CN102153535A - Benzopyranyl-3-alcohol esterified derivative serving as antineoplastic multidrug resistance inhibitor and preparation method and application of benzopyranyl-3-alcohol esterified derivative - Google Patents
Benzopyranyl-3-alcohol esterified derivative serving as antineoplastic multidrug resistance inhibitor and preparation method and application of benzopyranyl-3-alcohol esterified derivative Download PDFInfo
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Abstract
The invention provides a benzopyranyl-3-alcohol esterified derivative and a preparation method of the benzopyranyl-3-alcohol esterified derivative. The benzopyranyl-3-alcohol esterified derivative is shown as the following formula I, wherein in the formula I, R represents one or more of hydrogen, hydroxy, alkoxy, alkyl amino, alkyl acylamino, fluorine or benzoyl; the benzoyl contains one or more of hydroxy, alkoxy, alkyl amino, alkyl acylamino or fluorinated substituents, wherein alkyl in alkoxy, alkyl amino and alkyl acylamino is C1 to C10 straight chain or branched chain alkyl; X in the formula represents hydrogen or oxygen; and Y in the formula represents oxygen or nitrogen and hydrogen. The benzopyranyl-3-alcohol esterified derivative is low-toxic, has excellent antineoplastic multidrug resistance activity and can be used for preparing a medicament for treating breast cancer, colon cancer, prostatic cancer, leukemia, myeloma, pancreatic cancer and the like.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of chromene-3-alcohol esterification derivative and preparation method thereof and as the application of artitumor multi-medicine-resistant inhibitor.
Background technology
Chemotherapy is one of main method of treatment tumour, and the multidrug resistance of tumour cell (MDR) is the major cause of chemotherapy of tumors failure and tumor recurrence and transfer, makes chemotherapy face severe challenge.P-gp is the antitumor drug efflux pump of the dependent wide spectrum of ATP.
The P-gp inhibitor has roughly been developed three generations [Ramalingam, et al:Clin Lung Cancer 2005; 7:773].The first-generation suppresses ingestion of medicines originally as the P-gp substrate, effluxes the medicine ability but suppress P-gp, and toxic side effect is big, has seriously limited its clinical application.Represent medicine such as verapamil, it is the multidrug resistant reversal agent of finding early.The s-generation is representative with Valspodar (PSC-833), Biricodar (VX-710) and Dofequidar fumarate (MS-209) etc., and inhibition P-gp ability is 3～100 times of the first-generation, and toxic side effect decreases.But, because of while competitive inhibition cytochrome P-450 enzyme, change chemotherapeutics pharmacokinetics feature, increased toxicity, thereby restriction chemotherapeutics using dosage.Third generation inhibitor comprises Tariquidar (XR-9576) and Ontogen (ONT-093, OC1442093), and Zosuquidar trihydrochloride (LY-335979), Laniquidar (R-101933), Elacridar (GF-120918) etc., its characteristic feature is that selectivity suppresses P-gp, and longer duration, can the multiple chemotherapeutics of enhanced sensitivity, toxic side effect is little.XR-9576 is carrying out the anti-breast cancer phase iii clinical trial, and [Zhang Yan etc.: medicine estimates 2006 to demonstrate the excellent development prospect; 3:264].
The tea-polyphenol of low toxicity and activeconstituents NVP-XAA 723 thereof, L-Epicatechin gallate and catechin and gallate can combine with P-gp, can reverse the resistance of drug-resistant tumor cells such as CHRC5 and PS833 to antitumor drugs such as many gentle Mi Xing and Zorubicins, the resistance multiple is up to 1.8 times of [Wan Yong Feng, Current Drug Metabolism, 2006,7,755-809.].But it is low that catechin compounds has the artitumor multi-medicine-resistant activity, and shortcomings such as chemistry and biological metabolism unstable, so influenced it greatly as the application in the artitumor multi-medicine-resistant.
Summary of the invention
The present invention is directed in the prior art catechin compounds, to have the artitumor multi-medicine-resistant activity low, and shortcomings such as chemistry and biological metabolism unstable, a kind of chromene-3-alcohol esterification derivative and preparation method thereof is provided, described chromene-3-alcohol esterification derivative has the same bone shelf structure with NVP-XAA 723, but the pure esterification derivative of chromene-3-be low toxicity and have a good resistance tumor multi-medicine drug-resistant activity.The present invention also provides a kind of chromene-purposes of 3-alcohol esterification derivative in artitumor multi-medicine-resistant with general formula I structure.
For achieving the above object, the present invention adopts following technical proposals to be achieved:
A kind of artitumor multi-medicine-resistant inhibitor chromene-3-alcohol esterification derivative, it is represented by following general formula I:
R is one or more in hydrogen, hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl, fluorine or the benzoyl in the general formula I, described benzoyl contains one or more in hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl or the fluoro substituents, wherein alkyl is the alkyl with straight or branched of 1-10 carbon atom in alkoxyl group, alkylamino, the alkylamidoalkyl, X is hydrogen or oxygen in the formula, and Y is oxygen or nitrogen hydrogen in the formula;
Q is one or more in one or more substituent pyridines, piperidines, piperazine, triazine, imidazoles, pyrazoles, thiazole, thiophene, pyrans, furans, benzoglyoxaline, benzothiazole or the chromene in hydrogeneous, hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl or the fluorine in the general formula I; Or Q is represented by following general formula I I, III or IV:
R among general formula I I, III or the IV
1Be in hydrogen, hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl, fluorine or the benzoyl one or more, described benzoyl contains one or more in hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl, the fluoro substituents, wherein alkyl is the alkyl with straight or branched of 1-10 carbon atom in alkoxyl group, alkylamino, the alkylamidoalkyl, and n is 1-5; Or described R
1Group is one or more in one or more substituent pyridines, piperidines, piperazine, triazine, imidazoles, pyrazoles, thiazole, thiophene, pyrans, furans, benzoglyoxaline, benzothiazole or the chromene in hydrogeneous, hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl and the fluorine; Or described R
1Group is represented by following general formula V or VI:
R in the formula
2Be in hydrogen, hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl, fluorine or the benzoyl one or more; described benzoyl contains one or more in hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl or the fluoro substituents; wherein alkyl is the alkyl with straight or branched of 1-10 carbon atom in alkoxyl group, alkylamino, the alkylamidoalkyl, and m is 1-5.
