyl group, sec.-propyl or the tertiary butyl, above-mentioned do not replace the aryl that replaces comprise the compound of single or multiple rings, also comprise and contain polynuclear compound independent or aryl that merge, preferred aryl contains 6 to about 10 carboatomic ring atoms, particularly preferred aryl comprise do not replace replace phenyl, do not replace replace naphthyl, above-mentioned do not replace replace heterocyclic group comprise contain 1 to 3 independence or merge ring and from 5 fragrant heterocyclic radicals to about 10 annular atomses, preferred fragrant heterocyclic radical contains one, two or three are selected from N, the heteroatoms of O or S, for example comprise: furyl, imidazolyl, thiazolyl, isothiazolyl, quinolyl (comprising isoquinolyl), pyridyl, thienyl, pyrryl, indyl, triazolyl, benzimidazolyl-, benzofuryl, benzothienyl, benzothiazolyl.
Further preferred, described R bfor hydrogen, do not replace replace C 1-C 4alkyl, do not replace replace C 2-C 4thiazolinyl, do not replace replace aryl or do not replace replace heterocyclic group in one, wherein, above-mentioned do not replace replace C 1-C 4alkyl is preferably methyl, ethyl, propyl group, sec.-propyl or the tertiary butyl, above-mentioned do not replace the aryl that replaces comprise the compound of single or multiple rings, also comprise and contain polynuclear compound independent or aryl that merge, preferred aryl contains 6 to about 10 carboatomic ring atoms, particularly preferred aryl comprise do not replace replace phenyl, do not replace replace naphthyl, above-mentioned do not replace replace heterocyclic group comprise contain 1 to 3 independence or merge ring and from 5 fragrant heterocyclic radicals to about 10 annular atomses, preferred fragrant heterocyclic radical contains one, two or three are selected from N, the heteroatoms of O or S, for example comprise: furyl, imidazolyl, thiazolyl, isothiazolyl, quinolyl (comprising isoquinolyl), pyridyl, thienyl, pyrryl, indyl, triazolyl, benzimidazolyl-, benzofuryl, benzothienyl, benzothiazolyl.
Further preferred, described R yfor hydrogen or do not replace replace C 1-C 3one in alkyl, is preferably hydrogen, methyl, ethyl or propyl group, more preferably hydrogen.
In a preferred embodiment of the invention, be-CH-of described Z and W, described Y is-O-,-NH-or-NR y.
In a preferred embodiment of the invention, described Z is-CH-that described W is-N-that described Y is-O-.
In a preferred embodiment of the invention, be-N-of described Z and W, Y is-O-or-CH 2-.
Further illustrate, above-mentioned mention do not replace replace alkyl, thiazolinyl or cycloalkyl can be replaced by one or more following groups substituted position at it: halogen, alkoxyl group, amino;
Further illustrate, the above-mentioned aryl of mentioning or heterocyclic group can be replaced by one or more following groups substituted position at it: halogen, alkyl, haloalkyl, alkyl oxy, cycloalkyl, cycloalkyl amino acyl group, arylalkyl, alkyl acyl, arylalkyl acyl group, heterocyclic radical acyl group.
Above-mentioned mention do not replace replace alkyl, thiazolinyl, cycloalkyl, aryl or heterocyclic group also can be replaced by one or more suitable group in one or more available positions, for example halogen, OR a,=O, SR a, SOR a, SO 2r a, NO 2, NHR a, NR ar b,=N-R a, NHCOR a, CN, COR a, OCOR a, COOR a, the C that does not replace or replace 1-C 3alkyl, the C that does not replace or replace 2-C 4thiazolinyl, do not replace or replace aryl, and do not replace or replace heterocyclic group, wherein each R 1and R 2group, independently selected from lower group, comprises hydrogen, halogen, OH, COH, NO 2, NH 2, SH, CN, CO 2h.
A preparation method for above-mentioned replacement two aryl oxide compounds, its reaction process is as follows:
Be specially: under the effect of alkali, make the substituted ethyl benzoate reacting generating compound (IV) shown in halogeno-benzene or substituted aniline and the compound (III) of the replacement shown in compound (II), compound (IV) be hydrolyzed or chloride after with replace amine and carry out condensation reaction and make compound (I), i.e. replacement two aryl oxide class chemical combination of the present invention.
In a preferred embodiment of the invention, described X is F, Cl, Br or I.
A kind of above-mentioned replacement two aryl oxide compounds are in the application of preparing in tumour medicine.
The invention has the beneficial effects as follows: the obviously malignant proliferation phenotype of anticancer of replacement two aryl oxide compounds of the present invention, promote the expression of apoptosis factor albumen, a kind of novel potential antitumor drug is provided.
Brief description of the drawings
Fig. 1 is that the compound 8 in embodiments of the invention 32 suppresses liver cancer cell HepG2 propagation and colony formation result, wherein A is that compound 8 suppresses liver cancer cell HepG2 proliferation experiment result, and B is clone's formational situation and the column analysis chart that compound 8 suppresses liver cancer cell HepG2 under different concns;
Fig. 2 is the Western blot experimental result of the expression of the induction liver cancer cell HepG2 antiapoptotic factors albumen of the compound 8 in embodiments of the invention 32, wherein A demonstration compound 8 is induced the time-effect of liver cancer cell HepG2 antiapoptotic factors protein expression, and B demonstration compound 8 is induced the dose-effect relationship of liver cancer cell HepG2 antiapoptotic factors protein expression;
Fig. 3 is that the compound 12 in embodiments of the invention 32 suppresses liver cancer cell HepG2 propagation and colony formation result, wherein A is that compound 12 suppresses liver cancer cell HepG2 proliferation experiment result, and B is clone's formational situation and the column analysis chart that compound 12 suppresses liver cancer cell HepG2 under different concns;
Fig. 4 is the Western blot experimental result of the expression of the induction liver cancer cell HepG2 antiapoptotic factors albumen of the compound 12 in embodiments of the invention 32, wherein A demonstration compound 12 is induced the time-effect of liver cancer cell HepG2 antiapoptotic factors protein expression, and B demonstration compound 12 is induced the dose-effect relationship of liver cancer cell HepG2 antiapoptotic factors protein expression.
