CN102351852B - Coumarone compound, its preparation method and its application - Google Patents
Coumarone compound, its preparation method and its application Download PDFInfo
- Publication number
- CN102351852B CN102351852B CN201110242547.9A CN201110242547A CN102351852B CN 102351852 B CN102351852 B CN 102351852B CN 201110242547 A CN201110242547 A CN 201110242547A CN 102351852 B CN102351852 B CN 102351852B
- Authority
- CN
- China
- Prior art keywords
- arh
- compound
- methyl
- preparation
- oxazole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention provides a coumarone compound, a preparation method and an application in the medical and chemical field, the structural formula of the coumarone compound is shown as a following formula. The invention also relates to the preparation method of the compound and the application of the compound in preparation of medicines used for inhibiting tumor cells biological activity. According to the invention, a traditional PPAR agonist hydrophobic tail hydrophobic tail and a flexible intermediate coupling chain are taken as a mother nucleus, a cis-structure of CombretastinA-4 is referred so that the good antineoplastic activity is presented, the coumarone structure is taken as an aromatic ring center between an acidic head and the flexible coupling chain in the PPAR agonist, the preparation method of compound is established and optimized, and the prepared novel compound is carried out an experiment for screening the tumor cells. The preliminary antineoplastic tests confirm that the prepared partial novel compound has specific and exclusive tumor inhibition activity aimed at human prostatic cancer cells, the coumarone compound can be used for preparing the antitumor medicines and medicines for treating and preventing tumor.
Description
Technical field
What the present invention relates to is compound in a kind of medicine and chemical field and preparation method thereof, purposes, specifically a kind of
Benzofuran compounds and preparation method thereof, purposes.
Background technology
Peroxidase growth factor activated receptor (Peroxisome Proliferator-Activated Receptors, PPARS) be a nuclear hormone receptor superfamily, comprise tri-kinds of hypotypes of PPAR α, PPAR β and PPAR γ, first these hypotypes are to be found in African toad group.PPARS is a class ligand-dependent type transcription factor, can regulate the expression of the target body gene relevant with glucose metabolism to fat.Each PPAR acceptor can form a title complex with retinoic acid receptor X, and this title complex can be with specific peroxidase proliferator response factor (PPRE) in conjunction with the DNA sequence dna with identification target body gene.From the nineties in 20th century, PPAR is found to now, and PPARS acceptor is regarded as the target spot of potential treatment and prevention metabolic syndrome, and Pharmaceutical Chemist is studied related drugs with the metabolic syndrome such as Cardiovarscular, type-II diabetes mainly for this point.PPAR agonist mainly contains two target spot agonist three classes of PPAR alfa agonists (chlorine special class), PPAR gamma agonist (thiazolidinediones) and PPAR α/γ at present, wherein especially with PPAR gamma agonist most study.This three excitomotor has medicine listing separately, and the representative of PPAR alfa agonists has fenofibrate and gemfibrozil; The representative of PPAR gamma agonist has pioglitazone and rosiglitazone; The representative of PPAR α/gamma agonist has muraglitazar and tesaglitazar.Although these medicines are having significant curative effect aspect treatment metabolic syndrome, these class Side effects of pharmaceutical drugs are all more serious, liver toxicity, and oedema, body weight increases etc.
Researchist finds that PPAR γ acceptor can suppress the propagation of cell in the differentiation of induction lipocyte, thereby has caused the research of medicine scholar for the potential antitumor action of PPAR gamma agonist.If Christian Hafner etc. was at " Current Cancer Drug Targets " the 5th the 6th phase of volume " New Indications for Established Drugs:Combined Tumor-Stroma-Targeted Cancer Therapy with PPAR γ Agonists of 393 pages of 2005, COX-2 Inhibitors, mTOR Antagonists and Metronomic Chemotherapy " in point out that PPAR γ may serve as a new antineoplaston target spot, activity data shows that PPAR gamma agonist has the effect of inhibition tumor cell propagation, its possible mechanism has 2 points: (1) use PPAR gamma agonist is antitumor can raise cyclin dependant inhibitor, cause cyclin/cdk mixture to be passivated, can stablize the retinoblastoma albumen of non-phosphorylating state simultaneously, (2) PPAR gamma agonist can inducing tumor cell apoptosis, and part, owing to raising pro apoptotic protein BAX and BAD, excites the expression of several effector caspaseses simultaneously.Although research has been carried out for some time to PPAR agonist antineoplastic action, but the emphasis of at present Pharmaceutical Chemist research is all that to utilize known antidiabetic medicine be mainly that thiazolidine dione compounds is studied its antitumor mechanism as template, fewer for the research of the brand-new PPAR agonist with antitumor action.
Summary of the invention
The present invention is directed to the deficiency that prior art exists, novel benzofuran compounds of one class and preparation method thereof, purposes are provided, by preliminary antitumor test, confirm that the novel benzofuran compounds of the present invention can suppress the activity of kinds of tumor cells, can be for the preparation of the medicine of antineoplaston and prophylaxis of tumours.
The present invention is achieved by the following technical solutions, the benzofuran compounds the present invention relates to, and its structural formula is:
(a) R
1structure for shown in formula I or formula II:
Wherein, Z is any one in O, S, NH; R
6, R
7for hydrogen, C
1-C
5alkyl, nitro, carboxyl, fluorine, chlorine, bromine, ester group, hydroxyl, amino, amide group, alkoxyl group, aldehyde radical, aromatic base, assorted aromatic base in any one;
(b) R
2structure for shown in formula III, formula IV, formula (V) or formula VI:
Wherein, n
2be 1～3 integer, W is any one in O, S, NH, R
8, R
9, R
10, R
11for group replaces arbitrarily aromatic base or assorted aromatic base;
(c) R
3for hydrogen, C
1-C
5alkyl, nitro, carboxyl, fluorine, chlorine, bromine, ester group, hydroxyl, amino, amide group, alkoxyl group, aldehyde radical, aromatic base, assorted aromatic base in any one; X, Y is O, any one in S, NH; n
1it is 1～4 integer;
(d) R
4for hydrogen or C
1-C
5straight or branched alkyl;
(e) R
5for hydrogen, C
1-C
5alkyl, nitro, carboxyl, fluorine, chlorine, bromine, ester group, hydroxyl, amino, amide group, alkoxyl group, aldehyde radical, aromatic base, assorted aromatic base in any one.
