CN101362718A - 4-(4-benzamido phenoxy)-2-(methylcarbamoyl) pyridine derivatives, preparation method and application thereof - Google Patents
4-(4-benzamido phenoxy)-2-(methylcarbamoyl) pyridine derivatives, preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a derivative of 4-(4-benzoyl amino-phenoxy)-2-(methyl ammonia formyl) pyridine and a preparation method and purposes thereof, belonging to the chemical medicine field. The structure of the derivative is shown as Formula I: R1 is hydrogen, halogenated base, trifluoromethyl, nitro, alkoxy, dimethoxy or amino; R2 is hydrogen, halogenated base, trifluoromethyl, nitro, alkoxy, dimethoxy or amino; R3 is hydrogen, halogenated base, trifluoromethyl, nitro, alkoxy, dimethoxy or amino. The derivative can be used for preparing anti-tumor medicines.
Description
Technical field
The present invention relates to 4-(4-benzene carbon amide phenoxyl)-2-(methyl carbamyl) pyridine derivate and preparation method and purposes, belong to chemical field of medicaments.
Background technology
Malignant tumour has become the human dead second largest cause of the death, is seriously threatening human beings'health.And in China, according to recent statistics, tumour has become the first reason of China people death, show according to the sick survey data of learning of cri dernier cri: China has cancer patient more than 300 ten thousand people now, and the patient who dies from malignant tumour every year is about 1,300,000 people, and the malignant tumour case of 1,600,000 to 2,000,000 New Developments is arranged every year, and with 3% speed increase, cause grave danger for China people's life and health, bring huge pressure for society and family, restricted the Sustainable development of China's economy to a certain extent.Traditional tumor therapeuticing method is mainly the multidisciplinary synthesis treatment based on surgical operation.Because the selectivity of existing treatment means or medicine is not high, the normal cell of some type in the infringement body makes to occur obvious toxic and side effects in the therapeutic process when killing tumour cell.In recent years along with molecular biological progress with to the further investigation of pathogenesis of cancer mechanism, having occurred with the specific molecular is the antitumor drug of target spot, as gefitinib (Iressa), erlotinib (Tarceva), Gleevec (imatinib), Nexavar (sorafenib), Sutent (sunitinib malate) etc.Tumor vessel has important effect in the developing of solid tumor, studies have shown that, the growth and the transfer of any clinically detectable solid tumor that goes out depend on vasculogenesis.Propositions such as Folkman, the growth of solid tumor depends on the generation of blood vessel, if there is not blood vessel, diameter of tumor can not surpass 1～2mm, therefore, the new drug development of target tumor blood vessel has become a hot fields.Research has at present confirmed many and the closely-related cytokine receptor of tumor-blood-vessel growth, typically comprises vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR) or the like.Experimental study is found, suppresses the activity of these cytokine receptors and can destroy the vasculogenesis of tumour, thereby reach the purpose that suppresses tumor growth.
The important value of inhibitor in antitumor based on VEGFR2 and PDGFR etc., the present inventor has carried out in recent years at tumor vascular target small-molecule drug design and study on the synthesis work, some hypostazation compounds have been designed and synthesized, through the cell in vitro screening, find that some compounds wherein have certain inhibition activity to tumor cell proliferation, by further composition optimizes and synthetic, some novel compounds have been obtained, they demonstrate good inhibition activity on various tumor cell strains, and have also shown result preferably in the experiment in vivo.
Summary of the invention
The objective of the invention is to provides a class new compound for the medicine that antineoplastic vascular generates.
Technical scheme of the present invention provides the derivative of 4-(4-benzene carbon amide phenoxyl)-2-(methyl carbamyl) pyridine, and the structure of described derivative is suc as formula shown in the I:
Wherein, R
1Be hydrogen, halogeno-group, trifluoromethyl, nitro, alkoxyl group, dimethoxy or amino;
R
2Be hydrogen, halogeno-group, trifluoromethyl, nitro, alkoxyl group, dimethoxy or amino;
R
3Be hydrogen, halogeno-group, trifluoromethyl, nitro, alkoxyl group, dimethoxy or amino.
Preferably, R
1Be hydrogen, chloro base or trifluoromethyl; R
2Be hydrogen, chloro base or trifluoromethyl; R
3Be hydrogen, chloro base or trifluoromethyl.
More excellent, R
1Be hydrogen; R
2Be hydrogen, chloro base or trifluoromethyl; R
3Be hydrogen, chloro base or trifluoromethyl.