Embodiment
By reference to the accompanying drawings technical scheme of the present invention is further detailed and is described by embodiment below.
The preparation method of replacement two aryl oxide compounds of the present invention, its reaction process is as follows:
Under the effect of alkali, make the substituted ethyl benzoate reacting generating compound (IV) shown in halogeno-benzene or substituted aniline and the compound (III) of the replacement shown in compound (II), compound (IV) be hydrolyzed or chloride after with replace amine and carry out condensation reaction and make compound (I), i.e. replacement two aryl oxide class chemical combination of the present invention.
Concrete comprises the steps:
(1) synthetic method of intermediate acid:
(2) target compound synthetic method, comprises two kinds of A and B, and wherein A is as follows:
B is as follows:
The synthesis mode of B1 to B6 in said process is shown in following examples 1 to 6., the following embodiment 7 to 31 of synthetic concrete part of compound 1 to 17 and compound 18 to 25.
Embodiment 1:4-(4-fluorophenoxy) benzoic synthetic (B1)
By fluoro-1-4-iodobenzene 1.0mL (8.9moL), P-hydroxybenzoic acid 1.85g (13.4moL), cuprous iodide 170mg (0.9mmoL), N; N-N-methylsarcosine 276mg (2.7mmoL) and cesium carbonate 5.81g (17.8moL) are dissolved in 25mL1; in 4-dioxane, the lower 90 DEG C of heated and stirred of argon shield 24 hours.React complete, remove solvent under reduced pressure, add water, ethyl acetate extraction 3 times, organic layer washs with saturated brine, anhydrous sodium sulfate drying.Except desolventizing, silica gel column chromatography separates (ethyl acetate: sherwood oil=1:30) and obtains yellow liquid.8mL ethanol and 8mL water dissolution for the fluoro-4-phenoxy benzoic acid of the 1-ethyl ester 1.0g (4.1moL) of synthesized, add sodium hydroxide 1.82g (4.5moL), reflux 3 hours.React complete, cooling, remove solvent under reduced pressure, add 50mL water, 2M hcl acidifying, dichloromethane extraction, organic layer washs with saturated brine, anhydrous magnesium sulfate drying.Except desolventizing, obtain white solid 1.53g, two-step reaction yield 76%.
1H?NMR(600MHz,DMSO-d 6)δ：7.00(d,J＝8.8Hz,2H),7.17(d,J＝4.4Hz,1H),7.18(d,J＝4.6Hz,1H),7.28(t,J＝8.6Hz,2H),7.94(d,J＝8.8Hz,2H),12.82(br?s,1H)ppm。
13C?NMR(150MHz,DMSO-d 6)δ:116.8,117.0,122.0,125.2,131.7,151.1,161.3,166.7ppm。
Synthetic (B2) of embodiment 2:4-phenoxy benzoic acid
The synthetic method of the same embodiment 1 obtains B2 white solid, two step yields 87%.
1H?NMR(600MHz,DMSO-d 6)δ：7.02(d,J＝8.8Hz,2H),7.11(d,J＝7.7Hz,2H),7.23(t,J＝7.3Hz,1H),7.45(t,J＝7.5Hz,2H),7.95(d,J＝8.8Hz,2H),12.82(br?s,1H)ppm；。
13C?NMR(150MHz,DMSO-d 6)δ:117.2,119.9,124.7,125.2,130.3,131.7,155.1,161.0,166.8ppm。
Embodiment 3:4-(4-chlorophenoxy) benzoic synthetic (B3)
The synthetic method of the same embodiment 1 obtains B3 white solid, two step yields 80%.
1H?NMR(600MHz,DMSO-d 6)δ：7.05(d,J＝8.6Hz,2H),7.14(d,J＝8.8Hz,2H),7.48(d,J＝9.0Hz,2H),7.96(d,J＝8.8Hz,2H),12.86(br?s,1H)ppm。
13C?NMR(150MHz,DMSO-d 6)δ:117.5,121.6,125.7,128.5,130.2,131.7,154.1,160.5,166.7ppm。
Embodiment 4:4-(4-bromine phenoxy group) benzoic synthetic (B4)
The synthetic method of the same embodiment 1 obtains B4 white solid, two step yields 53%.
1H?NMR(600MHz,DMSO-d 6)δ：7.06(d,J＝8.4Hz,2H),7.08(d,J＝8.3Hz,2H),7.61(d,J＝8.3Hz,2H),7.95(d,J＝9.0Hz,2H),12.86(br?s,1H)ppm。
13C?NMR(150MHz,DMSO-d 6)δ:116.4,117.6,122.0,125.7,131.7,133.1,154.7,160.4,166.7ppm。
Embodiment 5:4-(4-methoxyphenoxy) benzoic synthetic (B5)
The synthetic method of the same embodiment 1 obtains B5 white solid, two step yields 57%.
1H?NMR(600MHz,DMSO-d 6)δ:3.77(s,3H),6.95(d,J＝8.8Hz,2H),7.00(d,J＝9.0Hz,2H),7.08(d,J＝9.0Hz,2H),7.92(d,J＝8.8Hz,2H),12.76(br?s,1H)ppm。
13C?NMR(150MHz,DMSO-d 6)δ:55.4,115.3,116.2,121.7,124.6,131.6,148.0,156.3,162.1,166.8ppm。
Embodiment 6:4-(4-nitrophenoxy) benzoic synthetic (B6)
The synthetic method of the same embodiment 1 obtains B6 yellow solid, two step yields 49%.