Further, described compound of Formula I is 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3,4, the 5-TMB, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3-methoxybenzoic acid ester, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 4-methoxybenzoic acid ester, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3,4-dimethoxybenzoic acid ester, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3,4,5-triethoxy benzoic ether, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3,4,5-triolefin propoxy benzoic acid ester, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3-fluorobenzoic acid ester, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 4-fluorobenzoic acid ester, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3-dimethylamino-4-fluorobenzoic acid ester, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3-acetylaminohydroxyphenylarsonic acid 4-fluorobenzoic acid ester, 5,7-dimethoxy-2-(3,4, the 5-trimethoxy)-3,4-dihydro-chromene-3-alcohol, 3-(3,4,5-trimethoxy-benzamide base)-4-fluorobenzoic acid ester, 5,7-dimethoxy-2-(3,4, the 5-trimethoxy)-3,4-dihydro-chromene-3-alcohol, 3-(3,4-dimethoxy benzoylamino)-4-fluorobenzoic acid ester, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, the 4-Methoxycinnamate, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3,4-dimethoxy-cinnamic acid ester, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3,4,5-trimethoxy cinnamic acid ester or 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3,4-dimethoxyphenylacetic acid ester.
Described compound of Formula I prepares as follows: with methylene dichloride, chloroform or dimethyl formamide are solvent, triethylamine in the 1-2 mol ratio, pyridine, diisopropyl ethyl amine, N-methylmorpholine or to N, under the existence of N-dimethyl aminopyridine, make 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3, the methoxyl group that contains of 4-dihydro-chromene-3-alcohol and 1-5 mol ratio, oxyethyl group, allyloxy, fluorine, kharophen, dimethylamino or contain the Benzoyl chloride of methoxy benzamide base, reaction such as phenyllacetyl chloride or cinnamyl chloride, prepare described chromene-3-alcohol esterification derivative, the mol ratio of described use reagent is with respect to 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol.
Or described compound of Formula I prepares as follows: with methylene dichloride, chloroform or dimethyl formamide are solvent, triethylamine in the 1-2 mol ratio, pyridine, diisopropyl ethyl amine, N-methylmorpholine or to N, under the existence of N-dimethyl aminopyridine, the 1-2 mol ratio is to dimethyl aminopyridine (DMAP), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) or N, under the N'-carbonyl dimidazoles catalysts such as (CDI), make 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3, the methoxyl group that contains of 4-dihydro-chromene-3-alcohol and 1-5 mol ratio, oxyethyl group, allyloxy, fluorine, kharophen, dimethylamino or contain the phenylformic acid of methoxy benzamide base, reaction such as toluylic acid or styracin, prepare described chromene-3-alcohol esterification derivative, the mol ratio of described use reagent is with respect to 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol.
Further again, described chromene-3-alcohol esterification derivative is used for the treatment of application in the medicine of mammary cancer, colorectal carcinoma, prostate cancer, leukemia, myelomatosis and carcinoma of the pancreas in preparation.
Wherein, described chromene-3-alcohol esterification derivative is as oral medication or parenteral medication; Described oral medication is tablet, capsule or Drug coating, and described parenteral drug formulation is injection or suppository.
Can further describe the synthetic route of general formula I of the present invention in conjunction with following structure iron:
Reagent and reaction conditions:
(a): saturated hydrogen chloride methanol solution, room temperature (HCl/MeOH, rt);
(b): salt of wormwood/methyl-sulfate/acetone/glycol dimethyl ether, (K refluxes
2CO
3/ Me
2SO
4/ acetone/DME, reflux);
(c): salt of wormwood/methyl alcohol/glycol dimethyl ether, room temperature (K
2CO
3/ MeOH/DME, rt);
(d): 3-methoxybenzoic acid, 4-methoxybenzoic acid, 3,4-dimethoxybenzoic acid, 3,4,5-triethoxy phenylformic acid, 3,4,5-triolefin propoxy benzoic acid, 3-fluorobenzoic acid, 4-fluorobenzoic acid, 3-dimethylamino-4-fluorobenzoic acid or 3-acetamido-4-fluorobenzoic acid are to dimethyl aminopyridine (DMAP)/1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI)/methylene dichloride (CDI), room temperature;
(e): 3-(3,4-dimethoxy benzoylamino)-4-fluorobenzoic acid or 3-(3,4,5-trimethoxy-benzamide base)-the 4-fluorobenzoic acid, to dimethyl aminopyridine (DMAP)/1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI)/methylene dichloride (CDI), room temperature;
(f): 4-methoxy cinnamic acid, 3,4-dimethoxy-cinnamic acid or 3,4, the 5-trimethoxy cinnamic acid is to dimethyl aminopyridine (DMAP)/1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI)/methylene dichloride (CDI), room temperature;
(g): 3, the 4-dimethoxyphenylacetic acid is to dimethyl aminopyridine (DMAP)/1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI)/methylene dichloride (CDI), room temperature.
Compared with prior art, advantage of the present invention with positively effect is: the chromene of described general formula I of the present invention-3-alcohol esterification derivative is compared with the s-generation such as Valspodar (PSC-833) etc. with first-generation artitumor multi-medicine-resistant inhibitor such as verapamil etc., and the artitumor multi-medicine-resistant effect is strong and toxic side effect is little.Comprise that with third generation inhibitor (ONT-093 OC1442093) waits and compares, and the chromene of described general formula I of the present invention-3-alcohol esterification derivative demonstrates the selectivity that suppresses P-gp better for Tariquidar (XR-9576) and Ontogen.
The chromene of described general formula I of the present invention-3-alcohol esterification derivative be low toxicity and good resistance tumor multi-medicine drug-resistant activity is arranged, described chromene-3-alcohol esterification derivative can be used to prepare the medicine that treatment is used for the treatment of mammary cancer, colorectal carcinoma, prostate cancer, leukemia, myelomatosis and carcinoma of the pancreas etc.
Embodiment
Below in conjunction with embodiment technical scheme of the present invention is described in further detail.
Embodiment 1: preparation 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3,4,5-TMB (in the synthetic route structure iron shown in 3).