Optimum, the derivative of described 4-(4-benzene carbon amide phenoxyl)-2-(methyl carbamyl) pyridine is:
4-(4-(2-trifluoromethyl) benzamide phenoxyl)-2-(methyl carbamyl) pyridine,
4-(4-(3-trifluoromethyl) benzamide phenoxyl)-2-(methyl carbamyl) pyridine,
4-(4-(4-trifluoromethyl) benzamide phenoxyl)-2-(methyl carbamyl) pyridine,
Or 4-(4-(4-chlorine) benzamide phenoxyl)-2-(methyl carbamyl) pyridine.
Second technical problem to be solved by this invention provides the synthetic method of compound shown in the above-mentioned formula I; prepare by acylation reaction by 4-(4-amino-benzene oxygen)-2-(methyl carbamyl) pyridine and respective compound, specifically can adopt following several method:
A, by 4-(4-amino-benzene oxygen)-2-(methyl carbamyl) pyridine and substituted benzoyl chloride with pyridine as solvent and acid binding agent, prepare by acylation reaction.
B, by 4-(4-amino-benzene oxygen)-2-(methyl carbamyl) pyridine and substituted benzoyl chloride with tetrahydrofuran (THF) as solvent and salt of wormwood as acid binding agent, prepare by acylation reaction.
Wherein 4-(4-amino-benzene oxygen)-2-(methyl carbamyl) pyridine can be bought acquisition, also can be prepared according to the prior art disclosed method by 4-(4-chlorine) anilino-2-(methyl carbamyl) pyridine and p-aminophenol.
The 3rd technical problem to be solved by this invention provides the purposes of above-mentioned 4-(4-benzene carbon amide phenoxyl)-2-(methyl carbamyl) pyridine derivate in the preparation antitumor drug.
The present invention also provides a kind of pharmaceutical composition, is to add pharmaceutically by the 4-shown in the above-mentioned formula I (4-benzene carbon amide phenoxyl)-2-(methyl carbamyl) pyridine derivate that the complementary composition of acceptable is prepared from.This pharmaceutical composition can be used for preparing antitumor drug.
Beneficial effect of the present invention is: 4-of the present invention (4-benzene carbon amide phenoxyl)-2-(methyl carbamyl) pyridine derivate is to obtain on the basis of a large amount of screenings; has anti-tumor activity, for the development and application of antitumor drug provides new selection.
Description of drawings
Fig. 1 compound 4-(4-(3-trifluoromethyl) benzamide phenoxyl)-2-(methyl carbamyl) pyridine is to the restraining effect of different tumour cells.
Wherein symbol 1 expression compound is to the restraining effect of human lung carcinoma cell line (A549), and 2 expression compounds are to the restraining effect of human hepatoma cell strain (HepG2), and 3 expression compounds are to the restraining effect of human colon cancer cell strain (HCT116).
Embodiment
The derivative of 4-provided by the invention (4-benzene carbon amide phenoxyl)-2-(methyl carbamyl) pyridine is suc as formula shown in the I:
Wherein, R
1Be hydrogen, halogeno-group, trifluoromethyl, nitro, alkoxyl group, dimethoxy or amino;
R
2Be hydrogen, halogeno-group, trifluoromethyl, nitro, alkoxyl group, dimethoxy or amino;
R
3Be hydrogen, halogeno-group, trifluoromethyl, nitro, alkoxyl group, dimethoxy or amino.
The synthetic method of compound shown in the above-mentioned formula I is prepared by acylation reaction by 4-(4-amino-benzene oxygen)-2-(methyl carbamyl) pyridine and respective compound, specifically can adopt following several method:
One, 4-(4-amino-benzene oxygen)-2-(methyl carbamyl) pyridine is dissolved in the pyridine, slowly adds the R substituted benzoyl chloride under the room temperature, be warmed up to 80 ℃.Under the nitrogen protection about 1 hour, reaction finished.In reaction system, add water, stirred 10 minutes, add saturated NaHCO
3Solution produces to no bubble, uses ethyl acetate extraction, and organic layer is washed with saturated common salt, anhydrous MgSO
4Drying, concentrate crude product, re-crystallizing in ethyl acetate gets pure product.
Two, the mixture with 4-(4-amino-benzene oxygen)-2-(methyl carbamyl) pyridine and salt of wormwood is dissolved in the tetrahydrofuran (THF) (THF), under the stirring at room, slowly drips acyl chlorides, stirs then 1 hour, filter product.
