CN105085506B - The medical usage of 2 [epoxide of 4 (benzoxazoles 2) phenoxy group] fatty acyl pyridine amine - Google Patents
The medical usage of 2 [epoxide of 4 (benzoxazoles 2) phenoxy group] fatty acyl pyridine amine Download PDFInfo
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- CN105085506B CN105085506B CN201410208125.3A CN201410208125A CN105085506B CN 105085506 B CN105085506 B CN 105085506B CN 201410208125 A CN201410208125 A CN 201410208125A CN 105085506 B CN105085506 B CN 105085506B
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- phenoxy group
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Abstract
The present invention relates to 2 shown in chemical constitution Formulas I or formula II [4 (epoxide of benzoxazole 2) phenoxy group] fatty acyl pyridine amine：R, R in formula1It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl；X1、X2、X4、X5、X6、X7、X8、X10It is selected from：Hydrogen, deuterium or C1~C2Alkyl；X3It is selected from：Fluorine, chlorine, bromine；X3It is selected from：Nitro；X9It is selected from：Fluorine, chlorine, bromine；2 [epoxide of 4 (benzoxazoles 2) phenoxy group] application of the fatty acyl pyridine amine in cancer therapy drug is prepared.
Description
Technical field
The present invention relates to a kind of compound and its new application, and specifically 2- [4- (benzoxazole -2- epoxides) phenoxy group] fat
Application of the fat acyl pyridine amine in cancer therapy drug is prepared.
Background technology
4- aryloxyphenoxies acid derivative is with extensive bioactivity, wherein fragrant phenoxy propanoic derivatives are made
For its Typical Representative, existing more than the 20 individual commercial varieties in agricultural herbicide.4- aryloxyphenoxy acid derivatives simultaneously
Also have in the research of cancer therapy drug a large amount of reports [Investigational New Drugs, 1999,16:287–296；
Investigational New Drugs, 1998,16:129–139；Acta Pharmaceutica Sinica, 2005,40 (9):814-819], wherein
XK469 (2- (4- (7- chloroquinoxalin-2-yloxies base) phenoxy group) propionic acid) is that du pont company carries out the clinical research of I phase
A new type antineoplastic medicine, XK469 has very wide antitumor spectra, and Small side effects are effective to a variety of solid tumor models, such as colon
[J Med Chem, 2001,44 (11) such as cancer Colon38 and breast cancer:1758-76].The China of 2- phenoxy group alkane acid amides application
Patent of invention is as follows：(1) 2- [4- (benzoxazole -2- bases epoxide) phenoxy group] alkane acid amides and its application, CN103086995A,
It is 2013.5.8 open；(2) 2- (4- aryloxyphenoxies) alkane acid amides and its application, CN103086921A, 2013.5.8 are disclosed；
(3) 2- [4- (quinoxaline -2- bases epoxide) phenoxy group] alkane acid amides and its application, CN103086985A, 2013.5.8 are disclosed；(4)
Thick miscellaneous phenoxy carboxylic acyloxy aminated compounds of N- epoxides with bioactivity and preparation method thereof, 2013.1.31 applications,
CN201310038398.3；(5) fragrant phenoxy carboxylic acyloxy aminated compounds of N- (aryl alkyl) and preparation method and application,
2013.7.2 apply, CN201310274623.3；(6) the fragrant phenoxy carboxylic acyloxy aminated compounds of N- (alkoxy aryl) and its system
Preparation Method and application, 2013.7.2 applications, CN201310273568.6.
The active anticancer of 2- [4- (benzoxazole -2- epoxides) phenoxy group] fatty acyl pyridine amine does not research and develop report.
The content of the invention
The invention provides the 2- shown in Formulas I or formula II [4- (benzoxazole -2- epoxides) phenoxy group] fatty acyl pyridine amine：
R, R in formula1It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl；X1、X2、X4、X5、X6、X7、X8、
X10It is selected from：Hydrogen, deuterium or C1~C2Alkyl；X3It is selected from：Fluorine, chlorine, bromine；X3It is selected from：Nitro；X9It is selected from：Fluorine, chlorine, bromine.