In the saturated hydrogen chloride methanol solution of 50 mL, add full acetylated NVP-XAA 723 2.0 g, 2.5 mmol, solid slowly dissolves, and it is faint yellow that solution shows.Stirring at room is reacted 12 h, and solution colour is deepened gradually, finally becomes burgundy, and the TLC detection reaction is complete.The reaction solution rotary evaporation is removed methyl alcohol and is obtained NVP-XAA 723 (EGCG).EGCG continues to add glycol dimethyl ether-acetone mixed solvent 100 mL without being further purified, and makes it whole dissolvings, adds 7.5 g salt of wormwood afterwards, 10 mL methyl-sulfates.Reflux 48 h, evaporate to dryness.Saturated sodium carbonate solution is washed 3 times, ethyl acetate extraction.Combining extraction liquid, anhydrous magnesium sulfate drying spends the night.Filtering and concentrating, silica gel column chromatography (ethyl acetate: sherwood oil=1:2) get white solid, the petroleum ether-ethyl acetate recrystallization gets white crystal 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3,4,5-TMB 0.6 g, productive rate: 42.8 %.
1H?NMR(CDCl
3,?600?MHz)?δ(ppm):?7.16?(s,?2?H),?6.69?(s,?2?H),?6.24?(d,?J?=?1.2?Hz,?1?H),?6.12?(d,?J?=?1.2?Hz,?1?H),?5.66-5.64?(m,?1?H),?5.08?(bs,?1?H),?3.85-3.78?(m,?24?H),?3.05-3.01?(m,?2?H).?
13C?NMR(CDCl
3,?150?MHz)?δ(ppm):?165.2,?159.9,?158.9,?155.6,?153.2,?153.0,?142.6,?138.0,?133.5,?128.4,?125.2,?107.3,?104.0,?100.2,?93.3,?92.0,?77.9,?77.8,?68.7,?61.0,?60.9,?60.8,?60.5,?56.4,?56.3,?56.1,?56.1,?55.5,?26.0。
Embodiment 2: preparation 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol (in the synthetic route structure iron shown in 4).
With 5 of embodiment 1 preparation, 7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3,4,5-TMB (0.50 g, 0.86 mmol) is dissolved in the mixed solvent of 10 mL methyl alcohol and 10 mL glycol dimethyl ethers, adds 0.2 g K again
2CO
3, stirring at room reaction, TLC detection reaction progress.Behind 1 h, raw material disappears.Evaporate to dryness gets white solid, adds 20 mL ethyl acetate, filters insolubles, and rotary evaporation concentrates, and silica gel column chromatography separates (ethyl acetate: sherwood oil=1:4), get product 0.28 g, productive rate: 87 %.
1H?NMR(CDCl
3,?500?MHz)?δ(ppm):?6.70?(s,?2?H),?6.31?(?d,?J?=8.0?Hz,?1?H),?6.13?(?d,?J?=8.0?Hz,?1?H),?6.59-6.57?(m,?1?H),?5.03-5.01?(m,?1?H),?4.11-4.09?(m,?1?H),?3.87-3.78?(m,?15?H),?2.99-2.97?(m,?2?H).?
13C?NMR(CDCl
3,?125?MHz)?δ(ppm):?160.1,?158.8,?155.0,?153.3,?132.9,?103.6,?103.5,?99.6,?93.3,?92.3,?77.3,?77.1,?76.8,?67.7,?60.8,?56.2,?55.5,?55.4,?26.0。
Embodiment 3: preparation 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 4-methoxybenzoic acid ester (in the synthetic route structure iron shown in 5).
Get 4-methoxybenzoic acid (0.18 g, 1.18 mmol) and 5,7-dimethoxy-2-(3; 4; the 5-trimethoxyphenyl)-3, and 4-dihydro-chromene-3-alcohol (200mg, 0.53mmol); add again Dimethylamino pyridine (0.26 g; 2.15 mmol) with 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.29 g, 2.15 mmol), under the nitrogen protection; be dissolved in 20 ml anhydrous methylene chlorides, stirring at room 24 h react completely.Saturated sodium bicarbonate solution is given a baby a bath on the third day after its birth time, collects organic phase, anhydrous magnesium sulfate drying 4 h, be spin-dried for crude product, post separates (petrol ether/ethyl acetate=3/1 v/v), makes pure product 0.18 g, productive rate 68%.
1H?NMR(CDCl
3,?500?MHz)
δ(ppm):?7.56-7.55?(m,?1?H),?7.54?(s,?1?H),?7.26?(d,?
J?=?16?Hz,?1?H),?7.04?(d,?
J?=?8?Hz,?1?H),?6.71?(s,?1?H),?6.25?(s,?1?H),?6.12?(s,?1?H),?5.65-5.63?(m,?1?H),?5.07-5.05?(m,?1?H),?3.80-3.72?(m,?18?H),?3.06-3.02?(m,?2?H).?
13C?NMR(CDCl
3,?125?MHz)
δ(ppm):?165.4,?159.7,?159.5,?158.9,?155.5,?153.1,?133.4,?131.4,?129.3,?122.0,?119.1,?114.7,?103.9,?100.2,?93.5,?92.0,?77.9,?68.7,?60.8,?55.9,?55.4,?26.0。
Embodiment 4: preparation 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3-methoxybenzoic acid ester (in the synthetic route structure iron shown in 6).
With the 3-methoxybenzoic acid is raw material, and the preparation method is identical with compound 5 in the synthetic route structure iron, and productive rate is 67%;
1H NMR (CDCl
3, 500 MHz)
δ(ppm): 7.26 (d,
J=16 Hz, 2 H), 6.89 (d,
J=16 Hz, 2 H), 6.71 (s, 2 H), 6.25 (s, 1 H), 6.12 (s, 1 H), 5.65-5.63 (m, 1 H), 5.07-5.06 (m, 1 H), 3.80-3.72 (m, 18 H), 3.06-3.02 (m, 2 H).
13C NMR (CDCl
3, 125 MHz)
δ(ppm): 165.3,164.2,159.7,159.5,158.9,155.5,153.1,133.3,130.1,129.3,122.0,93.5,92.0,77.9,68.7,60.7,56.0,55.4,26.1.
Embodiment 5: preparation 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3,4-dimethoxybenzoic acid ester (in the synthetic route structure iron shown in 7).