4-(4-amino-benzene oxygen)-2-(methyl carbamyl) pyridine synthetic method comprises following several:
Method one: under the room temperature p-aminophenol is dissolved in dry DMF, adds potassium tert.-butoxide again, nitrogen protection was stirred 2 hours down.Add N-methyl-(4-chloro-2-pyridyl) methane amide and salt of wormwood, reacting by heating 6 hours.Pour ethyl acetate and water in the room temperature downhill reaction liquid, the collected organic layer drying is spin-dried for and obtains thick product, and recrystallization obtains brown crystal.
Method two: N-methyl-(4-chloro-2-pyridyl) methane amide is dissolved among the THF, adds p-aminophenol, phase-transfer catalyst Polyethylene Glycol-600, sodium hydroxide and 45% sodium hydroxide solution, backflow 12h.Steam and remove THF, add entry in the residuum, filter, filter cake is with Virahol recrystallization, cold isopropanol washing, and 40 ℃ of drying under reduced pressure get the light brown solid.
The invention will be further elaborated below in conjunction with embodiment.Embodiment only is used to illustrate the present invention, rather than limits the present invention by any way.
The preparation of embodiment 1 4-(4-amino-benzene oxygen)-2-(methyl carbamyl) pyridine
Synthetic route is as follows:
1, the preparation of 4-chloro-2-pyridine formyl chloride hydrochloride
Prepare according to existing disclosed method by the 2-pyridine carboxylic acid, for example: in the exsiccant reaction flask, with 2-pyridine carboxylic acid (30.00g, 0.244mmol) and NaBr (4.00g, 0.040mmol) mix after, join in the chlorobenzene (40ml), treat slowly to add when suspension is heated to 50 ℃ thionyl chloride (61ml, 0.840mmol), make the gas (SO that emits
2, HCl) controlled effectively.Mixture heating up to 85 ℃ stirred 19 hours.After reaction finishes, be cooled to 20 ℃, revolve to steam and remove excessive thionyl chloride and chlorobenzene mixture.(65.70g 75.5ml), revolves once more to steam and removes still residual thionyl chloride and a large amount of chlorobenzenes, and the gained crude product is dissolved in toluene, and (84.80g 97.5ml), uses to treat the next step to add toluene again.Also can buy acquisition.
2, the preparation of N-methyl-(4-chloro-2-pyridyl) methane amide
Prepared according to existing disclosed method by 4-chloro-2-(chloroformyl) pyridine hydrochloride, for example: (95.50g 0.77mol) is chilled to-5 ℃ to 25% methylamine solution, drips the toluene solution of above-mentioned 4-chloro-2-(chloroformyl) pyridine hydrochloride below 20 ℃.Drip Bi Tongwen reaction 90 minutes.Standing demix, toluene layer water (45ml * 2) washing removes solvent under reduced pressure, adds THF (170ml) in the residue brown oil, is chilled to 5 ℃, 36% hydrochloric acid of dropping below 20 ℃ (29.40g, 0.30mol).Finish equality of temperature and stirred 1 hour, filter, filter cake washs with THF (20ml * 2), in water-soluble (120ml), add 20% sodium hydroxide solution and transfer to pH=7, stirred 30 minutes, filter, filter cake water (20ml * 2) washing, 20 ℃ of drying under reduced pressure get white solid (38.60g, productive rate 93.1%, in the 2-pyridine carboxylic acid), mp35～38 ℃.Also can buy acquisition.
1H?NMR(400MHz，CDCl
3)δ：3.00(s，3H，NHCH
3)，7.40(dd，J＝1.9、5.2Hz，1H)，7.95(br，s，1H，NH)，8.18(d，J＝1.9Hz，1H，pyridine)，8.41(d，J＝5.2Hz，1H，pyridine)。
Mass spectrum: (m/e) 170 (M+1).
3, the preparation of 4-(4-amino-benzene oxygen)-2-(methyl carbamyl) pyridine
N-methyl-(4-chloro-2-pyridyl) methane amide (3.40g, 0.02mol) be dissolved in THF (16ml), add p-aminophenol (2.40g, 0.02mol), phase-transfer catalyst Polyethylene Glycol-600 (2.40g), sodium hydroxide (1.20g, 0.03mol) and 45% sodium hydroxide solution (2.7ml), refluxed 12 hours.Steam to remove the THF solvent, add entry (20ml) in the residuum, filter, filter cake is with Virahol recrystallization, cold isopropanol (5ml * 2) washing, 40 ℃ of drying under reduced pressure, light brown solid (3.50g, productive rate 72.2%), mp108～110 ℃.