2- [4- (benzoxazole -2- epoxides) phenoxy group] fatty acyl pyridine amine also known as N- (pyridine -2- bases) -2- [4- (benzos
Oxazole -2- epoxides) phenoxy group] fatty acid amide (I) or N- (pyridine -2- bases) -2- [4- (benzoxazole -2- epoxides) phenoxy group] fat
Fat acid amides (II).
The preparation method of 2- [4- (benzoxazole -2- epoxides) phenoxy group] fatty acyl pyridine amine (I or II), it is characterised in that
Its preparation reaction is as follows：
Or
R, R in formula1It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl；X1、X2、X4、X5、X6、X7、X8、
X10It is selected from：Hydrogen, deuterium or C1~C2Alkyl；X3It is selected from：Fluorine, chlorine, bromine；X3It is selected from：Nitro；X9It is selected from：Fluorine, chlorine, bromine.
2- provided by the invention [4- (benzoxazole -2- epoxides) phenoxy group] fatty acyl pyridine amine (I or II) has anticancer
Activity, the application in cancer therapy drug is prepared：
R, R in formula1It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl；X1、X2、X4、X5、X6、X7、X8、
X10It is selected from：Hydrogen, deuterium or C1~C2Alkyl；X3It is selected from：Fluorine, chlorine, bromine；X3It is selected from：Nitro；X9It is selected from：Fluorine, chlorine, bromine.
N- (3- nitropyridine -2- bases) -2- [4- (6- Lv benzoxazole -2- epoxides) phenoxy group] propionyl provided by the invention
Application of the amine in Antilung gland cancer medicine is prepared.
Embodiment
Following examples are intended to illustrate invention rather than limitation of the invention further.
Embodiment 1
The preparation of N- (3- nitropyridine -2- bases) -2- [4- (6- Lv benzoxazole -2- epoxides) phenoxy group] propionamide
2- [4- (6- Lv benzoxazole -2- epoxides) phenoxy group] propionyl chloride (3.3mmol), dichloromethane (40mL), 2- ammonia
The 4-dimethylaminopyridine (DMAP) of base -3- nitropyridines (3.3mmol) and catalytic amount, 10min is stirred, triethylamine is added dropwise
(1.0g, 10mmol), flowed back 7h, and reaction solution is poured into 150ml frozen water, dichloromethane extraction, anhydrous sodium sulfate drying, precipitation,
Column chromatography obtains N- (3- nitropyridine -2- bases) -2- [4- (6- Lv benzoxazole -2- epoxides) phenoxy group] propionamide, fusing point
156.0~156.3 DEG C；1H NMR (300MHz, CDCl3)δ：1.74 (d, J=6.6Hz, 3H, CH3), 4.90 (q, J=6.6Hz,
1H, CH), 7.12~7.45 (m, 8H, phenyl ring-H, pyridine ring-H, benzoxazole-H), 8.53 (dd, J1=8.1Hz, J2=
1.2Hz, 1H, pyridine ring-H), 8.79 (d, J=3.0Hz, 1H, benzoxazole-H), 11.20 (s, 1H, NH)；13C NMR
(75MHz, CDCl3)δ：18.45,75.70,110.64,116.59,119.19,119.76,121.63,125.05,128.81,
133.74,134.81,139.38,145.02,147.32,148.41,154.16,154.59,162.68,169.77；LC-MS,
m/z：455.0[M+1]+。
Embodiment 2
The preparation of N- (pyridine -2- bases) -2- [4- (benzoxazole -2- epoxides) phenoxy group] fatty acid amide (I)
R, R in formula1It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl；X1、X2、X4、X5、X6、X7、X8、
X10It is selected from：Hydrogen, deuterium or C1~C2Alkyl；X3It is selected from：Fluorine, chlorine, bromine；X3It is selected from：Nitro；X9It is selected from：Fluorine, chlorine, bromine.