With 3, the 4-dimethoxybenzoic acid is a raw material, and the preparation method is identical with compound 5 in the synthetic route structure iron, and productive rate is 71%;
1H NMR (CDCl
3, 600 MHz)
δ(ppm): 7.58-7.56 (m, 1 H), 7.42 (s, 1 H), (7.11-7.09 m, 1 H), 6.70-6.68 (m, 2 H), (6.24 s, 1 H), 6.11 (s, 1 H), 5.65-5.63 (m, 1 H), (5.06-5.04 m, 1 H), 3.88-3.71 (m, 21 H), 3.03-3.00 (m, 2 H).
13C NMR (CDCl
3, 150 MHz)
δ(ppm): 165.4,159.7,159.0,155.6,148.7,137.9,133.5,123.8,122.6,112.3,110.2,104.0,100.3,93.4,92.0,78.1,68.3,60.9,60.5,58.5,56.1,56.1,55.5,26.2.
Embodiment 6: preparation 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3,4,5-triethoxy benzoic ether (in the synthetic route structure iron shown in 8).
With 3,4,5-triethoxy phenylformic acid is a raw material, and the preparation method is identical with compound 5 in the synthetic route structure iron, productive rate 65%;
1H NMR (CDCl
3, 600 MHz) and δ 7.13 (s, 2 H), 6.68 (s, 2 H), 6.23 (d, J=1.1 Hz, 1 H), (6.10 s, 1 H), 5.62 (s, 1 H), (5.06 s, 1 H), 4.08-4.04 (q, J=7.1,6.6 Hz, 2 H), 4.01-3.97 (q, J=6.6,7.1 Hz, 4 H), 3.78-3.69 (m, 15 H), 3.02 (d, J=2.76 Hz, 2 H), 1.38-1.35 (t, J=7.14,6.6 Hz, 6 H), 1.32-1.29 (t, J=7.14,7.14 Hz, 3 H).
13C NMR (CDCl
3, 150 MHz) and δ (ppm): 165.3,159.8,159.0,155.6,153.2,152.7,142.5,137.9,133.5,124.9,108.7,104.0,100.3,93.3,91.9,69.0,68.6,64.9,60.9,56.0,56.0,55.5,26.0.
Embodiment 7: preparation 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3,4,5-triolefin propoxy benzoic acid ester (in the synthetic route structure iron shown in 9).
With 3,4,5-triolefin propoxy benzoic acid is a raw material, and the preparation method is identical with compound 5 in the synthetic route structure iron, and productive rate is 73%;
1H NMR (CDCl
3, 600 MHz) and δ 7.17 (s, 2 H), 6.67 (s, 2 H), (6.24 d, J=2.76 Hz, 1 H), 6.12 (s, 1 H), 6.07-5.94 (m, 3 H), 5.65 (t, J=2.22,1.08 Hz, 1H), 5.37 (d, J=1.08 Hz, 1 H), 5.34 (d, J=1.62 Hz, 1H), 5.29-5.26(d, m, J=15.76,1 H), 5.25 (d, J=1.08 Hz, 1 H), (5.23 d, J=1.08 Hz, 1 H), 5.16-5.14 (d, J=10.44 Hz, 1 H), 5.06 (s, 1 H), (4.57-4.56 d, J=6.06 Hz, 2 H), 4.52-4.51 (dd, J=1.38,5.22 Hz, 4 H), 3.79-3.68 (m, 15 H), 3.02 (d, J=2.76 Hz, 2 H).
13C NMR (CDCl
3, 150 MHz) and δ (ppm): 164.9,159.8,158.9,158.9,155.5,153.2,152.2,142.1,142.1,138.1,134.1,133.4,133.0,133.0,125.0,118.0,109.2,109.1,104.1,100.2,93.4,92.0,91.9,77.8,74.0,74.0,70.0,70.0,69.9,68.5,56.0,55.4,55.3,26.0.
Embodiment 8: preparation 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3-fluorobenzoic acid ester (in the synthetic route structure iron shown in 10).
With the 3-fluorobenzoic acid is raw material, and the preparation method is identical with compound 5 in the synthetic route structure iron, and productive rate is 70%;
1H NMR (CDCl
3, 600 MHz) and δ 7.96-7.93 (m, J=5.52,8.82 Hz, 2 H), (7.03-7.00 t, J=8.82,8.22 Hz, 2 H), 6.69 (s, 2 H), 6.25 (d, J=2.16 Hz, 1H), (6.11 d, J=1.62 Hz, 1 H), 5.67 (s, 1 H), 5.06 (s, 1 H), 3.78-3.71 (m, 15 H), 3.04 (d, J=2.76 Hz, 2 H).
13C NMR (CDCl
3, 150 MHz) and δ (ppm): 166.6,164.9,164.5,159.7,158.9,155.5,153.2,137.9,133.3,132.2,126.3,115.5,115.4,100.1,93.5,92.0,77.8,68.7,60.7,55.9,55.4,26.1.
Embodiment 9: preparation 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 4-fluorobenzoic acid ester (in the synthetic route structure iron shown in 11).
The 4-fluorobenzoic acid is a raw material, and the preparation method is identical with compound 5 in the synthetic route structure iron, and productive rate is 72%;
1H NMR (CDCl
3, 600 MHz) and δ 7.74-7.73 (d, J=7.68 Hz, 1 H), (7.63-7.61 dd, J=1.62,9.36 Hz, 1 H), (7.36-7.32 m, 1 H), 7.22-7.19 (td, J=2.22,8.22 Hz, 1 H), 6.70 (s, 2 H), 6.26 (d, J=2.22 Hz, 1 H), 6.12 (d, J=2.16 Hz, 1 H), 5.66-5.65 (t, J=2.22,3.30 Hz, 1 H), 5.07 (s, 1 H), 3.81-3.74 (m, 15 H), (3.07 d, J=3.30 Hz, 2 H).
13C NMR (CDCl
3, 150 MHz) and δ (ppm): 163.3,161.6,159.8,158.9,155.5,153.2,138.0,133.3,132.3,132.2,132.2,130.0,129.9,125.5,120.2,120.0,116.6,116.5,103.8,100.0,93.6,92.1,77.8,69.1,60.8,56.0,55.4,55.4,26.0.
Embodiment 10: preparation 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3-dimethylamino-4-fluoro-benzoic ether (in the synthetic route structure iron shown in 12).