The preparation of embodiment 2 4-(4-amino-benzene oxygen)-2-(methyl carbamyl) pyridine
(0.70g, (0.72g, 6.40mmol) nitrogen protection was stirred 2 hours down 6.40mmol) to be dissolved in 7ml dry DMF adding potassium tert.-butoxide with p-aminophenol under the room temperature.Adding N-methyl-(4-chloro-2-pyridyl) methane amide (0.50g, 2.90mmol), salt of wormwood (0.20g, 1.40mmol), reacting by heating 6 hours.Under the room temperature reaction solution is poured in (ethyl acetate 200ml+ water 20ml) mixed solution, collected organic layer is removed solvent, gets thick product, and column chromatography for separation obtains brownish black solid 0.41g, (productive rate 57.1%).
1H?NMR(400MHz，CDCl
3)：3.0(d，J＝5.2Hz，3H，-NHCH
3)，3.7(br，s，2H，-NH
2)，6.7(d，J＝8.8Hz，2H)，6.9(m，3H)，7.67(d，J＝2.4Hz，1H)，8.0(s，1H，NH)，8.3(d，J＝6Hz，1H)
MS-ESI(m/z)：244.4(M+1)，266.4(M+23)
The preparation of embodiment 3 Compound I a:4-(4-(2-trifluoromethyl) benzamide phenoxyl)-2-(methyl carbamyl) pyridine
(0.20g 0.82mmol) is dissolved in the pyridine (1.5ml), and (0.21ml 2.90mmol), is warmed up to 80 ℃ slowly to add the o-trifluoromethyl Benzoyl chloride under the room temperature with 4-(4-amino-benzene oxygen)-2-(methyl carbamyl) pyridine.Nitrogen protection was reacted about 1 hour down, the monitoring of TCL method, and raw material reaction is intact to be reaction end.In reaction system, add water (3ml), stirred 10 minutes.Reaction solution adds saturated NaHCO
3Solution produces to no bubble, uses ethyl acetate extraction, and organic layer is washed with saturated common salt, anhydrous MgSO
4Drying, concentrate crude product, the crude product re-crystallizing in ethyl acetate must light pink colour purity product (0.17g, productive rate 50%).
MS-ESI(m/z)：414.2(M—1)
The preparation of embodiment 4 compounds ibs: 4-(4-(3-trifluoromethyl) benzamide phenoxyl)-2-(methyl carbamyl) pyridine
(0.50g 2.06mmol) is dissolved in the pyridine (3ml), and (2.47ml 5.2mmol), is warmed up to 80 ℃ slowly to add m-trifluoromethyl benzoyl chloride under the room temperature with 4-(4-amino-benzene oxygen)-2-(methyl carbamyl) pyridine.Under the nitrogen protection about 1 hour, the TCL monitoring, it is reaction end that starting compound react.In reaction system, add water (6ml), stirred 10 minutes.Reaction solution adds saturated NaHCO
3Solution produces to no bubble, uses ethyl acetate extraction, and organic layer is washed with saturated common salt, anhydrous MgSO
4Drying, concentrate crude product, column chromatography for separation obtains lightpink compound 0.51g (productive rate 60%).
1H?NMR(400MHz，DMSO-d6)：2.97(d，J＝4.8，3H)，7.18(m，1H)，7.26(d，J＝9.2Hz，2H)，7.4(d，J＝2.4Hz，1H)，7.8(m，1H)，7.92(d，J＝9.2Hz，2H)，7.99(d，J＝7.6Hz，2H)，8.3(m，2H)，8.5(d，J＝5.2Hz，1H)，8.8(m，1H)，10.63(s，1H)
MS-ESI(m/z)：416.2(M+1)
The preparation of embodiment 5 Compound I c:4-(4-(4-trifluoromethyl) benzamide phenoxyl)-2-(methyl carbamyl) pyridine
(0.20g 0.82mmol) is dissolved in the pyridine (1.5ml) 4-(4-amino-benzene oxygen)-2-(methyl carbamyl) pyridine, and (1.6ml 2.0mmol), is warmed up to 80 ℃ to trifluoromethyl benzoyl chloride in slow adding under the room temperature.Under the nitrogen protection about 1 hour, in reaction system, add water (3ml), stirred 10 minutes, add saturated NaHCO then
3Solution produces to no bubble, uses ethyl acetate extraction, organic layer saturated common salt water washing, anhydrous MgSO
4Drying, concentrate crude product 0.34g, re-crystallizing in ethyl acetate, pure product (0.19g, productive rate 55%).