N- (pyridine -2- bases) -2- [4- (benzoxazole -2- epoxides) phenoxy group] fatty acid amide is prepared by the method for embodiment 1
(I)。
Embodiment 3
The preparation of N- (pyridine -2- bases) -2- [4- (benzoxazole -2- epoxides) phenoxy group] fatty acid amide (II)
R, R in formula1It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl；X1、X2、X4、X5、X6、X7、X8、
X10It is selected from：Hydrogen, deuterium or C1~C2Alkyl；X3It is selected from：Fluorine, chlorine, bromine；X3It is selected from：Nitro；X9It is selected from：Fluorine, chlorine, bromine.
N- (pyridine -2- bases) -2- [4- (benzoxazole -2- epoxides) phenoxy group] fatty acid amide is prepared by the method for embodiment 1
(Ⅱ)。
Embodiment 4
The antitumor activity of 2- [4- (benzoxazole -2- epoxides) phenoxy group] fatty acyl pyridine amine
1. antitumor activity principle
Mtt assay biological activity test is also known as MTT colorimetric methods, is a kind of method for detecting cell survival and growth.MTT is analyzed
Method is with living cells metabolin reducing agent tetrazolium bromide [3- (4,5- dimethyl -2- thiazoles) -2,5- diphenyl bromination tetrazoles；3-(4,
5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide, MTT] based on.MTT is a kind of
The dyestuff of hydrogen atom can be received.The dehydrogenase related to NADP in the cell can convert the MTT of yellow in living cells mitochondria
Into the first a ceremonial jade-ladle, used in libation (formazon) of insoluble bluish violet, and dead cell is then without this function.After dissolving formazon with DMSO, one
OD value is determined with ELIASA under standing wave length, can both quantify the survival rate for measuring cell.Observed according to the change of OD value
Inhibitory action of the sample to tumour cell.
2. antitumor activity is tested
Sample：2- [4- (benzoxazole -2- epoxides) phenoxy group] fatty acyl pyridine amine (I or II)：
R, R in formula1It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl；X1、X2、X4、X5、X6、X7、X8、
X10It is selected from：Hydrogen, deuterium or C1~C2Alkyl；X3It is selected from：Fluorine, chlorine, bromine；X3It is selected from：Nitro；X9It is selected from：Fluorine, chlorine, bromine.
Cell line：Lung adenocarcinoma cell line A549 (offer of Xiangya Medical College, Zhongnan Univ cell bank).
Reagent：(U.S.'s hero's life technology is public for tetrazolium bromide (MTT), RPMI1640 nutrient solutions, NBCS, antibiotic
Department)；Pancreatin (AMRESCO companies of the U.S.)；96 well culture plates (hero Life Technologies, Inc. of the U.S.)；Dimethyl sulfoxide (DMSO) (the U.S.
Sigma companies).
Instrument：HFsafe-1500 types superclean bench, HF151UV types CO2(Shanghai power Shen scientific instrument are limited for incubator
Company)；XSP-15C types inverted microscope (the rectangular optical instrument Co., Ltd in Shanghai)；Multiskan MK3 types ELIASA is (beautiful
Thermo companies of state)；Ultra-pure water preparing instrument (Milli-Q companies of the U.S.).
Experimental implementation：Test of the sample for cancer cell.In experimentation, per sample (p.s.) sets 5 concentration gradients
(1.000 μm of ol/mL, 0.300 μm of ol/mL, 0.100 μm of ol/mL, 0.030 μm of ol/mL and 0.010 μm of ol/mL), each concentration
Four parallel samples, every group of experiment is parallel 3 times, and is drawn a conclusion by blank group control.ELIASA detects each hole OD values, detection
Wavelength 570nm.
3. antitumor activity evaluation
1) cell inhibitory rate calculates：
2)IC50Value calculates
Sample solution concentration logarithm value and cell inhibitory rate linear regression, calculate sample using software and dense is suppressed to the half of cell
Spend IC50Value.Active testing result shows, N- (3- nitropyridine -2- bases) -2- [4- (6- Lv benzoxazole -2- epoxides) benzene oxygen
Base] propionamide is to the IC of human umbilical vein endothelial cell50It is worth for 0.046mM.