1H?NMR(600MHz,DMSO-d 6)δ：7.23-7.25(m,4H),8.03(d,J＝8.6Hz,?2H),8.28(d,J＝9.2Hz,2H),12.99(br?s,1H)ppm。
13C?NMR(150MHz,DMSO-d 6)δ:118.7,119.6,126.3,127.4,131.9,143.0,158.4,161.5,166.6ppm。
Embodiment 7: compound 1 synthetic
In the round-bottomed flask of 10mL, add N, N-dimethyl-ethylenediamine (44.1mg, 0.5mmol), the new methylene dichloride steaming of 4-phenoxy benzoic acid (107.1mg, 0.5mmol) and 3mL.Add subsequently N-hydroxy benzo triazole (HOBt) (81.7mg, 0.6mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (115.0mg, 0.6mmol and N-methylmorpholine (NMM) (151.7mg, 1.5mmol).After ice bath 30min, remove ice bath.Stirred overnight at room temperature, TCL detection reaction is complete.Reaction solution water/dichloromethane extraction, merge organic phase, organic phase is used 10% hydrochloric acid soln (× 3) successively, 5% sodium hydrogen carbonate solution (× 1), water (× 1), saturated nacl aqueous solution washing, anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure obtains crude product.Crude product separates (methyl alcohol: methylene dichloride=1:20) with silicagel column, obtains yellow oil, yield 97%.
1H?NMR(400MHz,CDCl 3)δ:2.31(s,6H),2.57(t,J＝5.8Hz,2H),3.54(q,J＝5.0Hz,2H),6.95(br?s,1H),7.01(d,J＝8.8Hz,2H),7.06(d,J＝7.8Hz,2H),7.17(t,J＝7.5Hz,1H),7.38(t,J＝8.5Hz,2H),7.80(d,J＝8.8Hz,2H)ppm。
HRMS (ESI, m/z) calculated value C 17h 21n 2o 2[M+H] +285.1603; Measured value 285.1598.
Embodiment 8: compound 2 synthetic
The synthetic method of the same embodiment 7 obtains compound 2 and obtains yellow oil, yield 88%.
1H?NMR(400MHz,CDCl 3)δ:1.10(t,J＝7.3Hz,6H),2.68(q,J＝7.3Hz,4H),2.76(t,J＝5.8Hz,2H),3.55(q,J＝5.3Hz,2H),4.89(br?s,1H),6.98(d,J＝8.8Hz,2H),7.04(d,J＝8.5Hz,2H),7.16(t,J＝7.5Hz,1H),7.37(t,J＝7.5Hz,3H),7.80(d,J＝8.8Hz,2H)ppm。
13C?NMR(150MHz,CDCl 3)δ：11.1,36.8,46.8,51.5,117.6,119.7,124.1,128.8,129.8,155.9,160.2,166.7ppm。
HRMS (ESI, m/z) calculated value C 19h 25n 2o 2[M+H] +313.1916; Measured value 313.1911.
Embodiment 9: compound 3 synthetic
The synthetic method of the same embodiment 7 obtains compound 3 and obtains white solid, yield 87%.
1H?NMR(400MHz,CDCl 3)δ:2.49(t,J＝4.5Hz,4H),2.59(t,J＝6.0Hz,2H),3.53(q,J＝5.5Hz,2H),3.71(t,J＝4.8Hz,4H),6.70(br?s?1H),7.00(d,J＝8.0Hz,2H),7.04(d,J＝7.5Hz,2H),7.16(t,J＝7.5Hz,1H),7.37(t,J＝7.3Hz,2H),7.74(d,J＝8.8Hz,2H)ppm。
13C?NMR(150Hz,CDCl 3)δ:36.0,53.3,56.9,66.9,117.7,119.7,124.2,128.7,128.9,129.9,155.9,160.3,166.6ppm。
HRMS (ESI, m/z) calculated value C 19h 23n 2o 3[M+H] +327.1709, measured value 327.1703.
Embodiment 10: compound 4 synthetic
The synthetic method of the same embodiment 7 obtains compound 4 and obtains white solid, yield 87%.
1H?NMR(400MHz,CDCl 3)δ:1.70–1.79(m,2H),1.92–2.02(m,2H),2.37-2.45(m,2H),4.57(m,1H),6.47(br?s,1H),6.97(d,J＝8.8Hz,2H),7.03(d,J＝7.5Hz,2H),7.16(t,J＝7.3Hz,1H),7.37(t,J＝7.5Hz,2H),7.75(d,J＝8.8Hz,2H)ppm。
13C?NMR(150MHz,CDCl 3)δ:15.1,31.1,45.1,117.6,119.6,124.1,128.8,129.0,129.9,155.9,160.2,165.9ppm。
HRMS (ESI, m/z) calculated value C 17h 18nO 2[M+H] +268.1338, measured value 268.1332, [M+Na] +290.1146, found290.1151.
Embodiment 11: compound 5 synthetic
The synthetic method of the same embodiment 7 obtains compound 5 and obtains white solid, yield 90%.
1H?NMR(400MHz,CDCl 3)δ:1.43–1.53(m,2H),1.59-1.76(m,4H),2.04-2.11(m,2H),4.37(m,1H),6.18(br?s,1H),6.98(d,J＝8.8Hz,2H),7.03(d,J＝7.8Hz,2H),7.16(t,J＝7.5Hz,1H),7.37(t,J＝7.5Hz,2H),?7.73(d,J＝8.8Hz,2H)ppm。
13C?NMR(150MHz,CDCl 3)δ:23.7,34.0,51.6,117.7,119.5,124.0,128.7,129.3,129.8,156.0,160.0,166.5ppm。
HRMS (ESI, m/z) calculated value C 18h 20nO 2[M+H] +282.1494, measured value 282.1489, [M+Na] +304.1303, measured value 304.1308.