With 3-dimethylamino-4-fluoro-phenylformic acid is raw material, and the preparation method is identical with compound 5 in the synthetic route structure iron, and productive rate is 73%; 1H NMR (CDCl
3, 600 MHz) and δ 7.47-7.45 (m, 2 H), 6.96-6.92 (m, 1 H), (6.69 s, 1 H), 6.24 (d, J=2.22 Hz, 1 H), (6.11 d, J=2.16 Hz, 1 H), 5.65-5.64 (t, J=3.30,2.76 Hz, 1 H), 5.06 (s, 1 H), 3.79-3.71 (m, 15 H), 3.03 (d, J=3.3 Hz, 2 H), 2.80 (s, 6 H).
13C NMR (CDCl
3, 150 MHz) and δ (ppm): 165.1,159.8,159.0,158.8,155.6,153.2,140.9,140.8,137.9,133.5,126.4,122.9,122.8,119.9,116.1,115.9,103.9,100.2,93.4,92.0,78.0,68.6,60.9,56.0,55.5,42.6,42.6,26.1.
Embodiment 11: preparation 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3-acetamido-4-fluoro-benzoic ether (in the synthetic route structure iron shown in 13).
With 3-(N-ethanoyl)-4-fluoro-phenylformic acid is raw material, and the preparation method is identical with compound 5 in the synthetic route structure iron, and productive rate is 78%;
1H NMR (CDCl
3, 600 MHz) and δ 8.84-8.82 (d, J=6.6 Hz, 1 H), 7.67 (s, 1 H), (7.33 s, 1 H), 7.06-7.03 (t, J=8.82,9.9 Hz, 1 H), 6.72 (s, 2 H), 6.27 (d, J=2.16 Hz, 1 H), 6.11 (d, J=2.22 Hz, 1 H), 5.64 (s, 1 H), 5.07 (s, 1 H), 3.80-3.75 (m, 15 H), (3.05 t, J=3.3 Hz, 2 H), 2.19 (s, 3 H).
13C NMR (CDCl
3, 150 MHz) and δ (ppm): 168.6,164.5,159.7,158.9,156.5,155.5,153.1,137.7,133.4,126.6,126.4,124.4,114.9,114.8,103.9,100.1,93.6,92.0,77.7,69.0,60.7,56.0,55.3,25.9,24.0.
Embodiment 12: preparation 5,7-dimethoxy-2-(3,4, the 5-trimethoxy)-3,4-dihydro-chromene-3-alcohol, 3-(3,4,5-trimethoxy-benzamide base)-4-fluorobenzoic acid ester (in the synthetic route structure iron shown in 14).
(3,4,5-trimethoxy-benzamide base)-the 4-fluorobenzoic acid is a raw material with 3-, and the preparation method is identical with compound 5 in the synthetic route structure iron, and productive rate is 76%;
1H NMR (CDCl
3, 600 MHz) and δ 8.96-8.95 (dd, J=1.68,7.68 Hz, 1 H), (7.94 d, J=2.76 Hz, 1 H), 7.71-7.69 (m, 1 H), (7.47 d, J=1.62 Hz, 1 H), 7.39-7.37 (dd, J=1.68,8.22 Hz, 1H), 7.11-7.08 (dd, J=8.22,9.90 Hz, 1 H), 6.91-6.90 (d, J=8.22 Hz, 1 H), 6.74 (s, 2 H), 6.27 (d, J=2.22 Hz, 1 H), 6.11 (d, J=2.58 Hz, 1 H), 5.66-5.65 (t, J=2.88,3.18 Hz, 1 H), 5.08 (s, 1 H), 3.95-3.73 (m, 24 H), 3.06 (d, J=3.30 Hz, 2 H).
13C NMR (CDCl
3, 150 MHz) and δ (ppm): 165.2,164.5,159.7,158.9,155.6,153.5,153.2,141.8,137.7,133.4,129.6,127.0,126.8,126.7,124.2,115.1,115.0,104.6,103.8,100.0,93.6,92.1,77.3,77.1,76.9,69.1,60.9,56.5,56.1,26.1.
Embodiment 13: preparation 5,7-dimethoxy-2-(3,4, the 5-trimethoxy)-3,4-dihydro-chromene-3-alcohol, 3-(3,4-dimethoxy benzene methylamino)-4-fluorobenzoic acid ester (in the synthetic route structure iron shown in 15).
(3,4-dimethoxy benzoylamino)-the 4-fluorobenzoic acid is a raw material with 3-, and the preparation method is identical with compound 5 in the synthetic route structure iron, and productive rate is 71%;
1H NMR (CDCl
3, 600 MHz) and δ 8.91-8.90 (d, J=6.00 Hz, 1 H), 7.96 (s, 1 H), 7.75-7.73 (m, 1 H), 7.14-7.11 (t, J=9.90,8.82 Hz, 1 H), 7.09 (s, 2 H), 6.76 (s, 2 H), 6.29 (s, 1 H), 6.13 (s, 1H), 5.68(s, 1 H), 5.10 (s, 1 H), (3.91-3.75 m, 24 H), 3.05 (S, 2 H).
13C NMR (CDCl
3, 150 MHz) and δ (ppm): 164.9,164.6,159.7,158.9,155.6,154.9,153.2,152.5,149.4,137.7,133.4,127.0,126.7,126.5,124.0,119.7,115.0,114.8,110.8,110.5,103.8,100.2,93.6,92.1,77.9,69.1,60.9,56.2,56.1,26.1.
Embodiment 14: preparation 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 4-Methoxycinnamate (in the synthetic route structure iron shown in 16).
With the 4-methoxy cinnamic acid is raw material, and the preparation method is identical with compound 5 in the synthetic route structure iron, and productive rate is 78%;
1H NMR (CDCl
3, 600 MHz) and δ 7.55-7.52 (d, J=15.96 Hz, 1 H), 7.39-7.37 (d, J=8.82 Hz, 2 H), 6.86-6.84 (d, J=8.22 Hz, 2 H), (6.73 s, 2 H), 6.25-6.22 (d, J=15.96 Hz, 1 H), (6.24 s, 1 H), 6.12 (s, 1 H), (5.61 s, 1 H), 5.03 (s, 1 H), (3.82-3.78 m, 18 H), 2.99 (m, 2 H).