Preferably, its structural formula is:
Wherein, R
12, R
13for hydrogen, C
1-C
5alkyl, nitro, carboxyl, fluorine, chlorine, bromine, ester group, hydroxyl, amino, amide group, alkoxyl group, aldehyde radical, aromatic base, assorted aromatic base in any one.
Preferably, its structural formula is:
Wherein, R
14, R
15for hydrogen, C
1-C
5alkyl, nitro, carboxyl, fluorine, chlorine, bromine, ester group, hydroxyl, amino, amide group, alkoxyl group, aldehyde radical, aromatic base, assorted aromatic base in any one.
Second aspect, the invention still further relates to the method for aforementioned benzofuran compounds, comprises the steps:
(1) get 2 of 1 molar equivalent, the Benzyl Chloride of 4-Dihydroxy benzaldehyde and 1.2 molar equivalents refluxes and within 12 hours, obtains 4-(benzyloxy)-Benzaldehyde,2-hydroxy in acetonitrile;
(2) get 4-(the benzyloxy)-Benzaldehyde,2-hydroxy of 1 molar equivalent and the replacement aldehyde of 1.2 molar equivalents refluxes and within 2 hours, obtains (E)-5-(benzyloxy)-2-substituted ethylene base phenol in zinc-titanium tetrachloride-Tetrahydrofuran System;
(3) (E)-5-(benzyloxy)-2-substituted ethylene base phenol stirring at room temperature in 6 molar equivalent salt of wormwood and 6 molar equivalent iodine of getting 1 molar equivalent obtains 6-(benzyloxy)-2-for 12 hours and replaces cumarone;
(4) get the 6-(benzyloxy) of 1 molar equivalent-2-and replace cumarone and be dissolved in methylene dichloride, add the titanium tetrachloride of 1.3 molar equivalents to obtain 6-hydroxyl-2-and replace cumarone;
(5) get the 6-hydroxyl of 1 molar equivalent-2-and replace cumarone and be dissolved in acetonitrile, add 2-(5-methyl-2-benzene base oxazole-4-yl) ethyl methane sulfonate of 1 molar equivalent and the salt of wormwood of 2 molar equivalents to reflux and within 12 hours, obtain 5-methyl-2-phenyl-4-(2-(2-replaces cumarone-6-oxygen base) ethyl) oxazole;
(6) getting 5-methyl-2-phenyl-4-(2-(2-replaces cumarone-6-oxygen base) ethyl) oxazole of 1 molar equivalent and the replacement acyl chlorides of 1.5 molar equivalents is dissolved in methylene dichloride, add the tin tetrachloride of 1.2 molar equivalents, stirring at room temperature obtains 1-(2-replacement-6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group) cumarone-3-yl) for 12 hours and replaces ketone;
(7) get 5-methyl-2-phenyl-4-(2-(2-replace cumarone-6-oxygen base) ethyl) oxazole and the phosphorus oxychloride of 8 molar equivalents and the N of 8 molar equivalents of 1 molar equivalent, dinethylformamide refluxes and obtains 6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl benzofurans-3-formaldehyde in 1,2-ethylene dichloride;
(8) get 3 of 6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl benzofurans-3-formaldehyde of 1 molar equivalent and 1 molar equivalent, 4,5-trimethoxy-aniline obtains (E)-3 for 12 hours in reflux in toluene, 4,5-trimethoxy-N-((6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl benzofurans-3-yl) methylene radical) aniline;
(9) get (E)-3 of 1 molar equivalent, 4, the sodium borohydride of 5-trimethoxy-N-((6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl benzofurans-3-yl) methylene radical) aniline and 1.5 molar equivalents stirs and obtains 3 in methyl alcohol, 4,5-trimethoxy-N-((6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl benzofurans-3-yl) methyl) aniline.
The third aspect, the invention still further relates to aforementioned benzofuran compounds in the purposes for the preparation of in inhibition tumor cell biologically active drug.
Preferably, described tumour cell is human breast cancer cell, Human Prostate Cancer Cells, African green monkey kidney inoblast, human cervical carcinoma cell, mouse leukemia cell.
The present invention has following beneficial effect: the present invention is using the middle connection chain of traditional PPAR agonist hydrophobic tail and flexibility as parent nucleus, there is good anti-tumor activity with reference to the cis-structure of Combretastin A-4, acid head and flexibly connect the aromatic ring center between chain in using cumarone structure as PPAR agonist, set up and optimize the preparation method of compound, and the novel cpd of preparation is carried out to tumour cell screening experiment, confirm that by preliminary antitumor test prepared part new compound has for the special narrow spectrum tumors inhibition activity of Human Prostate Cancer Cells, can be for the preparation of the medicine of antineoplaston and prophylaxis of tumours.
Brief description of the drawings
Fig. 1 is preparation method's synthetic route schematic diagram of benzofuran compound.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in detail.Following examples will contribute to those skilled in the art further to understand the present invention, but not limit in any form the present invention.It should be pointed out that to those skilled in the art, without departing from the inventive concept of the premise, can also make some distortion and improvement.These all belong to protection scope of the present invention.
embodiment 1
Synthetic (Fig. 1) of 4-(benzyloxy)-Benzaldehyde,2-hydroxy I: by 2,4-Dihydroxy benzaldehyde (100mg, 0.72 mmol) be dissolved in acetonitrile (15ml), then add potassiumiodide (179.3mg, 1.08mmol) and sodium bicarbonate (90.7 mg, 1.08mmol), after adding, slowly drip Benzyl Chloride (100 ul, 0.87mmol), reflux 12 hours.After having reacted, cancellation adds water, be extracted with ethyl acetate, merge organic phase, with saturated common salt water washing three times, after anhydrous sodium sulfate drying, concentrating under reduced pressure, obtain 4-(benzyloxy)-Benzaldehyde,2-hydroxy 110mg (colorless solid, yield 67%) through silica gel chromatography column purification (sherwood oil: ethyl acetate=10:1).