Embodiment 12: compound 6 synthetic
The synthetic method of the same embodiment 7 obtains compound 6 and obtains white solid, yield 89%.
1H?NMR(400MHz,CDCl 3)δ:0.84-0.91(m,2H),1.38-1.49(m,2H),1.64-1.79(m,4H),2.01-2.05(m,2H),3.97(m,1H),5.96(br?d,1H),7.00(d,J＝8.0Hz,2H),7.04(d,J＝7.5Hz,2H),7.17(t,J＝7.3Hz,2H),7.38(t,J＝7.5Hz,2H),7.74(d,J＝8.8Hz,2H)ppm。
13C?NMR(150MHz,CDCl 3)δ:24.9,25.5,33.1,48.6,117.7,119.5,124.0,128.7,129.5,129.8,156.0,160.0,165.9ppm。
HRMS (ESI, m/z) calculated value C 19h 22nO 2[M+H] +296.1651, measured value 296.1645, [M+Na] +318.1460, measured value 318.1465.
Embodiment 13: compound 7 synthetic
The synthetic method of the same embodiment 7 obtains compound 7 and obtains white solid, yield 90%.
1H?NMR(400MHz,CDCl 3)δ:7.08(t,J＝8.8Hz,4H),7.16(t,J＝7.3Hz,1H),7.19(t,J＝7.3Hz,1H),7.40(q,J＝7.3Hz,4H),7.63(d,J＝7.5Hz,2H),7.77(br?s,1H),7.86(d,J＝9.0Hz,2H)。
13C?NMR(150MHz,CDCl 3)δ:117.3,119.5,120.6,120.7,124.1,124.2,128.5,128.8,129.1,129.2,129.7,155.5,160.5ppm。
HRMS (ESI, m/z) calculated value C 19h 16nO 2[M+H] +290.1181, measured value 290.1176, [M+Na] +312.0990, measured value 312.0995.
Embodiment 14: compound 8 synthetic
The synthetic method of the same embodiment 7 obtains compound 8 and obtains white solid, yield 47%.
1H?NMR(600MHz,DMSO-d 6)δ:7.10(t,J＝7.0Hz,4H),7.18(t,J＝8.9Hz,2H),7.22(t,J＝7.4Hz,1H),7.44(t,J＝7.5Hz,2H),7.81(q,J＝7.8Hz,2H),8.00(d,J＝8.6Hz,2H),10.25(s,1H)ppm。
13C?NMR(150MHz,DMSO-d 6)δ:115.5,115.7,117.9,120.0,122.6,122.7,124.8,129.8,130.4,130.7,156.0,160.3,165.1ppm。
HRMS (ESI, m/z) calculated value C 19h 15fNO 2[M+H] +308.1087, measured value 308.1081, [M+Na] +330.0896, measured value 330.0901.
Embodiment 15: compound 9 synthetic
The synthetic method of the same embodiment 7 obtains compound 9 and obtains white solid, yield 50%.
1H?NMR(600MHz,DMSO-d 6)δ:6.73(d,J＝8.6Hz,2H),7.07(d,J＝8.9Hz,2H),7.10(d,J＝8.6Hz,2H),7.22(t,J＝7.3Hz,1H),7.45(t,J＝7.6Hz,2H),7.50(d,J＝8.6Hz,2H),7.96(d,J＝8.9Hz,2H),9.92(s,1H),9.95(s,1H)ppm。
13C?NMR(150MHz,DMSO-d 6)δ:115.0,117.4,119.5,122.3,124.3,129.7,129.8,130.2,130.7,153.7,155.7,159.5,164.2ppm。
HRMS (ESI, m/z) calculated value C 19h 16nO 3[M+H] +306.1130, measured value 306.1125, [M+Na] +328.0938, measured value 328.0944.
Embodiment 16: compound 10 synthetic
The synthetic method of the same embodiment 7 obtains compound 10 and obtains white solid, yield 91%.
1H?NMR(400MHz,CDCl 3)δ:1.87-1.93(m,2H),1.96(m,1H),2.15(m,1H),2.77-2.91(m,2H),5.40(q,J＝5.3Hz,1H),6.34(br?s,1H),7.01(d,J＝8.8Hz,2H),7.05(d,J＝8.5Hz,2H),7.14-7.21(m,4H),7.37(q,J＝8.5Hz,3H),7.77(d,J＝9.0Hz,2H)ppm。
13C?NMR(150MHz,CDCl 3)δ:20.1,29.2,30.2,47.9,117.8,119.6,124.1,126.3,127.3,128.7,128.8,129.0,129.2,129.9,136.7,137.7,156.0,160.3,166.0ppm。
HRMS (ESI, m/z) calculated value C 23h 22nO 2[M+H] +344.1651, measured value 344.1645, [M+Na] +366.1459, measured value 366.1465.
Embodiment 17: compound 11 synthetic
The synthetic method of the same embodiment 7 obtains compound 11 and obtains white solid, yield 90%.
1H?NMR(400MHz,CDCl 3)δ:1.87-1.93(m,2H),1.96(m,1H),2.15(m,1H),2.77-2.91(m,2H),5.40(q,J＝5.3Hz,1H),6.30(br?s,1H),7.01(d,J＝8.8Hz,2H),7.05(d,J＝8.5Hz,2H),7.14-7.21(m,4H),7.37(q,J＝8.3Hz,3H),7.77(d,J＝8.8Hz,2H)ppm。
13C?NMR(150MHz,CDCl 3)δ:20.1,29.2,30.1,47.9,117.7,119.5,124.1,126.2,127.2,128.5,128.9,129.1,129.8,136.7,136.7,137.5,155.9,160.2,166.0ppm。
HRMS (ESI, m/z) calculated value C 23h 22nO 2[M+H] +344.1651, measured value 344.1645, [M+Na] +366.1455, measured value 366.1465.