13C NMR (CDCl
3, 150 MHz) and δ (ppm): 166.5,161.6,159.7,159.0,155.5,153.2,145.1,137.9,133.4,129.8,127.0,115.3,114.4,104.0,100.4,93.5,92.1,77.9,67.6,60.9,56.2,55.5,55.4,26.2.
Embodiment 15: preparation 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3,4-dimethoxy-cinnamic acid ester (in the synthetic route structure iron shown in 17).
With 3, the 4-dimethoxy-cinnamic acid is a raw material, and the preparation method is identical with compound 5 in the synthetic route structure iron, and productive rate is 65%;
1H NMR (CDCl
3, 600 MHz)
δ7.52 (d,
J=15.6 Hz, 1 H), 7.26 (s, 1 H), 7.02 (dd,
J=1.8 Hz, 8.4Hz, 1 H), 6.96 (d,
J=1.8 Hz, 1 H), 6.73 (s, 2 H), 6.25-6.24 (m, 2 H), 5.76 (d,
J=12.6 Hz, 1 H), 5.64-5.62 (m, 1 H), 5.04-5.02 (m, 1 H), 3.89-3.80 (m, 21 H), 3.01-2.99 (m, 2 H).
13C NMR (CDCl
3, 150 MHz) and δ 166.3,159.6,158.9,155.3,153.1,151.2,149.1,145.2,137.8,133.2,127.1,122.7,115.4,110.9,109.3,103.8,100.3,93.3,92.0,77.8,67.4,60.8,56.1,55.9,55.8,55.4,55.3,26.1.
Embodiment 16: preparation 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3,4,5-trimethoxy cinnamic acid ester (in the synthetic route structure iron shown in 18).
With 3,4, the 5-trimethoxy cinnamic acid is a raw material, and the preparation method is identical with compound 5 in the synthetic route structure iron, and productive rate is 65%;
1H NMR (CDCl
3, 600 MHz) and δ 7.50-7.46 (d, J=15.96 Hz, 1 H), (6.72 s, 2 H), 6.66 (s, 2 H), (6.29-6.26 dd, J=1.08,15.96 Hz, 1 H), (6.25 s, 1 H), 6.13 (s, 1 H), (5.66 s, 1 H), 5.05 (s, 1 H), (3.85-3.79 m, 24 H), 3.00 (m, 2 H).
13C NMR (CDCl
3, 150 MHz) and δ (ppm): 166.2,159.8,159.1,155.4,153.5,153.3,145.4,140.3,137.8,133.3,129.8,117.1,105.3,104.0,100.4,93.5,92.1,77.8,67.6,61.0,60.9,56.2,55.5,55.5,26.2.
Embodiment 17: preparation 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3,4-dimethoxyphenylacetic acid ester (in the synthetic route structure iron shown in 19).
With 3, the 4-dimethoxyphenylacetic acid is a raw material, and the preparation method is identical with compound 5 in the synthetic route structure iron, and productive rate is 72%;
1H NMR (CDCl
3, 500 MHz)
δ(ppm): 6.80-6.79 (m, 1 H), 6.69-6.68 (m, 1 H), (6.67-6.66 m, 1 H), 6.43 (s, 2 H), (6.21 s, 1 H), 6.04 (s, 1 H), (5.57-5.55 m, 1 H), 5.09-5.08 (m, 1 H), (3.85-3.64 m, 21 H), 3.35 (s, 2 H), 3.08-3.05 (m, 2 H).
13C NMR (CDCl
3, 125 MHz)
δ(ppm): 171.3,159.4,156.7,152.9,150.1,149.2,134.9,127.5,122.7,113.6,112.4,102.5,100.7,78.2,69.9,61.3,59.3,56.9,56.8,42.2,26.0.
Embodiment 18, the chromene-antitumor mdr cell experiment of 3-alcohol esterification derivative.
Identical (the Zhang Pu Yong of method of present embodiment test method and bibliographical information
J Med Chem. 2010,53:5108-5120).The described chromene of 1 μ M general formula I of the present invention-3-alcohol esterification derivative acts on P-gp high expression level MDA435LCC6 mammary cancer drug-resistant cell strain with the taxol (Paclitaxel) of 1 nM, 5 nM, 10 nM, 50 nM, 100 nM or 183.2 nM respectively, record respectively MDA435LCC6 mammary cancer drug-resistant cell strain inhibiting rate, calculate the half-inhibition concentration (IC of taxol
50), and calculate chromene-3-alcohol esterification derivative and reverse multiple (RF).Antitumor mdr cell experimental result such as table 1.
Paclitaxel half-inhibition concentration during the compound of Paclitaxel half-inhibition concentration when reversing the compound of multiple (RF) formula=nothing associating use/have associating use.
The IC of table 1,1 μ M chromene-3-alcohol esterification derivative and Paclitaxel acting in conjunction Paclitaxel when LCC6MDR mammary cancer drug-resistant cell strain
50And chromene-3-alcohol esterification derivative reverses multiple (RF)
| Unite the compound (concentration is 1 μ M) of use with Paclitaxel | Paclitaxel half-inhibition concentration (μ M) | Reverse multiple (RF) |
| Do not have | 158.7 | 1.0 |
| Compound 3 | 21.0 | 7.6 |
| Compound 4 | 155.2 | 1.0 |
| Compound 5 | 45.2 | 3.5 |
| Compound 6 | 147.7 | 1.1 |
| Compound 7 | 19.5 | 8.1 |
| Compound 8 | 112.9 | 1.4 |
| Compound 9 | 12.0 | 13.3 |
| Compound 10 | 97.1 | 1.6 |
| Compound 11 | 53.3 | 3.0 |
| Compound 12 | 36.0 | 4.4 |
| Compound 13 | 14.8 | 10.7 |
| Compound 14 | 3.3 | 47.7 |
| Compound 15 | 3.0 | 53.8 |
| Compound 16 | 21.9 | 7.3 |
| Compound 17 | 8.7 | 18.3 |
| Compound 18 | 3.7 | 43.5 |
| Compound 19 | 143.6 | 1.1 |
| Verapamil | 38.0 | 4.2 |
Table 1 result show in the chromene of the present invention-3-alcohol esterification derivative compound 3,7,9,12,13,14,15,16,17 and 18 and the Paclitaxel acting in conjunction when P-gp high expression level MDA435LCC6 mammary cancer drug-resistant cell strain, the reversing drug resistance multiple is equal to or greater than verapamil, is potent multidrug-resistance reversal agent; And the reversing drug resistance multiple of compound 4,5,6,8,10,11 and 19 is the multidrug-resistance reversal agent of poor efficiency all less than verapamil.