1H?NMR(400MHz，DMSO-d6)：2.8(d，J＝4.8Hz，3H，NHCH
3)，7.1(q，1H)，7.2(d，J＝8.8Hz，2H)，7.4(d，J＝2.4Hz，1H)，7.9(t，J＝4.8Hz，4H)，8.1(d，J＝8.4Hz，2H)，8.5(d，J＝5.6Hz，1H)，8.7(d，J＝4.8Hz，1H)，10.6(s，1H)
MS-ESI(m/z)：414.2(M—1)
The preparation of embodiment 6 Compound I d:4-(4-(4-chlorine) benzamide phenoxyl)-2-(methyl carbamyl) pyridine
4-(4-amino-benzene oxygen)-2-(methyl carbamyl) pyridine (0.40g; 1.65mmol) (0.45g, mixture 3.30mmol) are dissolved among the THF (4ml), under the stirring at room with salt of wormwood; drip parachlorobenzoyl chloride (0.43g; 2.47mmol) THF (4ml) solution, drip to finish stirred suction filtration 1 hour; get crude product; with the mixing solutions recrystallization of methyl alcohol and methylene dichloride, promptly get product (0.41g, productive rate 65.9%).
1H?NMR(400MHz，DMSO-d
6)：2.97(d，J＝4.4Hz，3H，-NHCH
3)，7.0(d，J＝14.4Hz，1H)，7.1(d，J＝14.4Hz，2H)，7.2(d，J＝8.4Hz，1H)，7.5(t，J＝4.2Hz，2H)，7.7(m，2H)，7.9(m，2H)，8.5(d，J＝5.2Hz，1H)，8.7(d，J＝4Hz，1H)，10.4(s，H)
MS-ESI(m/z)：382.1(M+1)，405.9(M+23)
The pharmacodynamic experiment part
Test routine cell inhibitory effect experiment
1, experiment material
(InvitrogenCorporation, USA), thiazole bromide blue tetrazolium (MTT), methyl-sulphoxide (DMSO) are Sigma company (USA) product available from Gibco BRL company for RPMI-1640, DMEM, foetal calf serum, pancreatin etc.The new compound that the present invention relates to is synthetic voluntarily by my laboratory, is mixed with the 20mg/ml storage liquid with DMSO during experiment in vitro, puts 4 ℃ of refrigerators and keeps in Dark Place standbyly, faces the time spent to be diluted to desired concn with complete culture solution.
Clone and cultivation: used used human hepatoma cell strain (HepG2), human colon cancer cell strain (SW480 and HCT116), human breast cancer cell strain (MCF7) and the human lung carcinoma cell line (A549) of this experiment of this experiment all purchased the ATCC company in the U.S..
Human hepatoma cell strain (HepG2) is with the DMEM perfect medium, the 5%CO that contain 10% foetal calf serum, 100U/mL penicillin, 100 μ g/mL Streptomycin sulphates
2, 37 ℃ of cultivations.
Human colon cancer cell strain (HCT116 and SW480), human breast cancer cell strain (MCF7) and human lung carcinoma cell line (A549) RPMI-1640 perfect medium, the 5%CO that contains 10% foetal calf serum, 100U/mL penicillin, 100 μ g/mL Streptomycin sulphates
2, 37 ℃ of cultivations.
2, experimental technique (mtt assay)
Adjusting cell concn with complete culture solution is 2 * 10
4/ mL, be inoculated in 96 orifice plates, every hole 200 μ L, overnight incubation, use next day the Ia～Id (final concentration be respectively 20,10,5,2.5,1.25,0.625,0.312mg/ml) of various dose to handle cell respectively, establish isopyknic solvent control group simultaneously, DMSO concentration is 0.1% (0.1% DMSO on cell proliferation does not have influence).Each group is established 5 multiple holes, 37 ℃, 5%CO
2Cultivate.After cultivating 48 and 72 hours, get 1 culture plate, every hole adds 5mg/mL MTT reagent 20 μ L, continue to cultivate 2h, abandon supernatant, add DMSO 150 μ L again, vibration mixing 15min, (λ=570nm) measure absorbancy (A) value (the A value is directly proportional with viable count) gets its mean value with microplate reader.Relative cell proliferation inhibition rate (%)=(solvent control group A
570-experimental group A
570)/solvent control group A
570* 100%.Below each compound pair cell increment restraining effect, all adopt cell proliferation inhibition rate (%) expression.
3, experimental result
The on cell proliferation restraining effect of Compound I a～Id on different tumor cell lines sees Table 1.
Table 1
The result shows, behind compounds ib effect A549, HepG2 and the HCT116 cell, increases with drug level, and cell inhibitory effect obvious more (Fig. 1) has dose-dependently (P＜0.05).Each dosage group is compared with the solvent control group, and cell proliferation inhibition rate difference all has statistical significance (P＜0.05) relatively.Compounds ib is handled A549, the half-inhibition concentration (IC of HepG2 and HCT116 cell 48h
50) be about 21.5 μ g/ml, 18.2 μ g/ml and 8.1 μ g/ml respectively.
Claims (9)
- 4-shown in [claim 1] formula I (4-benzene carbon amide phenoxyl)-2-(methyl carbamyl) pyridine derivate:
Wherein, R 1Be hydrogen, halogeno-group, trifluoromethyl, nitro, alkoxyl group, dimethoxy or amino;R 2Be hydrogen, halogeno-group, trifluoromethyl, nitro, alkoxyl group, dimethoxy or amino;R 3Be hydrogen, halogeno-group, trifluoromethyl, nitro, alkoxyl group, dimethoxy or amino. - [claim 2] 4-according to claim 1 (4-benzene carbon amide phenoxyl)-2-(methyl carbamyl) pyridine derivate is characterized in that: R 1Be hydrogen, chloro base or trifluoromethyl; R 2Be hydrogen, chloro base or trifluoromethyl; R 3Be hydrogen, chloro base or trifluoromethyl.
- [claim 3] 4-according to claim 2 (4-benzene carbon amide phenoxyl)-2-(methyl carbamyl) pyridine derivate is characterized in that: R 1Be hydrogen; R 2Be hydrogen, chloro base or trifluoromethyl; R 3Be hydrogen, chloro base or trifluoromethyl.
- [claim 4] 4-according to claim 3 (4-benzene carbon amide phenoxyl)-2-(methyl carbamyl) pyridine derivate, it is characterized in that: described derivative is:4-(4-(2-trifluoromethyl) benzamide phenoxyl)-2-(methyl carbamyl) pyridine,4-(4-(3-trifluoromethyl) benzamide phenoxyl)-2-(methyl carbamyl) pyridine,4-(4-(4-trifluoromethyl) benzamide phenoxyl)-2-(methyl carbamyl) pyridine,Or 4-(4-(4-chlorine) benzamide phenoxyl)-2-(methyl carbamyl) pyridine.
- The method of the 4-shown in [claim 5] preparation formula I (4-benzene carbon amide phenoxyl)-2-(methyl carbamyl) pyridine derivate is characterized in that: obtained by the nitrogen acylation prepared in reaction by 4-(4-amino-benzene oxygen)-2-(methyl carbamyl) pyridine and respective compound.
- The method of the 4-shown in [claim 6] preparation formula I according to claim 5 (4-benzene carbon amide phenoxyl)-2-(methyl carbamyl) pyridine derivate, it is characterized in that: it be by 4-(4-amino-benzene oxygen)-2-(methyl carbamyl) pyridine and respective compound with pyridine as solvent and acid binding agent, obtain by the nitrogen acylation prepared in reaction;Or by 4-(4-amino-benzene oxygen)-2-(methyl carbamyl) pyridine and R substituted benzoyl chloride with tetrahydrofuran (THF) as solvent, salt of wormwood as acid binding agent, obtain by the nitrogen acylation prepared in reaction.
- The purposes of 4-shown in [claim 7] formula I (4-benzene carbon amide phenoxyl)-2-(methyl carbamyl) pyridine derivate in the preparation antitumor drug.
- 4-shown in [claim 8] formula I (4-benzene carbon amide phenoxyl)-2-(methyl carbamyl) pyridine derivate adds the pharmaceutical composition that the complementary composition of acceptable pharmaceutically is prepared from.
- The purposes of the described pharmaceutical composition of [claim 9] claim 8 in the preparation antitumor drug.
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2008
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Assignee: Sichuan Hairong Pharmaceutical Industry Co., Ltd. of Yangzijiang Pharmaceutical Assignor: Sichuan University Contract record no.: 2011510000151 Denomination of invention: 4- (4- benzoyl phenoxy) -2- (meth) pyridine derivative and preparation method and application thereof Granted publication date: 20101208 License type: Exclusive License Open date: 20090211 Record date: 20110816 |