Embodiment 18: compound 12 synthetic
The synthetic method of the same embodiment 7 obtains compound 12 and obtains white solid, yield 89%.
1H?NMR(400MHz,CDCl 3)δ:1.87-1.93(m,2H),1.96(m,1H),2.15(m,1H),2.77-2.91(m,2H),5.40(q,J＝5.3Hz,1H),6.29(br?s,1H),7.01(d,J＝?8.8Hz,2H),7.05(d,J＝8.5Hz,2H),7.14-7.21(m,4H),7.37(q,J＝8.3Hz,3H),7.77(d,J＝8.8Hz,2H)ppm。
13C?NMR(150MHz,CDCl 3)δ:20.1,29.2,30.2,47.9,117.8,119.6,124.1,126.3,127.3,128.7,128.8,129.0,129.2,129.9,136.7,137.6,156.0,160.3,166.0ppm。
HRMS (ESI, m/z) calculated value C 23h 22nO 2[M+H] +344.1651, measured value 344.1645, [M+Na] +366.1454, measured value 366.1465.
Embodiment 19: compound 13 synthetic
The synthetic method of the same embodiment 7 obtains compound 13 and obtains white solid, yield 30%.
1H?NMR(600MHz,CDCl 3)δ:1.88-1.92(m,2H),1.94(m,1H),2.15(m,1H),2.78-2.88(m,2H),5.38(q,J＝5.9Hz,1H),6.41(d,J＝8.1Hz,1H),6.96(d,J＝8.6Hz,2H),7.01(d,J＝4.4Hz,1H),7.02(d,J＝4.4Hz,1H),7.07(t,J＝8.3Hz,2H),7.13(d,J＝7.3Hz,1H),7.12-7.22(m,2H),7.33(d,J＝7.3Hz,1H)7.76(d,J＝8.8Hz,2H)ppm。
13C?NMR(150MHz,CDCl 3)δ:20.1,29.2,30.2,47.9,116.4,116.6,117.3,121.2,121.3,126.3,127.3,128.7,128.9,129.2,136.6,137.7,151.7,160.6,165.9ppm。
HRMS (ESI, m/z) calculated value C 23h 21fNO 2[M+H] +362.1556, measured value 362.1552, [M+Na] +384.1369, measured value 384.1370.
Embodiment 20: compound 14 synthetic
The synthetic method of the same embodiment 7 obtains compound 14 and obtains white solid, yield 35%.
1H?NMR(600MHz,CDCl 3)δ:1.87-1.92(m,2H),1.94(m,1H),2.14(m,1H),2.78-2.88(m,2H),5.38(q,J＝5.9Hz,1H),6.44(br?s,1H),6.98(d,J＝8.4Hz,4H),7.14(d,J＝7.3Hz,1H),7.12-7.22(m,2H),7.33(d,J＝8.8Hz,3H)7.78(d,J＝8.8Hz,2H)ppm。
13C?NMR(150MHz,CDCl 3)δ:20.1,29.2,30.2,47.9,117.9,120.8,126.3,127.3,128.6,128.9,129.2,129.5,129.9,136.6,137.6,154.6,159.8,165.8ppm。
HRMS (ESI, m/z) calculated value C 23h 21clNO 2[M+H] +378.1261, measured value 378.1255, [M+Na] +400.1080, measured value 400.1075.
Embodiment 21: compound 15 synthetic
The synthetic method of the same embodiment 7 obtains compound 15 and obtains white solid, yield 23%.
1H?NMR(600MHz,CDCl 3)δ:1.88-1.93(m,2H),1.95(m,1H),2.14(m,1H),2.78-2.88(m,2H),5.38(q,J＝5.9Hz,1H),6.42(br?s,1H),6.92(d,J＝8.6Hz,2H),6.99(d,J＝8.4Hz,2H),7.13(d,J＝7.2Hz,1H),7.17-7.22(m,2H),7.34(d,J＝7.3Hz,1H),7.47(d,J＝8.6Hz,2H),7.78(d,J＝8.8Hz,2H)ppm。
13C?NMR(150MHz,CDCl 3)δ:20.0,29.2,30.2,47.9,116.7,118.0,121.2,?126.3,127.3,128.7,128.9,129.2,129.5,132.8,136.6,137.6,155.3,159.7,165.8ppm。
HRMS (ESI, m/z) calculated value C 23h 21brNO 2[M+H] +422.0756, measured value 422.0750, [M+Na] +444.0571, measured value 444.0570.
Embodiment 22: compound 16 synthetic
The synthetic method of the same embodiment 7 obtains compound 16 and obtains white solid, yield 29%.
1H?NMR(600MHz，CDCl 3)δ:1.88-1.93(m,2H),1.95(m,1H),2.13-2.17(m,1H),2.78-2.88(m,2H),5.39(q,J＝6.1Hz,1H),6.50(br?s,1H),7.05(d,J＝9.2Hz,2H),7.12(t,J＝8.8Hz,3H),7.17-7.21(m,2H),7.34(d,J＝8.3Hz,1H),7.87(d,J＝8.8Hz,2H),8.21(d,J＝9.2Hz,2H)ppm。
13c NMR (150MHz, CDCl 3) δ: 20.0,29.2,30.1,48.0,117.8,119.9,150.9,126.3,127.3,128.6,129.2,129.3,131.4,136.4,137.6,143.1,157.5,162.2,165.6ppm HRMS (ESI, m/z) calculated value C 23h 21n 2o 4[M+H] +389.1501, measured value 389.1496, [M+Na] +411.1321, measured value 411.1315.
Embodiment 23: compound 17 synthetic
The synthetic method of the same embodiment 7 obtains compound 17 and obtains white solid, yield 29%.