Embodiment 19, chromene-3-alcohol esterification derivative toxotest
Detect new synthetic compound inhibiting rate to tumour cell MDA435LCC6, drug-resistant tumor cell MDA435LCC6MDR and l cell L929 etc. when 1 μ M, 5 μ M, 10 μ M, 50 μ M and the 100 μ M, calculation of half inhibitory concentration respectively with MTS proliferation assay method.Toxotest result such as table 2.
Table 2, chromene-3-alcohol esterification derivative are to LCC6 breast cancer cell, LCC6MDR breast cancer cell mdr cell and L929 l cell half-inhibition concentration (IC
50, μ M)
Table 2 result show chromene of the present invention-3-alcohol esterification derivative to the half-inhibition concentration of tumour cell MDA435LCC6, drug-resistant tumor cell MDA435LCC6MDR and l cell L929 all greater than 75 μ M, prove that chromene of the present invention-3-alcohol esterification derivative be safe multidrug-resistance reversal agent.
Chromene of the present invention-3-alcohol esterification derivative can be used as oral medication or non-enterally administer.As oral medication can be tablet, capsule or Drug coating, and the parenteral drug formulation has injection and suppository etc.These preparations all can be according to the known method preparation of those skilled in the art.For making tablet, capsule, the used auxiliary material of Drug coating is the auxiliary agent of conventional usefulness, for example starch, gelatin, gum arabic, silica or polyoxyethylene glycol; The used solvent of liquid dosage form is water, ethanol, propylene glycol, plant oil such as Semen Maydis oil, peanut oil or olive wet goods for example.Containing in the preparation of The compounds of this invention also can have other auxiliary agents, for example tensio-active agent, lubricant, disintegrating agent, sanitas, correctives or pigment etc.
Above embodiment is only in order to illustrating technical scheme of the present invention, but not limits it; Although the present invention is had been described in detail with reference to previous embodiment, for the person of ordinary skill of the art, still can make amendment to the technical scheme that previous embodiment is put down in writing, perhaps part technical characterictic wherein is equal to replacement; And these modifications or replacement do not make the essence of appropriate technical solution break away from the spirit and scope of the present invention's technical scheme required for protection.
Claims (6)
1. an artitumor multi-medicine-resistant inhibitor chromene-3-alcohol esterification derivative is characterized in that it is represented by following general formula I:
R is one or more in hydrogen, hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl, fluorine or the benzoyl in the general formula I, described benzoyl contains one or more in hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl or the fluoro substituents, wherein alkyl is the alkyl with straight or branched of 1-10 carbon atom in alkoxyl group, alkylamino, the alkylamidoalkyl, X is hydrogen or oxygen in the formula, and Y is oxygen or nitrogen hydrogen in the formula;
Q is one or more in one or more substituent pyridines, piperidines, piperazine, triazine, imidazoles, pyrazoles, thiazole, thiophene, pyrans, furans, benzoglyoxaline, benzothiazole or the chromene in hydrogeneous, hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl or the fluorine in the general formula I; Or Q is represented by following general formula I I, III or IV:
R among general formula I I, III or the IV
1Be in hydrogen, hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl, fluorine or the benzoyl one or more, described benzoyl contains one or more in hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl, the fluoro substituents, wherein alkyl is the alkyl with straight or branched of 1-10 carbon atom in alkoxyl group, alkylamino, the alkylamidoalkyl, and n is 1-5; Or described R
1Group is one or more in one or more substituent pyridines, piperidines, piperazine, triazine, imidazoles, pyrazoles, thiazole, thiophene, pyrans, furans, benzoglyoxaline, benzothiazole or the chromene in hydrogeneous, hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl and the fluorine; Or described R
1Group is represented by following general formula V or VI:
R in the formula
2Be in hydrogen, hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl, fluorine or the benzoyl one or more; described benzoyl contains one or more in hydroxyl, alkoxyl group, alkylamino, alkylamidoalkyl or the fluoro substituents; wherein alkyl is the alkyl with straight or branched of 1-10 carbon atom in alkoxyl group, alkylamino, the alkylamidoalkyl, and m is 1-5.
2. a kind of chromene according to claim 1-3-alcohol esterification derivative, it is characterized in that described compound of Formula I is 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3,4, the 5-TMB, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3-methoxybenzoic acid ester, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 4-methoxybenzoic acid ester, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3,4-dimethoxybenzoic acid ester, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3,4,5-triethoxy benzoic ether, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3,4,5-triolefin propoxy benzoic acid ester, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3-fluorobenzoic acid ester, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 4-fluorobenzoic acid ester, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3-dimethylamino-4-fluorobenzoic acid ester, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3-acetylaminohydroxyphenylarsonic acid 4-fluorobenzoic acid ester, 5,7-dimethoxy-2-(3,4, the 5-trimethoxy)-3,4-dihydro-chromene-3-alcohol, 3-(3,4,5-trimethoxy-benzamide base)-4-fluorobenzoic acid ester, 5,7-dimethoxy-2-(3,4, the 5-trimethoxy)-3,4-dihydro-chromene-3-alcohol, 3-(3,4-dimethoxy benzoylamino)-4-fluorobenzoic acid ester, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, the 4-Methoxycinnamate, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3,4-dimethoxy-cinnamic acid ester, 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3,4,5-trimethoxy cinnamic acid ester or 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol, 3,4-dimethoxyphenylacetic acid ester.
3. the preparation method of a chromene according to claim 1 and 2-3-alcohol esterification derivative, it is characterized in that described compound of Formula I prepares as follows: with methylene dichloride, chloroform or dimethyl formamide are solvent, triethylamine in the 1-10 mol ratio, pyridine, diisopropyl ethyl amine, N-methylmorpholine or to N, under the existence of N-dimethyl aminopyridine, make 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3, the methoxyl group that contains of 4-dihydro-chromene-3-alcohol and 1-10 mol ratio, oxyethyl group, allyloxy, fluorine, kharophen, dimethylamino or contain the Benzoyl chloride of methoxy benzamide base, phenyllacetyl chloride or cinnamyl chloride react 0.5h-24h down at 0 ℃-25 ℃, prepare described chromene-3-alcohol esterification derivative, the mol ratio of described use reagent is with respect to 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol.