1HNMR (CDCl
3；300MHz), δ5.12(s, 2H, O
CH 2 Ph) 6.40-6.64(m, 2H, ArH), 7.41-7.43 (m, 6H, ArH), 9.73(s, 1H, CHO), 11.44(brs, 1H, OH)。
(E)-5-(benzyloxy)-2-(4-methoxyl-styrene) phenol II
1synthetic (Fig. 1): under nitrogen environment, by zinc powder (1.4g, 22mmol) be added in anhydrous tetrahydro furan (20ml), then the temperature of reaction system is dropped to-5～0 DEG C, at this temperature, drip titanium tetrachloride (1.2ml, 11mmol), after adding, the temperature of reaction system is risen to room temperature, stir half an hour, and then reflux 2.5 hours.After backflow finishes, the temperature of reaction system is dropped to-5～0 DEG C again, dropwise add 4-(benzyloxy)-Benzaldehyde,2-hydroxy (1g, 4.4mmol) and aubepine (721mg, tetrahydrofuran solution 5.3mmol), drips off rear backflow 2 hours.After reaction finishes, with 10% sodium bicarbonate aqueous solution cancellation reaction, then use dichloromethane extraction, merge organic phase, with saturated common salt water washing three times, after anhydrous sodium sulfate drying, concentrating under reduced pressure, obtain (E)-5-(benzyloxy)-2-(4-methoxyl-styrene) phenol 280 mg (colorless solid, yield 20%) through silica gel chromatography column purification (sherwood oil: ethyl acetate=5:1).
1hNMR (CDCl
3; 300MHz), δ 3.84 (s, 3H, OCH3), 5.05 (s, 2H, O
cH 2 ph), 6.48-6.49 (d, 1H, Ar, J=2.4Hz), 6.58-6.62 (dd, 1H, ArH, J=8.7Hz, 2.7Hz), 6.988-6.934 (dd, 2H, ArH, J=3Hz, 8.7Hz), (6.951-6.989 d, 1H, CH, J=11.4Hz), (7.133-7.155 d, 1H, ArH, J=6.6Hz), (7.365-7.548 m, 8H, ArH, CH).
embodiment 3
6-(benzyloxy)-2-methoxyl group benzo furans III
1synthetic (Fig. 1): by (E)-5-(benzyloxy-2-(4-methoxyl-styrene) phenol (280mg, 0.84mmol) be dissolved in tetrahydrofuran (THF) (15ml), add Anhydrous potassium carbonate (695 mg, 5.04mmol), stir after 10 minutes, add iodine (1.28g, 5.04mmol), stirring at room temperature 12 hours.After reaction finishes, with saturated sodium bicarbonate aqueous solution cancellation reaction, then drip saturated aqueous solution of sodium bisulfite and remove residual iodine, then be extracted with ethyl acetate, merge organic phase, with saturated common salt water washing three times, after anhydrous sodium sulfate drying, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=5:1), obtain 6-(benzyloxy)-2-methoxyl group benzo furans 150 mg (yellow solid, yield 54%).
1HNMR(CDCl
3；300MHz), δ3.87(s, 3H, OCH
3), 5.14(s, 2H, O
CH 2 Ph), 6.826(s, 1H, ArH), 6.889-6.918(d, 1H, ArH, J=8.7Hz), 6.968-6.991(d, 2H, ArH, J=6.9Hz), 7.132(s, 1H, CH), 7.350-7.503(m, 6H, ArH), 7.739-7.768(d, 2H, ArH, J=8.7Hz)。
embodiment 4
2-methoxyl group-6-hydroxyl benzofuran IV
1synthetic (Fig. 1): by 6-(benzyloxy)-2-methoxyl group benzo furans (50mg, 0.15ml) be dissolved in methylene dichloride (10ml), under room temperature, drip titanium tetrachloride (21.8ul, 0.20 mmol), drip off rear stirring at room temperature half an hour.After reaction finishes, use methyl alcohol cancellation, after concentrating under reduced pressure, obtain 2-methoxyl group-6-hydroxyl benzofuran 23mg (colorless solid, yield 63%) through silica gel chromatography column purification (sherwood oil: ethyl acetate=5:1).
1hNMR (CDCl
3; 300MHz), δ 3.968 (s, 3H, OCH
3), 4.94 (brs, 1H, OH), (6.854-6.878 d, 1H, ArH, J=7.2Hz), 6.914 (s, 1H, CH), 7.060-7.104 (m, 3H, ArH), 7.470-7.498 (d, 1H, ArH, J=8.4Hz), 7.836-7.864 (d, 2H, ArH, J=8.4Hz).
embodiment 5
Synthetic (Fig. 1) of 2-(5-methyl-2-Ben Ji oxazole-4-yl) methyl acetate: by bromo-4-3-oxopentanoic acid methyl esters (10g, 45mmol) be dissolved in (200ml) in toluene, then add benzamide (5.45g in batches, 45mmol), add rear backflow 12 hours.After having reacted, filter concentrating under reduced pressure, silica gel chromatography column purification (sherwood oil: ethyl acetate=10:1), obtains 2-(5-methyl-2-benzene base oxazole-4-yl) methyl acetate 4.4g (yellow oil, yield 40%).
1HNMR((CD
3)
2CO；300MHz), δ2.378(s, 3H, CH
3), 3.587(s, 2H, CH
2), 3.665(s, 3H, OCH
3), 7.473-7.499(m, 3H, ArH), 7.950-7.982(m, 2H, ArH)。
embodiment 6
Synthetic (Fig. 1) of 2-(5-methyl-2-Ben Ji oxazole-4-yl) ethanol: by Lithium Aluminium Hydride (207.1mg, 5.45 mmol) be dissolved in anhydrous diethyl ether (20ml), in the time of-5 DEG C, drip 2-(5-methyl-2-Ben Ji oxazole-4-yl) methyl acetate (890mg, diethyl ether solution 3.63mmol), after dropping finishes, stirring at normal temperature half an hour.After having reacted, in reaction system, drip saturated aqueous ammonium chloride solution cancellation, until white floss appears in reaction system.Filter, water washs by ethyl acetate, merges organic phase, with saturated salt solution washing three times, uses anhydrous sodium sulfate drying.Concentrating under reduced pressure obtains 2-(5-methyl-2-Ben Ji oxazole-4-yl) ethanol 710 mg (colorless solid, yield 96%).
1HNMR(CDCl
3；300MHz), δ2.347(s, 3H, CH
3), 2.754-2.792(t, 2H, CH
2 CH 2 , J=5.7Hz), 3.924-3.963(t, 2H,
CH 2 CH
2, J=5.8Hz), 6.0-6.5(brs, 1H, OH), 7.431-7.450(m, 3H, ArH), 7.989-8.021(m, 2H, ArH)。
embodiment 7
Synthetic (Fig. 1) of 2-(5-methyl-2-Ben Ji oxazole-4-yl) ethyl methane sulfonate: by 2-(5-methyl-2-Ben Ji oxazole-4-yl) ethanol (630mg, 3.1mmol) be dissolved in methylene dichloride (15ml), drip triethylamine (0.64ml, 4.65 mmol), then by methylsulfonyl chloride (0.37ml, 4.65mmol) in the time of 0 DEG C, be added drop-wise in reaction system, after dropping finishes, stirring at normal temperature 4 hours.After having reacted, in reaction system, drip saturated aqueous ammonium chloride solution cancellation, water washs by ethyl acetate, merges organic phase, with saturated salt solution washing three times, uses anhydrous sodium sulfate drying.Silica gel chromatography column purification after concentrating under reduced pressure (sherwood oil: ethyl acetate=5:1), obtains 2-(5-methyl-2-benzene base oxazole-4-yl) ethyl methane sulfonate 700 mg (colorless solid, yield 80%).