1H?NMR(600MHz，CDCl 3)δ:1.87-1.91(m,2H),1.93(m,1H),2.13-2.16?(m,1H),2.78-2.86(m,2H),3.82(s,3H),5.38(q,J＝5.9Hz,1H),6.40(br?s,1H),6.92(t,J＝9.2Hz,4H),7.00(d,J＝9.2Hz,2H),7.13(d,J＝7.2Hz,1H),7.16-7.21(m,2H),7.34(d,J＝7.2Hz,1H),7.74(d,J＝9.0Hz,2H)ppm。
13C?NMR(150MHz,CDCl 3)δ:20.1,29.2,30.2,47.8,114.9,116.7,121.2,126.3,127.2,128.3,128.7,128.8,129.2,136.7,137.6,148.9,156.4,161.4,166.0ppm。
HRMS (ESI, m/z) calculated value C 24h 24nO 3[M+H] +374.1756, measured value 374.1751, [M+Na] +396.1576, measured value 396.1570.
Embodiment 24: compound 18 synthetic
4-phenoxy benzoic acid (107.1mg will be added in the round-bottomed flask of 10mL; 0.5mmol) and the ethyl acetate solution of 3mL; under 0 DEG C of argon shield; drip two N; N-dimethyl methyl methane amide (DMF); slowly drip subsequently sulfur oxychloride (71.4mg, 0.6mmol).At 0 DEG C continue stir 1 hour, after change back stream 4 hours, removal of solvent under reduced pressure, stand-by.
Add successively cyclopropylamine (28.6mg, 34.7 μ L, 0.5mmol), triethylamine (151.8mg, 1.5mmol) and anhydrous methylene chloride by adding in the round-bottomed flask of 10mL, slowly drip the acyl chlorides dichloromethane solution of preparing above.Stirring at room temperature 2 hours, complete by TLC detection reaction.Reaction solution water/dichloromethane extraction, merge organic phase, organic phase is used 10% hydrochloric acid soln (× 3) successively, 5% sodium hydrogen carbonate solution (× 1), water (× 1), saturated nacl aqueous solution washing, anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure obtains crude product.Crude product separates (ethyl acetate: sherwood oil=1:10) with silicagel column, obtains white solid, yield 85%.
1H?NMR(600MHz,CDCl 3)δ:0.60-0.63(m,2H),0.80-0.83(m,2H),2.87(m,1H),6.68(br?s,1H),6.94(d,J＝8.9Hz,2H),7.01(d,J＝7.9Hz,2H),7.15(t,J＝7.3Hz,1H),7.35(t,J＝8.6Hz,2H),7.74(d,J＝8.6Hz,2H)ppm。
13C?NMR(150MHz,CDCl 3)δ:6.5,23.1,117.6,119.6,124.1,128.8,128.8,129.9,155.9,160.2,168.3ppm。
HRMS (ESI, m/z) calculated value C 16h 16nO 2[M+H] +254.1181, measured value 254.1176; [M+Na] +276.0987, measured value 276.0995.
Embodiment 25: compound 19 synthetic
The synthetic method of the same embodiment 24 obtains compound 19 and obtains yellow solid, two step yields 48%.
1H?NMR(600MHz,CDCl 3)δ:6.89-6.96(m,2H),7.08(t,J＝7.5Hz,4H),7.21(t,J＝7.5Hz,1H),7.41(t,J＝8.0Hz,2H),7.87(d,J＝8.8Hz,3H),8.40(td,J＝9.2Hz,1H)ppm。
13C?NMR(150MHz,CDCl 3)δ:102.4,102.6,102.7,110.2,110.3,110.4,116.8,119.0,123.5,127.4,128.1,129.0,154.6,160.2,163.8ppm。
HRMS (ESI, m/z) calculated value C 19h 14f 2nO 2[M+H] +326.0993, measured value 326.0987, [M+Na] +348.0805, measured value 348.0807.
Embodiment 26: compound 20 synthetic
The synthetic method of the same embodiment 24 obtains compound 20 and obtains yellow solid, two step yields 48%.
1H?NMR(600MHz,DMSO-d 6)δ:7.12(d,J＝8.9Hz,2H),7.13(d,J＝8.6Hz,2H),7.24(t,J＝7.5Hz,1H),7.46(t,J＝8.1Hz,2H),7.54(t,J＝9.2Hz,1H),8.00(d,J＝8.8Hz,2H),8.07(t,J＝7.7Hz,1H),8.28(dd,J＝5.9,2.8Hz,1H)ppm。
13C?NMR(150MHz,DMSO-d 6)δ:100.3,114.5,117.4,117.9,120.1,124.6,124.9,128.1,129.1,130.5,130.8,136.8,155.9,157.9,160.6,165.5ppm。
HRMS (ESI, m/z) calculated value C 20h 14fN 2o 2[M+H] +333.1039, measured value 333.1034, [M+Na] +355.0849, measured value 355.0853.
Embodiment 27: compound 21 synthetic
The synthetic method of the same embodiment 24 obtains compound 21 and obtains yellow solid, two step yields 48%.
1H?NMR(600MHz,CDCl 3)δ:7.05(d,J＝8.9Hz,2H),7.08(d,J＝7.6Hz,2H),7.22(t,J＝7.3Hz,1H),7.37(dd,J＝7.3Hz,2H),7.41(t,J＝7.6Hz,2H),7.79(br?s,1H),7.82(d,J＝8.9Hz,2H)ppm。
13C?NMR(150MHz,CDCl 3)δ:104.1,104.3,117.5,119.8,124.5,128.8,129.7,130.2,155.9,160.9,165.1ppm。
HRMS (ESI, m/z) calculated value C 19h 13f 3nO 2[M+H] +344.0898, measured value 344.0893, [M+Na] +366.0708, measured value 366.0712.
Embodiment 28: compound 22 synthetic
The synthetic method of the same embodiment 24 obtains compound 22 and obtains yellow solid, two step yields 15%.
1H?NMR(600MHz,CDCl 3)δ:7.05(d,J＝8.9Hz,2H),7.08(d,J＝7.6Hz,2H),7.22(t,J＝7.3Hz,1H),7.42(t,J＝7.6Hz,4H),7.84(d,J＝8.6Hz,2H),8.06(br?s,1H)ppm。
13C?NMR(150MHz,CDCl 3)δ:102.8,116.7,119.1,123.7,126.9,128.1,129.1,137.8,154.5,158.2,159.7,160.5,164.1ppm。
HRMS (ESI, m/z) calculated value C 19h 13f 2brNO 2[M+H] +404.0098, measured value 404.0092, [M+Na] +425.9912, measured value 425.9912.
Embodiment 29: compound 23 synthetic
The synthetic method of the same embodiment 24 obtains compound 22 and obtains yellow solid, two step yields 10%.
1H?NMR(400MHz,CDCl 3)δ:7.02(m,1H),7.08(t,J＝8.8Hz,4H),7.22(t,J＝7.5Hz,1H),7.42(t,J＝7.5Hz,2H),7.85(d,J＝9.0Hz,2H),7.19(br?s,1H),8,46(m,1H)ppm。
13C?NMR(150MHz,CDCl 3)δ:104.1,104.3,117.5,119.8,124.5,128.8,?129.7,130.2,155.9,161.0,165.1ppm。
HRMS (ESI, m/z) calculated value C 19h 13f 3nO 2[M+H] +344.0898, measured value 344.0893, [M+Na] +366.0708, measured value 366.0712.
Embodiment 30: compound 24 synthetic
The synthetic method of the same embodiment 24 obtains compound 24 and obtains yellow solid, two step yields 58%.
1H?NMR(600MHz,CDCl 3)δ:1.61-1.65(m,2H),1.68-1.72(m,2H),2.52(t,J＝6.3Hz,2H),2.66(t,J＝6.1Hz,2H),6.81(d,J＝7.5Hz,1H),6.89(d,J＝8.8Hz,2H),6.95(d,J＝7.7Hz,2H),6.99(t,J＝7.8Hz,2H),7.27(t,J＝8.0Hz,2H),7.56(d,J＝7.8Hz,1H),7.63(br?s,1H),7.71(d,J＝8.6Hz,2H)ppm。
13C?NMR(150MHz,CDCl 3)δ:22.5,22.8,24.5,29.7,117.8,119.8,120.8,124.3,125.7,126.4,128.8,128.9,129.3,129.9,135.4,138.0,155.8,160.6,165.0ppm。
HRMS (ESI, m/z) calculated value C 23h 22nO 2[M+H] +344.1651, measured value 344.1645, [M+Na] +366.1460, measured value 366.1465.
Embodiment 31: compound 25 synthetic
The synthetic method of the same embodiment 24 obtains compound 25 and obtains yellow solid, two step yields 41%.
1H?NMR(600MHz,CDCl 3)δ:7.12(d,J＝8.6Hz,4H),7.22(t,J＝7.6Hz,1H),7.42(t,J＝6.3Hz,2H),7.53-7.77(m,3H),7.76(d,J＝8.3Hz,1H),7.90(d,J＝8.3Hz,2H),7.98(d,J＝8.3Hz,2H),8.04(br?s,1H),8.15(s,1H)ppm。
13C?NMR(150MHz,CDCl 3)δ:117.9,119.9,120.9,121.5,124.4,125.8,126.1,126.2,126.4,127.7,128.8,129.0,129.3,130.1,132.5,134.2,155.9,160.9ppm。
HRMS (ESI, m/z) calculated value C 23h 18nO 2[M+H] +340.1338, measured value 340.1332, [M+Na] +362.1142, measured value 362.1151.
Embodiment 32: the biological assay that anti-tumor activity detects
The object of this mensuration is that the cell in vitro of assessing testing sample suppresses active (postponing or stop the ability of growth of tumour cell) or cytotoxic activity (killing the ability of tumour cell).The related cell strain of the present embodiment is as shown in table 1 below:
Table 1 cell strain
Title N°ATCC Species Tissue Character
HepG2 HB-8065 The mankind Liver Liver cancer
A549 CCL-185 The mankind Lung Lung cancer
HT-29 HTB-38 The mankind Colon Colorectal carcinoma
Hep3B HB-8064 The mankind Liver Liver cancer
PLC/PRF/5 CRL-8024 The mankind Liver Liver cancer
HeLa CCL-2 The mankind Uterine cervix Cervical cancer
[0235]?
A375 CRL-1619 The mankind Skin Skin carcinoma
Use MTT colorimetric estimation assessment cytotoxic activity:
Tetrazolium bromide (MTT) colorimetry is current a kind of most widely used method that detects cell survival and growth, make exogenous MTT be reduced to insoluble blue colored crystal first a ceremonial jade-ladle, used in libation (Formazan) by the succinodehydrogenase in plastosome, indirect reaction viable cell quantity.In this research, use and obtain by Shanghai American type culture collection warehousing (ATCC) from all cells strain of dissimilar human tumor.
Synthetic compound is configured to respectively to the solution of concentration 100mmol/L with 100%DMSO solution, then by its successively with ten times be diluted to 10,1, the liquid of 0.1mmol/L, be placed in-20 DEG C of refrigerators and store.
Take out human liver cancer cell HepG2 cell cryopreservation tube from-80 DEG C of refrigerators, in 37 DEG C of water-baths, thaw rapidly.After taking-up enchylema is centrifugal, abandoning supernatant, adds substratum that cell precipitation piping and druming is mixed, and adds in the 10mm culture dish that substratum is housed, shake up, and 37 DEG C, 5%CO 2, under saturated humidity condition, cultivate.Change liquid next day, discard substratum, with PBS washing 2 times, rejoin new culture medium culturing.
When Growth of Cells is to the 60-80% of culture dish, and in logarithmic growth week after date, cell dissociation is got off to make cell suspension.HepG2 (or A549, HT-29 etc.) cell suspension is evenly inoculated in respectively on 96 orifice plates, and 100 μ L are inoculated in every hole, i.e. 1000 cells/well.After cell overnight incubation, the medicine of different concns is diluted respectively to 1000 times with substratum, obtaining concentration unit is the pastille substratum of 0.1,1,10,100 μ mol/L, adds in 96 orifice plates.Every hole adds 100 μ L pastille substratum, and each concentration is established 8 secondary Kong Weiyi groups, separately establishes one group and adds 0.1%DMSO substratum as control group.Within every 24 hours, change dressings once, successive administration 72 hours.After 72 hours, every hole adds containing MTT substratum (MTT solution and substratum ratio are 1:4) 75 μ L, and lucifuge is hatched 4 hours, discards the substratum containing MTT, every hole adds 100%DMSO solution 120 μ L, separately establishes the acellular DMSO solution that directly adds of blank group.After fully vibration mixes, in microplate reader, measure the absorbancy OD value in every hole in 492nm place (absorbing wavelength).Inhibitory rate of cell growth is calculated according to following formula:
Use GraphPad Prism5.0 software to carry out linear analysis according to inhibiting rate corresponding to each drug level, obtain linear equation, when calculating inhibiting rate is 50%, corresponding drug level (unit is μ mol/L), is the 503nhibiting concentration (IC of testing sample to tumour cell 50value).IC is got in the experiment of each medicine in triplicate 50mean value.Concrete outcome is as shown in following table 2 and table 3:
Table 2 compound of the present invention is to HepG2, the biologically active data of A549 and HT-29 cell
Table 3 compound 8 of the present invention and the biologically active data of compound 12 to other different cell strains
The experimental group of getting compound 8 and 12 is carried out respectively the western blot analysis of different pharmaceutical concentration, the time-effect and the dose-effect relationship that promote the antiapoptotic factors protein expressions such as p21, p53 and Cl-caspase3 to observe it, its result in conjunction with MT reconnaissance T colorimetric estimation result as shown in Figures 1 to 4, result shows, the obviously malignant proliferation phenotype of anticancer of replacement two aryl oxide compounds of the present invention, and promote the expression of the antiapoptotic factors albumen such as p21, p53 and Cl-caspase3.
The above, be only preferred embodiment of the present invention, therefore can not limit according to this scope of the invention process, the equivalence done according to the scope of the claims of the present invention and description changes and modifies, and all should still belong in the scope that the present invention contains.

Claims (10)

1. replace two aryl oxide compounds, it is characterized in that: its structure is as follows:
Z is-CH-or-N-;
W is-CH-or-N-;
Y is-O-,-CH 2-,-NH-or-NR y-;
R 1for hydrogen, halogen, NO 2, CN, CF 3, OR a, COR a, COOR a, SO 2r a, SO 2nR ar b, NR ar b, NR acOR b, do not replace replace C 1-C 4alkyl, do not replace replace aryl or do not replace replace heterocyclic group in one;
R 2for hydrogen, do not replace replace C 1-C 4alkyl or halogen;
R be do not replace replace C 1-C 12alkyl, do not replace replace C 3-C 12cycloalkyl, do not replace replace C 2-C 12thiazolinyl, do not replace replace aryl, substituted alkylamine or do not replace replace heterocyclic group in one.
2. a kind of two aryl oxide compounds that replace as claimed in claim 1, is characterized in that: described R afor hydrogen, do not replace replace C 1-C 4alkyl, do not replace replace C 2-C 4thiazolinyl, do not replace replace aryl or do not replace replace heterocyclic group in one.
3. a kind of two aryl oxide compounds that replace as claimed in claim 2, is characterized in that: described R bfor hydrogen, do not replace replace C 1-C 4alkyl, do not replace replace C 2-C 4thiazolinyl, do not replace replace aryl or do not replace replace heterocyclic group in one.
4. a kind of two aryl oxide compounds that replace as claimed in claim 3, is characterized in that: described R yfor hydrogen and do not replace replace C 1-C 3one in alkyl.
5. the one as described in arbitrary claim in claim 1 to 4 replaces two aryl oxide compounds, it is characterized in that: be-CH-of described Z and W, described Y is-O-,-NH-or-NR y.
6. the one as described in arbitrary claim in claim 1 to 4 replaces two aryl oxide compounds, it is characterized in that: described Z is-CH-that described W is-N-that described Y is-O-.
7. the one as described in arbitrary claim in claim 1 to 4 replaces two aryl oxide compounds, it is characterized in that: be-N-of described Z and W, Y is-O-or-CH 2-.
8. a preparation method for the replacement two aryl oxide compounds described in arbitrary claim in claim 1 to 7, is characterized in that: its reaction process is as follows:
Be specially: under the effect of alkali, make the substituted ethyl benzoate reacting generating compound (IV) shown in halogeno-benzene or substituted aniline and the compound (III) of the replacement shown in compound (II), compound (IV) be hydrolyzed or chloride after with replace amine and carry out condensation reaction and make compound (I), i.e. replacement two aryl oxide class chemical combination of the present invention.
9. the preparation method of replacement two aryl oxide compounds as claimed in claim 8, is characterized in that: described X is F, Cl, Br or I.
In a claim 1 to 9 the replacement two aryl oxide compounds described in arbitrary claim in the application of preparing in tumour medicine.
CN201410232271.XA 2014-05-28 2014-05-28 Substituted diaryl ester compound, and preparation method and application thereof Pending CN104163772A (en)

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