Active testing result shows, 2- [4- (benzoxazole -2- epoxides) phenoxy group] fatty acyl pyridine amine has to cancer cell
There is good inhibitory activity, available for preparing cancer therapy drug.
Claims (5)
1. 2- [4- (benzoxazole -2- epoxides) phenoxy group] fatty acyl pyridine amine shown in chemical constitution Formulas I or formula II：
R, R in formula1It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight or branched alkyl；X1、X2、X4~X8And X10It is selected from：Hydrogen,
Deuterium or C1~C2Alkyl；X3It is selected from：Nitro；X9It is selected from：Fluorine, chlorine, bromine；Shown in Formulas I 2- [4- (benzoxazole -2- epoxides) benzene oxygen
Base] and fatty acyl pyridine amine also known as N- (pyridine -2- bases) -2- [4- (benzoxazole -2- epoxides) phenoxy group] fatty acid amide；The institute of formula II
2- [4- (benzoxazole -2- epoxides) phenoxy group] the fatty acyl pyridine amine also known as N- (pyridin-4-yl) -2- [4- (Ben Bing Evil shown
Azoles -2- epoxides) phenoxy group] fatty acid amide.
The preparation method of 2.N- (pyridine -2- bases) -2- [4- (benzoxazole -2- epoxides) phenoxy group] fatty acid amide (I), its feature
It is that its preparation reaction is as follows：
Wherein, R, R1、X1~X10Definition it is as claimed in claim 1.
The preparation method of 3.N- (pyridin-4-yl) -2- [4- (benzoxazole -2- epoxides) phenoxy group] fatty acid amide (II), it is special
Sign is that its preparation reaction is as follows：
Wherein, R, R1、X1~X10Definition it is as claimed in claim 1.
4. 2- [4- (benzoxazole -2- epoxides) phenoxy group] fatty acyl pyridine amine described in claim 1 is preparing Antilung gland cancer
Application in medicine.
5.N- (3- nitropyridine -2- bases) -2- [4- (6- Lv benzoxazole -2- epoxides) phenoxy group] propionamide is preparing anti-lung gland
Application in cancer drug.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1315831A (en) * | 1998-07-25 | 2001-10-03 | 东部韩农化学株式会社 | Herbicidal phenoxypropionic acid N-alkyl-N-2-fluorophenyl amide compounds |
| CN1688547A (en) * | 2002-07-03 | 2005-10-26 | 韦恩州立大学 | A-'7-halo-2-quino (xa-) linyloxy!phenoxy-propionic acid derivatives as antineoplastic agents |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62161774A (en) * | 1986-01-10 | 1987-07-17 | Aguro Kanesho Kk | Acid amide derivative |
| JPH0217187A (en) * | 1988-07-06 | 1990-01-22 | Kumiai Chem Ind Co Ltd | Phenoxypropionamide derivative and herbicide |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1315831A (en) * | 1998-07-25 | 2001-10-03 | 东部韩农化学株式会社 | Herbicidal phenoxypropionic acid N-alkyl-N-2-fluorophenyl amide compounds |
| CN1688547A (en) * | 2002-07-03 | 2005-10-26 | 韦恩州立大学 | A-'7-halo-2-quino (xa-) linyloxy!phenoxy-propionic acid derivatives as antineoplastic agents |
Non-Patent Citations (2)
| Title |
|---|
| "N-phenyl Substitutent Effect on the Herbicidal Activity of 2-(4-(6-chloro-2-benzoxazolyloxy)phenoxy)-N-phenylpropionamide Derivatives against Rice Plant with Pre- and Post-emergence";Nack-Do Sung，et al.;《J.Korean Soc.Agric.Chem.Biotechnol》;20001231;第43卷(第1期);52-56 * |
| "N-杂环甲基2-(4-杂芳氧基苯氧基)丙酰胺的合成及除草活性";刘祈星，等;《高等学校化学学报》;20140228;第35卷(第2期);262-269 * |
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