1H NMR(CDCl
3；300 MHz), δ2.365(s, 3H, CH
3), 2.935-2.978(m, 5H, CH
2 CH 2 , CH
3), 4.509-4.553(t, 2H,
CH 2 CH
2, J=6.6Hz), 7.423-7.446(m, 3H, ArH),7.957-7.990(m, 2H, ArH)。
embodiment 8
4-(2-(2-(4-anisole) cumarone-6-oxygen base) ethyl)-5-methyl-2-Ben Ji oxazole V
1synthetic (Fig. 1): by 2-(5-methyl-2-Ben Ji oxazole-4-yl) ethyl methane sulfonate (690mg, 2.45mmol), 2-methoxyl group-6-hydroxyl benzofuran (588.2mg, 2.45mmol) and salt of wormwood (675.8mg, 4.9mmol) be dissolved in acetonitrile (20ml), reflux 12 hours.After having reacted, in reaction system, drip saturated aqueous ammonium chloride solution cancellation, water washs by ethyl acetate, merges organic phase, with saturated salt solution washing three times, uses anhydrous sodium sulfate drying.Silica gel chromatography column purification after concentrating under reduced pressure (sherwood oil: ethyl acetate=5:1), obtain 4-(2-(2-(4-anisole) cumarone-6-oxygen base) ethyl)-5-methyl-2-Ben Ji oxazole 520mg (yellow solid, yield 50%).
1H NMR(CDCl
3；300 MHz), δ 2.415(s, 3H, CH
3), 3.065-3.021(t, 2H,
CH 2 CH
2, J=6.6Hz), 3.852(s, 3H, OCH
3), 4.334-4.292(t, 2H, CH
2 CH 2 , J=6.3Hz), 6.802(s, 1H, CH), 6.830-6.859(d, 1H, ArH, J=8.7Hz), 6.951-6.980(d, 2H, ArH, J=8.7Hz), 7.065(s, 1H, ArH), 7.353-7.447(m, 4H, ArH), 7.723-7.748(d, 2H, ArH, J=7.5Hz), 8.001-8.025(m, 2H, ArH)。
embodiment 9
1-(2-(4-p-methoxy-phenyl)-6-(2-(5-methyl-2-phenyl-4-yl) oxyethyl group) cumarone-3-yl) ethyl ketone VI
1synthetic (Fig. 1): by 4-(2-(2-(4-anisole) cumarone-6-oxygen base) ethyl)-5-methyl-2-Ben Ji oxazole (50mg, 0.12mmol) and Acetyl Chloride 98Min. (12.7ul, 0.18mmol) be dissolved in methylene dichloride (10ml), drip tin tetrachloride (17.1ul, 0.144mmol), stirring at room temperature 12 hours.After reaction finishes, water cancellation, is then extracted with ethyl acetate, and merges organic phase, with saturated salt solution washing three times, uses anhydrous sodium sulfate drying.Silica gel chromatography column purification after concentrating under reduced pressure (sherwood oil: ethyl acetate=3:1), obtain 1-(2-(4-p-methoxy-phenyl)-6-(2-(5-methyl-2-phenyl-4-yl) oxyethyl group) cumarone-3-yl) ethyl ketone 28mg (yellow solid, yield 51%).
1H NMR(CDCl
3；300 MHz), δ2.051(s, 3H, CH
3), 2.415(s, 3H, CH
3), 3.065-3.021(t, 2H,
CH 2 CH
2, J=6.6Hz), 3.852(s, 3H, OCH
3), 4.334-4.292(t, 2H, CH
2 CH 2 , J=6.3Hz), 6.830-6.859(d, 1H, ArH, J=8.7Hz), 6.951-6.980(d, 2H, ArH, J=8.7Hz), 7.065(s, 1H, ArH), 7.353-7.447(m, 4H, ArH), 7.723-7.748(d, 2H, ArH, J=7.5Hz), 8.001-8.025(m, 2H, ArH)。
embodiment 10
(E)-1-(2-(4-p-methoxy-phenyl)-6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group) cumarone-3-yl)-3-(3,4,5-trimethoxyphenyl) third-2-alkene-1-ketone VI
2synthetic (Fig. 1); By 1-(2-(4-p-methoxy-phenyl)-6-(2-(5-methyl-2-phenyl-4-yl) oxyethyl group) cumarone-3-yl) ethyl ketone (28mg, 0.059mmol) He 3,4,5-TMB (12mg, 0.059mmol) be dissolved in methyl alcohol (15ml), then add potassium hydroxide (6.6mg, 0.118mmol), reflux 12 hours.After reaction finishes, with the cancellation of 1N hydrochloric acid, the pH value of solution is transferred to 1.Then use dichloromethane extraction, merge organic phase, with saturated salt solution washing three times, use anhydrous sodium sulfate drying.Silica gel chromatography column purification after concentrating under reduced pressure (sherwood oil: ethyl acetate=3:1), obtain (E)-1-(2-(4-p-methoxy-phenyl)-6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group) cumarone-3-yl)-3-(3,4,5-trimethoxyphenyl) third-2-alkene-1-ketone 10mg (solid, 25%).
1H NMR(CDCl
3；300MHz), δ2.586(s, 3H, CH
3), 3.035-3.079(d, 2H,
CH 2 CH
2, J=6.6Hz), 3.853(s, 12H, 4OCH
3), 4.428-0.472(d, 2H, CH
2 CH 2 , J=6.6Hz), 6.510(s, 1H, ArH), 6.809-6.861(d, 1H,
CH=CH, J=15.6Hz), 7.003-7.107(m, 5H, ArH), 7.429-7.443(m, 2H, ArH), 7.654-7.743(m, 4H, ArH),7.992-8.021(m, 2H, ArH)。
embodiment 11
(E)-5-(benzyloxy)-2-(2-(5-methyl furan-2-yl) vinyl) phenol II
2synthetic (Fig. 1): with reference to embodiment 2, yield 60%.