4. the preparation method of a chromene according to claim 1 and 2-3-alcohol esterification derivative, it is characterized in that described compound of Formula I prepares as follows: with methylene dichloride, chloroform or dimethyl formamide are solvent, triethylamine in the 1-10 mol ratio, pyridine, diisopropyl ethyl amine, N-methylmorpholine or to N, under the existence of N-dimethyl aminopyridine, the 1-10 mol ratio is to dimethyl aminopyridine (DMAP), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) or N, under the N'-carbonyl dimidazoles catalysts such as (CDI), make 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3, the methoxyl group that contains of 4-dihydro-chromene-3-alcohol and 1-10 mol ratio, oxyethyl group, allyloxy, fluorine, kharophen, dimethylamino or contain the phenylformic acid of methoxy benzamide base, toluylic acid or styracin react 0.5h-24h down at 0 ℃-25 ℃, prepare described chromene-3-alcohol esterification derivative, the mol ratio of described use reagent is with respect to 5,7-dimethoxy-2-(3,4, the 5-trimethoxyphenyl)-3,4-dihydro-chromene-3-alcohol.
5. the described chromene of claim 1-3-alcohol esterification derivative is used for the treatment of application in the medicine of mammary cancer, colorectal carcinoma, prostate cancer, leukemia, myelomatosis and carcinoma of the pancreas in preparation.
6. the application of chromene according to claim 5-3-alcohol esterification derivative is characterized in that described chromene-3-alcohol esterification derivative is as oral medication or parenteral medication; Described oral medication is tablet, capsule or Drug coating, and described parenteral drug formulation is injection or suppository.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102603692A (en) * | 2011-03-04 | 2012-07-25 | 中国海洋大学 | Chroman and chromene derivatives as tumor multidrug resistance inhibitor as well as preparation method and application of chroman and chromene derivatives |
| CN109912556A (en) * | 2017-12-13 | 2019-06-21 | 复旦大学 | Benzopyrone skeleton derivative and its preparation method and application |
| KR20190114500A (en) * | 2018-03-30 | 2019-10-10 | 건국대학교 산학협력단 | (-)-epigallocatechin gallate prodrugs , preparation method thereof and composition for mitochondrial biosis |
| CN111233809A (en) * | 2020-01-16 | 2020-06-05 | 广东省中医院（广州中医药大学第二附属医院、广州中医药大学第二临床医学院、广东省中医药科学院） | Millepachine-CA-4 derivative and preparation method and application thereof |
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| CN103408528B (en) * | 2013-08-13 | 2015-04-29 | 浙江大学 | Chroman compound, as well as preparation method and application thereof |
| AU2015213484B2 (en) | 2014-02-07 | 2015-11-05 | Kazia Therapeutics Limited | Functionalised benzopyran compounds and use thereof |
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| CN108129438A (en) * | 2017-12-25 | 2018-06-08 | 中国海洋大学 | A kind of compound of the chroman of benzene containing 2- parent nucleus and preparation method thereof |
| CN108658957B (en) * | 2018-05-04 | 2020-12-04 | 吉林大学 | Substituted chromene alcohol ester compound and application thereof in preparation of anti-cancer drugs |
| CN110845466B (en) * | 2019-11-27 | 2023-09-15 | 中国科学院成都有机化学有限公司 | Oxacyclonadiene derivatives, pharmaceutical compositions thereof, process for their preparation and their use |
| CN115232140B (en) * | 2022-08-12 | 2023-06-30 | 河南大学 | Tetrahydroquinoline chroman polycyclic compound and preparation method and application thereof |
Family Cites Families (3)
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| ES2660339T3 (en) * | 2004-08-19 | 2018-03-21 | The Hong Kong Polytechnic University | Gallate derivatives of (-) - epigallocatechin to inhibit proteasome |
| CN102078316A (en) * | 2011-01-24 | 2011-06-01 | 广西医科大学 | Application of epigallocatechin gallate derivative in antineoplastic drug |
| CN102153535A (en) * | 2011-03-04 | 2011-08-17 | 中国海洋大学 | Benzopyranyl-3-alcohol esterified derivative serving as antineoplastic multidrug resistance inhibitor and preparation method and application of benzopyranyl-3-alcohol esterified derivative |
-
2011
- 2011-03-04 CN CN2011100517921A patent/CN102153535A/en active Pending
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2012
- 2012-02-27 CN CN201210045877.3A patent/CN102603692B/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102603692A (en) * | 2011-03-04 | 2012-07-25 | 中国海洋大学 | Chroman and chromene derivatives as tumor multidrug resistance inhibitor as well as preparation method and application of chroman and chromene derivatives |
| CN102603692B (en) * | 2011-03-04 | 2014-07-02 | 中国海洋大学 | Chroman and chromene derivatives as tumor multidrug resistance inhibitor as well as preparation method and application of chroman and chromene derivatives |
| CN109912556A (en) * | 2017-12-13 | 2019-06-21 | 复旦大学 | Benzopyrone skeleton derivative and its preparation method and application |
| CN109912556B (en) * | 2017-12-13 | 2022-11-08 | 复旦大学 | Benzopyrone skeleton derivative and preparation method and application thereof |
| KR20190114500A (en) * | 2018-03-30 | 2019-10-10 | 건국대학교 산학협력단 | (-)-epigallocatechin gallate prodrugs , preparation method thereof and composition for mitochondrial biosis |
| KR102082041B1 (en) | 2018-03-30 | 2020-02-26 | 건국대학교 산학협력단 | (-)-epigallocatechin gallate prodrugs , preparation method thereof and composition for mitochondrial biosis |
| CN111233809A (en) * | 2020-01-16 | 2020-06-05 | 广东省中医院（广州中医药大学第二附属医院、广州中医药大学第二临床医学院、广东省中医药科学院） | Millepachine-CA-4 derivative and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102603692A (en) | 2012-07-25 |
| CN102603692B (en) | 2014-07-02 |
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