1HNMR(CDCl
3；300MHz), δ2.355(s, 3H, CH
3), 5.057(s, 2H, CH
2), 6.149-6.177(d, 1H, CH
CH, J=8.4 Hz), 6.189-6.200(d, 1H,
CHCH, J=3.3 Hz), 6.472-6.480(d, 1H, ArH, J=2.4 Hz), 6.571-6.579(d, 1H, ArH, J=2.4 Hz), 6.688(s, 1H, ArH), 6.765-6.819(d, 1H,
CH=CH, J=16.2 Hz), 7.073-7.128(d, 1H, CH=
CH, J=16.5 Hz), 7.372-7.426(m, 5H, ArH),8.634-8.653(brs, 1H, OH)。
embodiment 12
(E)-5-(benzyloxy)-2-styryl phenol II
3synthetic (Fig. 1): with reference to embodiment 2, yield 32%.
1H NMR(CDCl
3；300 MHz), δ5.079(s, 2H, CH
2), 6.474-6.482(d, 1H, ArH, J=2.4Hz), 6.523-6.531(d, 1H, ArH, J=2.4Hz), 6.608-6.644(d, 1H, CH=
CH, J=10.8Hz), 6.993-7.048(d, 1H,
CH=CH, J=16.5Hz), 7.138(s, 1H, ArH), 7.365-7.534(m, 5H, ArH), 8.105-8.133(brs, 1H, OH)。
embodiment 13
6-(benzyloxy)-2-(5-methyl furan-2-yl) cumarone III
2synthetic (Fig. 1); With reference to embodiment 3, yield 15%.
1HNMR(CDCl
3；300MHz), δ2.385(s, 3H, CH
3), 5.112(s, 2H, CH
2), 6.085-6.093(d, 1H, CHCH, J=2.4Hz), 6.611-6.600(d, 1H, CHCH, J=3.3Hz), 6.754(s, 1H, ArH), 6.923-6.931(d, 1H, ArH, J=2.4Hz), 6.952-6.959(d, 1H, ArH, J=2.1Hz), 7.256(s, 1H, CH), 7.375-7.452(m, 5H, ArH)。
embodiment 14
6-(benzyloxy)-2-phenyl benzofurans III
3synthetic (Fig. 1); With reference to embodiment 3, yield 54%.
1H NMR(CDCl
3；300 MHz), δ5.134(s, 2H, CH
2), 6.937-6.972(m, 2H, ArH), 7.116-7.141(m, 1H, ArH), 7.257-7.465(m, 10H, ArH), 7.822(s, 1H, CH)。
embodiment 15
2-phenyl-6-hydroxyl benzofuran IV
2synthetic (Fig. 1): with reference to embodiment 4, yield 90%.
1H NMR(CDCl
3； 300 MHz), δ4.5-5.0(brs, 1H, OH), 6.957-7.025(m, 2H, ArH), 7.269-7.302(m, 1H, ArH), 7.405-7.441(m, 5H, ArH), 7.839(s, 1H, CH)。
embodiment 16
2-(5-methyl furan-2-yl)-6-hydroxyl benzofuran IV
3synthetic (Fig. 1): with reference to embodiment 4, yield 60%.
1HNMR(CDCl
3；300MHz), δ2.478(s, 3H, CH
3), 6.864-6.893(d, 1H, CHCH, J=8.7Hz), 6.955-6.984(d, 1H, CHCH, J=8.7Hz), 7.066(s, 1H, CH), 7.523(s, 1H, ArH), 7.872-7.892(m, 2H, ArH), 9.843(brs, 1H, OH)。
embodiment 17
4-(2-(2-phenyl) cumarone-6-oxygen base) ethyl)-5-methyl-2-Ben Ji oxazole V
2(Fig. 1): with reference to embodiment 8, yield 48%.
1HNMR(CDCl
3；300MHz), δ2.420(s, 3H, CH
3), 3.010-3.054(t, 2H,
CH 2 CH
2, J=6.6Hz), 4.277-4.321(t, 3H, CH
2 CH 2 , J=6.6Hz), 6.818(s, 1H, ArH), 6.872-6.890(m, 2H, ArH), 6.950(s, 1H, CH), 7.088-7.433(m, 10H, ArH)。
embodiment 18
5-methyl-4-(2-(2-(5-methyl furan-2-yl) cumarone-6-oxygen base) ethyl)-2-Ben Ji oxazole V
3(Fig. 1): with reference to embodiment 8, yield 66%.
1HNMR(CDCl
3；300 MHz), δ2.058(s, 3H, CH
3), 2.389(s, 3H, CH
3), 3.014-3.058(t, 2H,
CH 2 CH
2, J=6.6Hz), 4.283-4.327(t, 2H, CH
2 CH 2 , J=6.6Hz), 6.089-6.097(d, 1H,
CHCH, J=2.4Hz), 6.602-6.613(d, 1H, CH
CH, J=3.3Hz), 6.749(s, 1H, CH), 6.868-6.875(d, 1H, ArH, J=2.1Hz), 7.050-7.054(d, 1H, ArH, J=1.2Hz), 7.270-7.292(m, 2H, ArH), 7.431-7.450(m, 3H, ArH), 7.998-8.030(m, 2H, ArH)。
embodiment 19
(6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-(5-methyl furan-2-yl) cumarone-3-yl) (3,4,5-trimethoxyphenyl) ketone VI
3synthetic (Fig. 1): with reference to embodiment 9, yield 35%.
1H NMR(CDCl
3； 300 MHz), δ2.056(s, 3H, CH
3), 2.436(s, 3H, CH
3), 3.075-3.119(t, 2H,
CH 2 CH
2, J=6.6 Hz), 3.993(s, 9H, 3OCH
3), 4.223-4.367(t, 2H, CH
2 CH 2 , J=6.6Hz), 6.863-6.874(d, 1H,
CHCH, J=3.3Hz), 6.892-6.912(d, 1H, CH
CH, J=2.4Hz), 7.102-7.116(m, 3H, ArH), 7.378-7.462(m, 3H, ArH),7.463-7.472(m, 2H, ArH)。
embodiment 20
1-(6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-(5-methyl furan-2-yl) cumarone-3-yl) ethyl ketone VI
4synthetic (Fig. 1): with reference to embodiment 9, yield 33%.
1HNMR(CDCl
3；300 MHz), δ2.413(s, 3H, CH
3), 2.453(s, 3H, CH
3), 2.677(s, 3H, CH
3), 3.029-3.073(t, 2H,
CH 2 CH
2, J=6.6Hz), 4.298-4.342(t, 2H, CH
2 CH 2 , J=6.6Hz), 6.213-6.224(d, 1H,
CHCH, J=3.3Hz), 6.947-6.658(d, 1H,CH
CH, J=3.3Hz), 7.137-7.144(d, 1H, ArH, J=2.1Hz), 7.147-7.159(d, 1H, ArH, J=3.6Hz), 7.430-7.485(m, 3H, ArH), 7.834(s, 1H, ArH), 8.003-8.024(m, 2H, ArH)。
embodiment 21
(6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-(5-methyl furan-2-yl) cumarone-3-yl) (4-(trifluoromethyl) phenyl) ketone VI
5synthetic (Fig. 1): with reference to embodiment 9, yield 14%.
1H NMR(CDCl
3； 300 MHz), δ2.287(s, 3H, CH
3), 2.265(s, 3H, CH
3), 2.967-3.011(t, 2H,
CH 2 CH
2, J=6.6Hz), 4.253-4.297(t, 2H, CH
2 CH 2 , J=6.6Hz), 6.213-6.224(d, 1H,
CHCH, J=3.3Hz), 6.947-6.658(d, 1H, CH
CH, J=3.3Hz), 7.039-7.061(d, 2H, ArH, J=6.6Hz), 7.137-7.144(d, 1H, ArH, J=2.1Hz), 7.147-7.159(d, 1H, ArH, J=3.6Hz), 7.393-7.402(m, 5H, ArH), 7.834(s, 1H, ArH), 7.997-8.010(m, 2H, ArH)。
embodiment 22
1-(6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl benzofurans-3-yl) ethyl ketone VI
6synthetic (Fig. 1): with reference to embodiment 9, yield 61%.
1HNMR(CDCl
3；300 MHz), δ2.223(s, 3H, CH
3), 2.532(s, 3H, CH
3), 3.006-3.050(t, 2H,
CH 2 CH
2, J=6.6Hz), 4.206-4.250(t, 2H, CH
2 CH 2 , J=6.6Hz), 7.137-7.144(d, 1H, ArH, J=2.1Hz), 7.147-7.159(d, 1H, ArH, J=3.6Hz), 7.376-7.627(m, 10H, ArH), 7.834(s, 1H, ArH)。
embodiment 23
(E)-1-(6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl benzofurans-3-yl)-3-(4-(trifluoromethyl) phenyl) third-2-alkene-1-ketone VI
7synthetic (Fig. 1): with reference to embodiment 10, yield 35%.
1HNMR(CDCl
3；300MHz), δ2.435(s, 3H, CH
3), 3.011-3.055(t, 2H,
CH 2 CH
2, J=6.6Hz), 4.483-4.527(t, 2H, CH
2 CH 2 , J=6.6Hz), 6.610-6.637(d, 2H, ArH, J=8.1Hz), 6.983-6.997(d, 1H, ArH, J=4.2Hz), 7.060-7.079(d, 1H, ArH, J=5.7Hz), 7.393-7.605(m, 13H, ArH,
CH=CH), 7.743(s, 1H, ArH)。
embodiment 24
6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl benzofurans-3-formaldehyde VI
8synthetic (Fig. 1): in the time of 0～5 DEG C by phosphorus oxychloride (94.9ul, 1.04mmol) be added drop-wise to N, dinethylformamide (80.8ul, 1.04 mmol) and 1, in 2-ethylene dichloride (10ml), stir after 10 minutes, by 4-(2-(2-phenyl) cumarone-6-oxygen base) ethyl)-5-methyl-2-Ben Ji oxazole (50mg, 0.13mmol) join in mixture solution, reflux 12 hours.After reaction finishes, reaction solution is poured in frozen water, with dichloromethane extraction, water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing successively, then used anhydrous sodium sulfate drying.After concentrating under reduced pressure, obtain 6-(2-(5-methyl-2-benzene base oxazole-4-yl) oxyethyl group)-2-phenyl benzofurans-3-formaldehyde 20 mg (solid, yield 37%) through silica gel chromatography column purification (sherwood oil: ethyl acetate=5:1).
1HNMR(CDCl
3；300 MHz), δ2.417(s, 3H, CH
3), 3.020-3.064(t, 2H,
CH 2 CH
2, J=6.6Hz), 4.317-4.361(t, 2H, CH
2 CH 2 , J=6.6Hz), 7.174-8.137(m, 13H, ArH), 10.312(s, 1H, CHO)。
embodiment 25
(6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl benzofurans-3-yl) methyl alcohol VI
9synthetic (Fig. 1): by 6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl benzofurans-3-formaldehyde (60mg, 0.14mmol) be dissolved in methyl alcohol (10ml), add sodium borohydride (8.1mg, 0.21mmol), stirring at room temperature 45 minutes.After reaction finishes, reaction solution is poured in frozen water, with dichloromethane extraction, merged organic phase, with saturated common salt water washing three times, then use anhydrous sodium sulfate drying.After concentrating under reduced pressure, obtain (6-(2-(5-methyl-2-benzene base oxazole-4-yl) oxyethyl group)-2-phenyl benzofurans-3-yl) methyl alcohol 12mg (yellow solid, yield 20%) through silica gel chromatography column purification (sherwood oil: ethyl acetate=3:1).
1HNMR(CDCl
3；300MHz), δ2.390(s, 3H, CH
3), 2.977-3.021(t, 2H,
CH 2 CH
2, J=6.6Hz), 4.234-4.278(t, 2H, CH
2 CH 2 , J=6.6Hz), 4.936(s, 2H,
CH 2 OH), 6.861-6.889(d, 2H, ArH, J=8.4Hz), 7.043(s, 1H, ArH), 7.376-7.470(m, 10H, ArH)。
embodiment 26
(E)-3,4,5-trimethoxy-N-((6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl benzofurans-3-yl) methylene radical) aniline VI
10synthetic (Fig. 1): by 6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl benzofurans-3-formaldehyde (50mg, 0.118mmol) He 3,4,5-trimethoxy-aniline (21.6mg, 0.118mmol) be dissolved in toluene (10ml), reflux 12 hours.After reaction finishes, concentrating under reduced pressure, obtain (E)-3 through silica gel chromatography column purification (sherwood oil: ethyl acetate=5:1), 4,5-trimethoxy-N-((6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl benzofurans-3-yl) methylene radical) aniline 23mg (yellow solid, yield 33%).
1HNMR(CDCl
3；300MHz), δ2.416(s, 3H, CH
3), 3.022-3.067(t, 2H,
CH 2 CH
2, J=6.6Hz), 3.906(s, 9H, 3OCH
3), 4.327-4.371(t, 2H, CH
2 CH 2 , J=6.6Hz), 6.462-6.497(d, 2H, ArH, J=10.5Hz), 6.982(s, 1H, ArH), 6.989-7.145(m, 2H, ArH), 7.425-7.505(m, 6H, ArH), 7.751-7.769(m, 2H, ArH), 7.990-8.011(m, 2H, ArH), 8.784(s, 1H,
CH=N)。
embodiment 27
3,4,5-trimethoxy-N-((6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl benzofurans-3-yl) methyl) aniline VI
11synthetic (Fig. 1): by (E)-3,4,5-trimethoxy-N-((6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl benzofurans-3-yl) methylene radical) aniline (17mg, 0.0289mmol) be dissolved in methyl alcohol (5 ml), add sodium borohydride (1.65mg, 0.0433mmol) and acetic acid (catalytic amount), stirring at room temperature 12 hours.After reaction finishes, reaction solution is poured in frozen water, with dichloromethane extraction, merged organic phase, with after saturated common salt water washing three times, then use anhydrous sodium sulfate drying.After concentrating under reduced pressure, obtain 3 through silica gel chromatography column purification (sherwood oil: ethyl acetate=3:1), 4,5-trimethoxy-N-((6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl benzofurans-3-yl) methyl) aniline 17mg (yellow solid, yield 100%).
1HNMR(CDCl
3；300 MHz), δ2.411(s, 3H, CH
3), 3.016-3.060(d, 2H,
CH 2 CH
2, J=6.6Hz),3.789(s, 9H, 3OCH
3), 4.299-4.343(d, 2H, CH
2CH
2, J=6.6Hz), 5.917(s, 2H, CH), 7.094-7.172(m, 3H, ArH), 7.421-7.476(m, 8H, ArH), 7.774-7.800(m, 2H, ArH), 7.979-7.994(m, 2H, ArH)。
the anti-tumor activity of embodiment 28, compound
Adopt tumor cell in vitro model, mtt assay carries out screening active ingredients test, and test operation step comprises:
(1) cell cultures
Cultivator breast cancer cell (MCF-7), Human Prostate Cancer Cells (DU-145) and African green monkey kidney inoblast (COS-7), all use containing the DMEM nutrient solution of 10% foetal calf serum and cultivate, human cervical carcinoma cell (Hela), mouse leukemia cell (K562) use containing 1640 nutrient solution of 10% foetal calf serum and cultivate.
Get the each pipe of human breast cancer cell frozen in liquid nitrogen (MCF-7), Human Prostate Cancer Cells (DU-145) and human cervical carcinoma cell (Hela), in 37 DEG C of water-bath recoveries, add 6 ml nutrient solutions, centrifugal 5 min of 1000 rpm, supernatant liquor inclines, repeat after twice, add after the DMEM substratum piping and druming evenly of 10 ml containing 10% foetal calf serum, being divided into two parts of kinds enters in 10 ml culturing bottles, being placed in 37 DEG C, the cell culture incubator of 5%CO2 hatches, go down to posterity in good time, required in order to experiment.
(2) medicine preparation
All compounds are now with the current, and compound is prepared with DMSO, and maximum concentration is 100mM, prepare and are placed on-20 DEG C of preservations, for repeatedly.When administration, again according to desired concn, progressively dilute with DMSO.
(3) MTT analytical method
The required cell of taking the logarithm vegetative period, plants into 96 well culture plates 100 μ l(approximately 2000～4000 cells in every hole after being adjusted into proper concn), and be placed in respectively 37 DEG C, 5%CO
2condition under hatch 24 h, the medicine preparing is added successively and is cultivated in plate hole, every hole 1 μ l, it is 100 μ M, 75 μ M, 50 μ M, 25 μ M, 10 μ M that its final concentration is respectively, each concentration is all established 3 multiple holes.Negative control is equal-volume substratum, establishes the DMSO solvent control of respective concentration simultaneously.96 well culture plates after administration are placed in to 37 DEG C, 5%CO
2condition under hatch 48 h.In every hole of 96 porocyte culture plates, add the 5.0 mg/ml MTT of 20 μ l, and be placed in 37 DEG C, 5%CO
2condition under hatch 4 h, then suck nutrient solution, and add 150 μ l DMSO in every hole, use microplate reader to detect each hole A490 value or A470 value, calculating inhibiting rate, use SPSS computed in software inhibition concentration IC50 value.
In table 1, positive control sample used is classical Remedies for diabetes rosiglitazone (Rosiglitazone) and the classical antitumor drug taxol Taxol with anti-tumor activity.Tumor cell in vitro inhibition test result shows, except the benzofuran compound with side chain not has certain cytotoxicity African green monkey kidney inoblast COS-7, the cytotoxicity equal >100uM of other compounds to African green monkey kidney inoblast COS-7, illustrates that this compounds toxicity is less.Compare the IC of compound (1,4,7) with positive control sample taxol (Taxol), rosiglitazone (Rosiglitazone)
50substantially all between 10～50 μ Μ; Compound 9 and 12 has narrow spectrum tumor inhibition effect for Human Prostate Cancer Cells (DU-145).
The test of table 1 benzofuran compounds anti-tumor biological
Claims (2)
1. a benzofuran compounds, is characterized in that, its structural formula is:
Wherein, R1 is 3,4,5-trimethoxy benzoyl, and R2 is 2-methyl-5-furyl, and R3 is (5-methyl-2-benzene base oxazole-4-yl) ethyl.
Described in a claim 1 benzofuran compounds in the purposes for the preparation of in inhibition tumor cell biologically active drug, it is characterized in that, described tumour cell is human breast cancer cell, Human Prostate Cancer Cells, African green monkey kidney inoblast, human cervical carcinoma cell, mouse leukemia cell.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110242547.9A CN102351852B (en) | 2011-08-23 | 2011-08-23 | Coumarone compound, its preparation method and its application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110242547.9A CN102351852B (en) | 2011-08-23 | 2011-08-23 | Coumarone compound, its preparation method and its application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102351852A CN102351852A (en) | 2012-02-15 |
| CN102351852B true CN102351852B (en) | 2014-06-18 |
Family
ID=45575521
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110242547.9A Expired - Fee Related CN102351852B (en) | 2011-08-23 | 2011-08-23 | Coumarone compound, its preparation method and its application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102351852B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103588763B (en) * | 2011-09-29 | 2016-07-06 | 上海交通大学 | 2-replaces-3-aryl ketone-6-(5-methyl-2-phenyl-4-ethyoxyl oxazole) benzofuran compound |
| CN102391260B (en) * | 2011-09-29 | 2014-12-10 | 上海交通大学 | 3-ketone-6-substituted-benzofuran compound as well as preparation method and application thereof |
| CN110746392B (en) * | 2019-10-31 | 2023-06-09 | 重庆医科大学 | Application of furan compounds in preparation of antitumor drugs |
| WO2021233352A1 (en) * | 2020-05-19 | 2021-11-25 | 上海交通大学 | Compound having response to endocytic release of cells and use thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0733631A1 (en) * | 1995-03-14 | 1996-09-25 | Takeda Chemical Industries, Ltd. | Benzofuran derivates useful as hypoglycemic and hypolidemic agents |
| WO2004063190A1 (en) * | 2003-01-06 | 2004-07-29 | Eli Lilly And Company | Fused heterocyclic derivates as ppar modulators |
| CN1678596A (en) * | 2002-08-30 | 2005-10-05 | 霍夫曼-拉罗奇有限公司 | Novel 2-arylthiazole compounds as pparalpha and ppargamma agonists |
| US20060135578A1 (en) * | 2002-09-10 | 2006-06-22 | Yu Momose | Five-membered heterocyclic compounds |
| CN100356917C (en) * | 2001-05-15 | 2007-12-26 | 霍夫曼-拉罗奇有限公司 | Carboxylic and substituted oxazole derivatives for use as PPAR-& and PPAR-r activators in the treatment of diabetes |
-
2011
- 2011-08-23 CN CN201110242547.9A patent/CN102351852B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0733631A1 (en) * | 1995-03-14 | 1996-09-25 | Takeda Chemical Industries, Ltd. | Benzofuran derivates useful as hypoglycemic and hypolidemic agents |
| CN100356917C (en) * | 2001-05-15 | 2007-12-26 | 霍夫曼-拉罗奇有限公司 | Carboxylic and substituted oxazole derivatives for use as PPAR-& and PPAR-r activators in the treatment of diabetes |
| CN1678596A (en) * | 2002-08-30 | 2005-10-05 | 霍夫曼-拉罗奇有限公司 | Novel 2-arylthiazole compounds as pparalpha and ppargamma agonists |
| US20060135578A1 (en) * | 2002-09-10 | 2006-06-22 | Yu Momose | Five-membered heterocyclic compounds |
| WO2004063190A1 (en) * | 2003-01-06 | 2004-07-29 | Eli Lilly And Company | Fused heterocyclic derivates as ppar modulators |
Non-Patent Citations (4)
| Title |
|---|
| Christian Hafner,等."New Indications for Established Drugs:Combined Tumor-Stroma-Targeted Cancer Therapy with PPARγ Agonists, COX-2 Inhibitors,mTOR Antagonists and Metronomic Chemotherapy".《Current Cancer Drug Targets》.2005,第5卷(第6期),第393-419页. * |
| ChristianHafner，等."NewIndicationsforEstablishedDrugs：CombinedTumor-Stroma-TargetedCancerTherapywithPPARγAgonists COX-2 Inhibitors，mTOR Antagonists and Metronomic Chemotherapy".《Current Cancer Drug Targets》.2005 |
| 顾中怡，等."抗癌药物Combretastatin A-4及其水溶性衍生物的合成".《中国新药杂志》.2008,第17卷(第15期),第1322-1325页. |
| 顾中怡,等."抗癌药物Combretastatin A-4及其水溶性衍生物的合成".《中国新药杂志》.2008,第17卷(第15期),第1322-1325页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102351852A (en) | 2012-02-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104030990B (en) | Phenyl amino pyrimidine compounds and application thereof | |
| RU2528408C2 (en) | Method for preparing dihydroindenamide compounds, pharmaceutical compositions containing these compounds and using them as protein kinase inhibitor | |
| WO2006046779A1 (en) | Carbazole derivative, solvate thereof, or pharmaceutically acceptable salt thereof | |
| US20190169140A1 (en) | Ido1 inhibitor and preparation method and application thereof | |
| CN102351852B (en) | Coumarone compound, its preparation method and its application | |
| CN1006792B (en) | Process for preparing hydroxy, alkoxypyrimidine | |
| US20140221374A1 (en) | Raf kinase inhibitors | |
| CN107445896B (en) | Phenyl hydroxamic acid compound with anti-tumor activity and application thereof | |
| CN104230905A (en) | Synthesis of dihydropyrazol sulfonamide derivatives containing benzodioxane skeletons and application of dihydropyrazol sulfonamide derivatives in anti-cancer drugs | |
| CN106660970A (en) | Quinazoline derivative | |
| CN109776607A (en) | Aryl phosphorus oxygen class and aryl phosphorus sulphur class compound and its preparation method and application | |
| CN111499591A (en) | ROR gamma modulators | |
| CN101463031B (en) | Indazole and tetrahydrochysene indazole compounds, and preparation, pharmaceutical composition and use thereof | |
| CN102391260B (en) | 3-ketone-6-substituted-benzofuran compound as well as preparation method and application thereof | |
| CN110240539A (en) | A kind of fluorine substituted diphenylamine ethane compound and preparation method and application | |
| CN106966986B (en) | N- benzyl heterocyclic nitro ketene semiamine analog derivative and synthetic method and antitumor application thereof | |
| CN108623511A (en) | A kind of indole amides class compound can be used for treating cancer | |
| CN108530337A (en) | A kind of alternative indole amides class compound for inhibiting stomach cancer cell | |
| US20030176474A1 (en) | Modulators of Rho C activity | |
| CN104230904A (en) | Synthesis of dihydropyrazol sulfonamide derivatives containing naphthalene ring skeletons and application of dihydropyrazol sulfonamide derivatives in anti-cancer drugs | |
| KR101118842B1 (en) | 5-1,3-diaryl-1H-pyrazol-4-ylmethylene-thiazolidine-2,4-dione derivatives useful as antitumor agent | |
| CN104163772A (en) | Substituted diaryl ester compound, and preparation method and application thereof | |
| CN116265453A (en) | Compounds as AR inhibitors and uses thereof | |
| CN102030756B (en) | 6,7-methylene-dioxy-1,2,3,4-tetrahydroisoquinoline derivative and preparation method and application thereof | |
| CN102086212A (en) | Antifungal agents of 2,3,4,5-tetrahydro-4H-benzo[b]thiopyrano[4,3,c]pyrazole-2-formamide derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140618 Termination date: 20170823 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |