CN110498784B - Nobiletin derivatives or pharmaceutically acceptable salts thereof, and preparation method and application thereof - Google Patents
Nobiletin derivatives or pharmaceutically acceptable salts thereof, and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a nobiletin derivative or a pharmaceutically acceptable salt thereof, and a preparation method and application thereof. The structure of the nobiletin derivative is shown as a formula (I); wherein R is1、R2、R3And R4Are respectively selected from hydrogen, halogen, hydroxyl, amino and C1‑6Substituted or unsubstituted alkoxy, C1‑6Substituted or unsubstituted ester group, C1‑6Substituted or unsubstituted alkylamino, C1‑6A substituted or unsubstituted amide group; r5Is selected from C3‑9Substituted or unsubstituted aromatic ring, C3‑9Substituted or unsubstituted aromatic heterocyclic ring; x is selected from O or NR6. The nobiletin derivative or the pharmaceutically acceptable salt thereof has a novel structure, and the compound has excellent inhibitory action on P-gp, can be prepared into a P-gp inhibitor for use, and can be used for treating and/or preventing related diseases caused by P-gp, particularly diseases related to tumor drug resistance; or mixed with other medicines for use, and is used as a drug resistance reversal agent, the reversal multiple is high, and the drug effect of the medicine can be obviously improved.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to nobiletin derivatives or pharmaceutically acceptable salts thereof, and a preparation method and application thereof.
Background
Tumor multidrug resistance (MDR) refers to a cross resistance that tumor cells can resist one kind of anti-tumor drugs and also resist other anti-tumor drugs with different structures and mechanisms of action, and is one of the important reasons for failure of tumor chemotherapy. The search of the combination of a reversal agent of multidrug resistance and an antitumor drug to restore the sensitivity of multidrug resistance tumor cells to the antitumor drug is one of the main approaches to overcome multidrug resistance.
Over-expression of P-glycoprotein (P-gp) is one of the main mechanisms leading tumor cells to generate multi-drug resistance, and the currently researched P-gp protein inhibitors such as verapamil, cyclosporine and other chemical reversal agents have large toxicity and are limited in clinical application. The development of the multi-drug resistance reversal agent with low toxicity and high efficiency is of great significance. Because natural products have the advantages of low toxicity, rich resources, multiple action targets and the like, many students turn the eyesight to natural medicines and screen out natural active ingredients with multi-drug resistance.
Nobiletin is derived from citrus reticulata blanco of Rutaceae, and has various pharmacological actions of resisting cell coagulation, thrombosis, fungi, inflammation, allergy, cholinesterase and epilepsy, and is also a promoter of carbohydrate metabolism, so that the nobiletin is used as a parent compound to research and develop compounds with more biological activities, and has a larger application prospect.
Disclosure of Invention
The invention aims to provide a nobiletin derivative or a pharmaceutically acceptable salt thereof. The compound takes nobiletin as a parent structure, and the structure of the compound is modified, so that the obtained compound has a novel structure; the compound has excellent inhibitory action on P-glycoprotein (P-gp), can be used as a P-gp inhibitor, and further can be prepared into medicaments for treating and/or preventing related diseases caused by P-gp, particularly diseases related to tumor drug resistance; or mixed with other medicines for use, and is used as a drug resistance reversal agent to improve the drug effect of the medicine.
The invention also aims to provide a preparation method of the nobiletin derivative or the pharmaceutically acceptable salt thereof.
The invention further aims to provide application of the nobiletin derivative or the pharmaceutically acceptable salt thereof or the nobiletin.
The above object of the present invention is achieved by the following scheme:
a nobiletin derivative or a pharmaceutically acceptable salt thereof is disclosed, wherein the structure of the nobiletin derivative is shown as the formula (I):
wherein R is1、R2、R3And R4Are respectively selected from hydrogen, halogen, hydroxyl, amino and C1-6Substituted or unsubstituted alkoxy, C1-6Substituted or unsubstituted ester group, C1-6Substituted or unsubstituted alkylamino, C1-6A substituted or unsubstituted amide group;
R5is selected from C3-9Substituted or unsubstituted aromatic ring, C3-9Substituted or unsubstituted aromatic heterocyclic ring; the aromatic heterocyclic ring is an aromatic ring containing N, O or S atoms;
x is selected from O or NR6(ii) a The R is6Selected from hydrogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Substituted or unsubstituted alkoxy or C1-6Substituted or unsubstituted alkylamino;
said C is1-6Substituted or unsubstituted alkoxy, C1-6Substituted or unsubstituted ester group, C1-6Substituted or unsubstituted alkylamino, C1-6Substituted or unsubstituted amide group, C3-9Substituted or unsubstituted aromatic ring and C3-9The substitution in the substituted or unsubstituted aromatic heterocycle is halogen, hydroxy, amino, C1-4Alkyl or C1-4Alkoxy groups.
Preferably, said R is1、R2、R3And R4Are respectively selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, ethylamino, propylamino and isopropylamino.
Preferably, said R is5Selected from substituted or unsubstituted phenyl, substituted or unsubstituted phenylpyridine or substituted or unsubstituted phenylbenzo [ d][1,3]Dioxin; wherein the substitution is C1-4Alkyl or C1-4Alkoxy groups.
Preferably, said R is6Is hydrogen or C1-6Substituted or unsubstituted alkyl, wherein C1-6Substitution in substituted or unsubstituted alkyl refers to substitution with halogen, hydroxy, or amino.
Preferably, said R is5Is selected from
Preferably, said R is6Is methyl, propyl, isopropyl, 2-methoxy-ethyl or N, N-dimethylethyl.
More preferably, the structure of the nobiletin derivative is as shown in any structure:
preferably, the pharmaceutically acceptable salt is a product obtained by reacting the nobiletin derivative shown as the formula (I) with acid.
Preferably, the acid is hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, methanesulfonic acid, salicylic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, fumaric acid, citric acid, acetic acid, tartaric acid, succinic acid, malic acid, or glutamic acid.
The invention also provides a preparation method of the nobiletin and the derivatives thereof, which comprises the following steps:
s1, mixing a compound shown in a formula 1 and a compound shown in a formula 2 in a solvent with an alkaline substance dissolved at a temperature of-30-25 ℃, and gradually heating to 25-100 ℃ for reaction to obtain a compound shown in a formula 3;
s2, reacting the compound shown in the formula 3 in a solvent in which an alkaline substance is dissolved or the alkaline substance and triethyl silicon-based triflate at room temperature and then heating to 40-100 ℃ to obtain a target product;
wherein R is1、R2、R3And R4Are respectively selected from hydrogen, halogen, hydroxyl, amino and C1-6Substituted or unsubstituted alkoxy, C1-6Substituted or unsubstituted ester group, C1-6Substituted or unsubstituted alkylamino, C1-6A substituted or unsubstituted amide group;
R5is selected from C3-9Substituted or unsubstituted aromatic ring, C3-9Substituted or unsubstituted aromatic heterocyclic ring; the aromatic heterocyclic ring is an aromatic ring containing N, O or S atoms;
x is selected from O or NR6(ii) a The R is6Selected from hydrogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Substituted or unsubstituted alkoxy or C1-6Substituted or unsubstituted alkylamino;
said C is1-6Substituted or unsubstituted alkoxy, C1-6Substituted or unsubstituted ester group, C1-6Substituted or unsubstituted alkylamino, C1-6Substituted or unsubstituted amide group, C3-9Substituted or unsubstituted aromatic ring and C3-9The substitution in the substituted or unsubstituted aromatic heterocycle is halogen, hydroxy, amino, C1-4Alkyl or C1-4Alkoxy groups.
Preferably, in steps S1 and S2, the basic substance is independently selected from one or more of diisopropylethylamine, triethylamine, diethylamine, 4-dimethylaminopyridine, piperidine, pyrrole, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, sodium tert-butoxide or potassium tert-butoxide.
Preferably, in steps S1, S2, the solvent is independently selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform, diethyl ether, benzene, toluene, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, acetonitrile, propionitrile, acetone, N-dimethylformamide, N-dimethylacetamide, or dimethylsulfoxide.
Preferably, the preparation process of the nobiletin comprises the following steps:
(1) reacting the compound shown in the formula 5 with an acetylation reagent in a solvent in the presence of a basic substance to obtain a compound shown in a formula 6;
(2) reacting the compound shown in the formula 6 in a solvent in the presence of Lewis acid to obtain a compound shown in a formula 7;
(3) reacting the compound of formula 7 with N-iodosuccinimide (NIS) in a solvent in the presence of an acidic substance to obtain a compound of formula 8;
(4) reacting the compound shown in the formula 8 with cuprous chloride in a solvent in the presence of sodium methoxide to obtain a compound shown in a formula 9;
(5) reacting the compound shown in the formula 9 with 3, 4-dimethoxy benzoyl chloride in a solvent in the presence of a basic substance to obtain a compound shown in a formula 10;
(6) the compound shown in the formula 10 reacts in a solvent dissolved with an alkaline substance or the alkaline substance and triethyl silicon-based triflate to obtain the compound nobiletin.
Preferably, in step (1), the acetylating reagent is acetic anhydride or acetyl chloride.
Preferably, in the step (1), the molar ratio of the compound shown in the formula 5 to the acetylation reagent is 1: 1-1: 20; more preferably 1:1 to 1: 2.
Preferably, in step (1), the solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform, diethyl ether, benzene, toluene, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, acetonitrile, propionitrile, acetone, acetic acid, N-dimethylformamide, N-dimethylacetamide, or dimethylsulfoxide.
Preferably, in the step (1), the basic substance is selected from one or more of diisopropylethylamine, triethylamine, diethylamine, 4-dimethylaminopyridine, piperidine, pyrrole, sodium acetate, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, sodium tert-butoxide or potassium tert-butoxide.
Preferably, in the step (1), the reaction temperature is-10-150 ℃, and the reaction time is 1-40 hours; more preferably, the temperature is 0-100 ℃ and the reaction time is 1-4 hours.
Preferably, in step (2), the lewis acid is selected from one or more of boron trifluoride, aluminum trichloride, aluminum trifluoromethanesulfonate, iron trichloride, tin tetrachloride or titanium tetrachloride.
Preferably, in the step (2), the molar ratio of the compound shown in the formula 6 to the Lewis acid is 1: 1-1: 30; more preferably 1:2 to 1: 25.
Preferably, in step (2), the solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform, diethyl ether, benzene, toluene or acetic acid.
Preferably, in the step (2), the reaction temperature is-10-150 ℃, and the reaction time is 1-40 hours; more preferably, the temperature is 0-100 ℃ and the reaction time is 1-4 hours.
Preferably, in the step (3), the molar ratio of the compound shown in the formula 7 to the NIS is 1: 1-10; more preferably 1:1 to 2.
Preferably, in step (3), the solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform, diethyl ether, benzene, toluene, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, acetonitrile or propionitrile.
Preferably, in step (3), the acidic substance is selected from one or more of p-toluenesulfonic acid, benzenesulfonic acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrochloric acid or sulfuric acid.
Preferably, in the step (3), the reaction temperature is 0-50 ℃, and the reaction time is 1-24 hours; more preferably, the temperature is 15-35 ℃, and the reaction time is 1-4 hours.
Preferably, in the step (4), the molar ratio of the compound shown in the formula 8 to sodium methoxide is 1: 1-30; more preferably 1:5 to 15.
Preferably, in the step (4), the solvent is one or more selected from tetrahydrofuran, 1, 4-dioxane, methanol, ethanol, N-dimethylformamide, N-dimethylacetamide and dimethylsulfoxide.
Preferably, in the step (4), the reaction temperature is 25-120 ℃, and the reaction time is 1-24 hours; more preferably, the temperature is 60-100 ℃ and the reaction time is 1-4 hours.
Preferably, in the step (5), the molar ratio of the compound shown in the formula 9 to 3, 4-dimethoxybenzoyl chloride is 1: 1-3; more preferably 1:1 to 1.5.
Preferably, in step (5), the solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform, diethyl ether, benzene, toluene, ethyl acetate, tetrahydrofuran, 1, 4-dioxane or acetonitrile.
Preferably, in the step (5), the basic substance is selected from one or more of diisopropylethylamine, triethylamine, diethylamine, 4-dimethylaminopyridine, piperidine, pyrrole, sodium acetate, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, sodium tert-butoxide or potassium tert-butoxide.
Preferably, in the step (5), the reaction temperature is-10 to 100 ℃, and the reaction time is 1 to 24 hours; more preferably, the temperature is 0-40 ℃ and the reaction time is 1-4 hours.
Preferably, in step (6), the solvent for the reaction is selected from one or more of dichloromethane, 1, 2-dichloroethane, chloroform, diethyl ether, benzene, toluene, ethyl acetate, tetrahydrofuran, 1, 4-dioxane or acetonitrile.
Preferably, in the step (6), the basic substance is selected from one or more of diisopropylethylamine, triethylamine, diethylamine, 4-dimethylaminopyridine, piperidine, pyrrole, sodium acetate, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, sodium tert-butoxide or potassium tert-butoxide.
Preferably, in the step (6), the reaction temperature is-10 to 120 ℃, and the reaction time is 1 to 24 hours; more preferably, the temperature is 20-100 ℃ and the reaction time is 1-12 hours.
The application of the nobiletin derivative or the pharmaceutically acceptable salt thereof or nobiletin in preparing P-gp inhibitor medicaments is also within the protection range of the invention.
Preferably, the nobiletin derivative or the pharmaceutically acceptable salt thereof or the application of nobiletin in preparing the medicines for treating the P-gp related diseases.
The invention also protects the application of the nobiletin derivative or the pharmaceutically acceptable salt thereof or the nobiletin in preparing a multidrug resistance reversal agent for tumors.
Preferably, the nobiletin derivative or the pharmaceutically acceptable salt thereof or the nobiletin and the anti-tumor drug are mixed for application.
Preferably, the P-gp inhibitor drug or the tumor multidrug resistance reversal agent can be prepared into clinically acceptable dosage forms by adding conventional auxiliary materials.
More preferably, the P-gp inhibitor drug or the tumor multidrug resistance reversal agent can be prepared into oral tablets, pills, capsules, injection or powder injection.
Compared with the prior art, the invention has the following beneficial effects:
the nobiletin derivative or the pharmaceutically acceptable salt thereof has a novel structure, and the compound has excellent inhibitory action on P-gp, can be prepared into a P-gp inhibitor for use, and can be used for treating and/or preventing related diseases caused by P-gp, particularly diseases related to tumor drug resistance; or mixed with other medicines for use, and is used as a drug resistance reversal agent, the reversal multiple is high, and the drug effect of the medicine can be obviously improved.
Drawings
FIG. 1 shows the anticancer effect of nobiletin and its derivatives in conjunction with paclitaxel administration in a nude mouse transplantation model of paclitaxel-resistant A549/T tumor cells.
Detailed Description
The present invention is further described in detail below with reference to specific examples, which are provided for illustration only and are not intended to limit the scope of the present invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
Example 1
In the compound shown in the formula (I), when X is O, the specific synthetic route is as follows:
(1) synthesis of Compound 12
The compound 3,4, 5-trimethoxyphenol and sodium acetate were added to acetic anhydride in sequence at room temperature, mixed and heated at 110 ℃ for 2 hours. After the reaction, the reaction system was concentrated under reduced pressure and extracted with ethyl acetate three times. Washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated to give phenyl acetate containing different substituents, compound 12.
(2) Synthesis of Compound 13
Compound 12 was added to the glacial acetic acid solution and boron trifluoride in ether (about 48%) was added. The reaction mixture was stirred at 70 ℃ for 2 hours and monitored by TLC for reaction completion. Then quenching the reaction system by water, extracting by ethyl acetate, washing by saturated saline solution, drying by anhydrous sodium sulfate, and purifying by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1) to obtain the hydroxyacetophenone containing different substituents, namely the compound 13.
(3) Synthesis of Compound 17
2, 3-Dimethoxypyridine (1.04g,7.5mmol) was added to a solution of 30mL of dichloromethane, followed by addition of liquid bromine (1.12g,7.0mmol), and the reaction was carried out at room temperature for 48 hours. After completion of the reaction, most of the solvent was removed by concentration and column chromatography (petroleum ether: ethyl acetate: 10:1) was carried out to obtain 2, 3-dimethoxy-5-bromopyridine (i.e. compound 15, 1.5g) as a white solid in 93% yield.1H NMR(400MHz,CDCl3)δ7.80(d,J＝2.0Hz,1H),7.16(d,J＝2.0Hz,1H),4.01(s,3H),3.89(s,3H).
2, 3-dimethoxy-5-bromopyridine (218mg,1.0mmol) was added to 5mL of N, N-dimethylformamide solution, cuprous cyanide (179.2mg, 4.0mmol) was added, and the temperature was raised to 160 ℃ under the protection of argon, and the reaction was completed after 8 hours. After cooling to room temperature, water was added for dilution, and extraction with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, concentration to remove the solvent, and column chromatography (petroleum ether: ethyl acetate 10:1) was performed to obtain the product 2, 3-dimethoxy-5-cyanopyridine (i.e., compound 16, 164.2mg,1.0mmol) as a white solid in 50% yield.1H NMR(400MHz,CDCl3)δ8.10(d,J＝1.6Hz,1H),7.18(d,J＝1.6Hz,1H),4.09(s,3H),3.93(s,3H).
2, 3-dimethoxy-5-cyanopyridine(164.2mg,1.0mmol) was added to 5.0mL of ethanol solution, 6M sodium hydroxide solution (1.67mL, 10mmol) was added at room temperature, and the reaction was allowed to warm to 90 ℃ for 16 hours. After the reaction was complete, the solvent was removed by concentration to give the product 5, 6-dimethoxynicotinic acid (i.e., compound 17, 133mg, 0.73mmol) as a beige powder in 73% yield.1H NMR(400MHz,CDCl3)δ8.53(d,J＝1.8Hz,1H),7.63(d,J＝1.8Hz,1H),4.11(s,3H),3.95(s,3H)。
(4) Synthesis of Compound 18
General Synthesis of Compound 18, 2-hydroxyacetophenone containing the various substituents (1.0mmol) was added to 5.0mL of dichloromethane. After addition of triethylamine (1.5mmol) at 0 ℃ benzoyl chloride (1.2mmol) containing different substituents was added to the system. The mixture was stirred at 0 ℃ to room temperature, after 3 hours, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 5:1) to give compound 18 containing various substituents.
2-hydroxyacetophenone containing the different substituents (1.0mmol) was added to 5mL of dichloromethane. After DMAP (1.5mmol) was added at 0 deg.C, picolinic acid (1.2mmol) containing various substituents was added to the system. The mixture was stirred at 0 ℃ to room temperature, after 3 hours, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and purified by silica gel column chromatography (petroleum ether/ethyl acetate 5:1) to give compound 18 containing various substituents.
(5) Synthesis of target Compound
General Synthesis of the object Compound (i.e., Compound 19) Compound 18(1.0mmol) having various substituents was added to dichloroethane (5.0mL), and triethylamine (3.0mmol) and trimethylsilyl trifluoromethanesulfonate (6.0mmol) were added. After 4 hours at 95 ℃, the reaction was quenched with methanol and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and purified by silica gel column chromatography (petroleum ether/ethyl acetate 2:1) to give compound 19 containing various substituents.
Referring to the above route, compounds C1-C7 were synthesized.
EXAMPLE 2 preparation of Compound C1
(1) Synthesis of Compound 13a
3,4, 5-trimethoxyphenol, Compound 11a (9.2g,50mmol) and sodium acetate (8.2g,100mmol) were added sequentially to acetic anhydride (47mL,500mmol) at room temperature and mixed, and heated at 110 ℃ for 2 hours. After the reaction, the reaction system was concentrated under reduced pressure and extracted with ethyl acetate three times. Washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated to give 3,4, 5-trimethoxyphenethyl ester, compound 12a (11.2g,49.5 mmo). White solid, yield 99%.1H NMR(400MHz,CDCl3)δ6.34(s,2H),3.83(s,9H),2.29(s,3H)。
Compound 12a (11.2g,49.5mmol) was added to glacial acetic acid (37.5mL) and boron trifluoride in ethyl ether (48%, 250mL) was added to the system. The reaction was stirred at 70 ℃ for 4 hours and the effect of the reaction was monitored by thin layer chromatography (petroleum ether/ethyl acetate 2: 1). After the reaction was completed, the reaction system was quenched with water and extracted with ethyl acetate three times. Washed with saturated brine and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (5: 1 petroleum ether/ethyl acetate) gave 2,3, 4-trimethoxy-6-hydroxyacetophenone, compound 13a (10.2g, 45.1mmol) as a yellow oil in 91% yield.1H NMR(500MHz,CDCl3)δ13.44(s,1H),6.24(s,1H),3.99(s,3H),3.89(s,3H),3.78(s,3H),2.66(s,3H)。
(2) Synthesis of Compound C1
2,3, 4-trimethoxy-6-hydroxyacetophenone, compound 13a (904mg,4.0mmol), was added to a 16mL dichloromethane solution, and triethylamine (1.47mL,12mmol) and 3, 4-dimethoxybenzoyl chloride (1.04g,5.2mmol) were added in this order at 0 ℃. The reaction system is heated from 0 ℃ to room temperature for 2 hours, and after the reaction is finished, the system is quenched by water and extracted by ethyl acetate for three times. Washed with saturated brine and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (petroleum ether/ethyl acetate ═ 5:1) gave the product 2-acetyl-3, 4, 5-trimethoxy-3, 4-dimethoxy-benzoic acid methyl ester (1.3g, 3.4mmol), a white solid, yield: 85 percent.1H NMR(400MHz,CDCl3)δ7.81(dd,J＝8.4,2.0Hz,1H),7.63(d,J＝2.0Hz,1H),6.96(d,J＝8.5Hz,1H),6.59(s,1H),3.98(s,3H),3.97(s,6H),3.91(s,3H),3.90(s,3H),2.51(s,3H)。
Methyl 2-acetyl-3, 4, 5-trimethoxy-3, 4-dimethoxy-benzoate (1.17g,3.0mmol) was added to 18mL of dichloroethane solution, triethylamine (1.2mL,9.0mmol) and trimethylsilyl trifluoromethanesulfonate (3.3mL,18mmol) were added, and the mixture was stirred at 95 ℃ for 2 hours. After completion of the reaction, the reaction mixture was quenched with methanol and extracted three times with ethyl acetate. Washed with saturated brine and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (petroleum ether/ethyl acetate ═ 2:1) gave the product 2- (3, 4-dimethoxyphenyl) -5,6, 7-trimethoxy-4H-benzopyran-4-one (905mg, 2.4mmol), a brown solid, yield: 81 percent.1H NMR(500MHz,CDCl3)δ7.51(d,J＝8.4Hz,1H),7.33(s,1H),6.98(d,J＝8.4Hz,1H),6.81(s,1H),6.60(s,1H),4.00(s,6H),3.99(s,3H),3.97(s,3H),3.93(s,3H)。
EXAMPLE 3 preparation of Compound C2
(1) Synthesis of Compound 13b
The raw material is replaced by 2,3, 4-trimethoxy-6-hydroxyacetophenone to react with nitric acid, and the product is obtained by the method of the step (2) in the example 2Obtaining the 2,3, 4-trimethoxy-5-nitro-6-hydroxyacetophenone as a yellow solid with the yield: 79 percent.1H NMR(400MHz,CDCl3)δ13.56(s,1H),4.10(s,3H),4.07(s,3H),3.81(s,3H),2.69(s,3H)。
(2) Synthesis of Compound C2
5.0mmol of 2,3, 4-trimethoxy-6-hydroxyacetophenone, 15mmol of triethylamine, 6.0mmol of 3, 4-dimethoxybenzoyl chloride and dichloromethane (25mL) solution. The product, methyl 2-acetyl-3, 4, 5-trimethoxy-6-nitrophenyl-3, 4-dimethoxy-benzoate, was obtained as an off-white solid in accordance with the procedure of step (4) in example 1, yield: 90 percent.1H NMR(500MHz,CDCl3)δ7.73(dd,J＝8.5,2.0Hz,1H),7.52(d,J＝2.0Hz,1H),6.92(d,J＝8.5Hz,1H),4.06(s,3H),4.02(s,3H),3.96(s,3H),3.95(s,3H),3.93(s,3H),2.52(s,3H)。
4.3mmol of 2-acetyl-3, 4, 5-trimethoxy-6-nitrophenyl-3, 4-dimethoxy-benzoic acid methyl ester, 13mmol of triethylamine, 25.6mmol of trimethylsilyl trifluoromethanesulfonate, 26mL of a dichloroethane solution. The product was obtained according to the procedure of step (5) in example 1,2- (3, 4-dimethoxyphenyl) -5,6, 7-trimethoxy-8-nitro-4H-chromen-4-one as a brown solid in yield: 84 percent.1H NMR(400MHz,CDCl3)δ7.42(dd,J＝8.5,2.1Hz,1H),7.28(d,J＝2.1Hz,1H),6.96(d,J＝8.6Hz,1H),6.63(s,1H),4.17(s,3H),4.05(s,3H),3.97(s,3H),3.96(s,3H),3.96(s,3H)。
The starting material, 2- (3, 4-dimethoxyphenyl) -5,6, 7-trimethoxy-8-nitro-4H-chromen-4-one, was reacted with palladium/carbon to obtain the product, 8-amino-2- (3, 4-dimethoxyphenyl) -5,6, 7-trimethoxy-4H-chromen-4-one, yellow solid, yield: 95 percent.1H NMR(400MHz,CDCl3)δ7.50(dd,J＝8.4,2.0Hz,1H),7.30(d,J＝2.0Hz,1H),6.98(d,J＝8.5Hz,1H),6.57(s,1H),4.04(s,3H),3.97(s,3H),3.97(s,3H),3.96(s,3H),3.91(s,3H)。
EXAMPLE 4 preparation of Compound C3
(1) Synthesis of Compound 13c
2,3, 4-trimethoxy-6-hydroxyacetophenone, compound 13a (4.436g,19.6mmol), was added to glacial acetic acid (15mL) and to sodium acetate (1.77g,21.6 mmol). Then at 0 deg.C, Br diluted with glacial acetic acid2(1.5mL,29.4mmol) was added dropwise to the reaction. Transferred to room temperature and stirred for 12 hours, poured into ice water (150mL) and filtered to give the product 2,3, 4-trimethoxy-5-bromo-6-hydroxyacetophenone, compound 13c, as a yellow solid, yield: 81 percent.1H NMR(400MHz,CDCl3)δ13.75(s,1H),4.05(s,3H),4.04(s,3H),3.83(s,3H),2.72(s,3H)。
(2) Synthesis of Compound C3
The starting materials were replaced with 2,3, 4-trimethoxy-5-bromo-6-hydroxyacetophenone and 3, 4-dimethoxybenzoyl chloride, and the product 8-bromo-2- (3, 4-dimethoxyphenyl) -5,6, 7-trimethoxy-4H-benzopyran-4-one was obtained according to the methods of steps (4) and (5) in example 1. White solid, yield: 59 percent.1H NMR(400MHz,CDCl3)δ7.64(dd,J＝8.5,2.1Hz,1H),7.53(d,J＝2.1Hz,1H),7.00(d,J＝8.5Hz,1H),6.75(s,1H),4.09(s,3H),4.00(s,3H),3.99(s,3H),3.97(s,3H),3.96(s,3H)。
EXAMPLE 5 preparation of Compound C4
(1) Synthesis of Compound 13d
The starting material was replaced with 2,3, 4-trimethoxyphenol, and the product, 2-hydroxy-3, 4, 5-trimethoxyacetophenone, was obtained according to the methods of the steps (1) and (2) in example 1.Yellow solid, yield: 89 percent.1H NMR(500MHz,CDCl3)δ12.44(s,1H),6.93(s,1H),4.04(s,3H),3.92(s,3H),3.85(s,3H),2.59(s,3H)。
(2) Synthesis of Compound C4
The starting material was replaced with 2-hydroxy-3, 4, 5-trimethoxyacetophenone and 3, 4-dimethoxybenzoyl chloride, and the product 2- (3, 4-dimethoxyphenyl) -7, 8-dimethoxy-4H-benzopyran-4-one was obtained as a pale yellow solid in the following steps (4) and (5) in example 1, yield: 82 percent.1H NMR(400MHz,CDCl3)δ7.57(s,1H),7.54(dd,J＝8.5,1.8Hz,1H),7.37(d,J＝1.8Hz,1H),6.98(d,J＝9.3Hz,2H),6.73(s,1H),4.03(s,3H),3.99(s,6H),3.97(s,3H)。
EXAMPLE 6 preparation of Compound C5
(1) Synthesis of Compound 13e
Dissolving raw material 2-hydroxy-3, 4, 5-trimethoxyacetophenone ((1.1g,5.0mmol) in 50mL acetonitrile solution, adding NIS (1.4g,6.0mmol) and p-toluenesulfonic acid (950mg,5.0mmol), reacting at room temperature for 2 hours, after the reaction is completed, concentrating to remove most of solvent, extracting ethyl acetate for three times, washing with saturated saline water, drying with anhydrous sodium sulfate, concentrating and spin-drying solvent to obtain the product 2-hydroxy-3, 4, 5-trimethoxy 6-iodo-acetophenone with the yield of 73%.1H NMR(500MHz,CDCl3)δ14.00(s,1H),4.02(d,J＝4.6Hz,3H),4.01(s,3H),3.80(s,3H),2.70(s,3H)。
2-hydroxy-3, 4, 5-trimethoxy-6-iodo-acetophenone (3.6g,10.2mmol) was dissolved in 30mL of DMF, followed by the addition of cuprous chloride (359mg,3.6mmol), the freshly prepared 4M sodium methoxide solution in methanol (25mL) was added to the system under argon protection, reacted at 90 ℃ for 20 minutes, poured into ice water and acidified with 5.0M HCl. Then extracting with ethyl acetateThe mixture was washed with saturated brine three times and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (petroleum ether/ethyl acetate 10:1) gave the product 2-hydroxy-3, 4,5, 6-tetramethoxyacetophenone, compound 13e (1.5g), as a pale yellow-green liquid, yield: 59 percent.1H NMR(500MHz,CDCl3)δ13.16(s,1H),4.08(s,3H),3.94(s,3H),3.86(s,3H),3.81(s,3H),2.68(s,3H)。
(2) Synthesis of Compound C5
The starting materials were replaced with 2-hydroxy-3, 4,5, 6-tetramethoxyacetophenone and piperonyl benzoyl chloride, and the product 2- (piperonyl) -5,6,7, 8-tetramethoxy-4H-benzopyran-4-one was obtained as described in steps (4) and (5) of example 1, as a white solid, yield: 79 percent.1H NMR(400MHz,MeOD–d4)δ7.62(dd,J＝8.3,1.6Hz,1H),7.47(d,J＝1.6Hz,1H),7.02(d,J＝8.3Hz,1H),6.66(s,1H),6.11(s,2H),4.12(s,3H),4.03(s,3H),3.94(s,3H),3.90(s,3H)。
EXAMPLE 7 preparation of Compound C6
Synthesis of compound C6:
the starting materials were replaced with 2-hydroxy-3, 4,5, 6-tetramethoxyacetophenone and 3,4, 5-trimethoxybenzoyl chloride, and the product, 2- (3,4, 5-trimethoxy) -5,6,7, 8-tetramethoxy-4H-benzopyran-4-one, was obtained as white solid in accordance with the procedures of steps (4) and (5) in example 1, in terms of yield: 80 percent.1H NMR(400MHz,CDCl3)δ7.17(s,2H),6.64(s,1H),4.11(s,3H),4.03(s,3H),3.96(s,12H),3.93(s,3H)。
EXAMPLE 8 preparation of Compound C7
Synthesis of compound C7:
the starting materials were replaced with 2-hydroxy-3, 4,5, 6-tetramethoxyacetophenone and 3, 4-dimethoxybenzoyl chloride, and the product, 2- (3, 4-dimethoxy) -5,6,7, 8-tetramethoxy-4H-benzopyran-4-one, was obtained as white solid in the following manner in steps (4) and (5) of example 1, yield: 78 percent.1H NMR(500MHz,CDCl3)δ7.57(d,J＝8.2Hz,1H),7.42(s,1H),7.00(d,J＝8.3Hz,1H),6.62(s,1H),4.11(s,3H),4.03(s,3H),3.98(s,3H),3.97(s,3H),3.96(s,6H)。
EXAMPLE 9 Synthesis of Compound C8
(1) Synthesis of Compound 13f
The starting material was replaced with 2, 3-dimethoxyphenol, and the product, 2-hydroxy-3, 4-dimethoxyacetophenone, was obtained according to the methods of steps (1) and (2) in example 1. Brown solid, yield: 95 percent.1H NMR(400MHz,CDCl3)δ12.67(s,1H),7.09(s,1H),6.48(s,1H),3.94(s,3H),3.89(s,3H),2.59(s,3H)。
(2) Synthesis of Compound C18
The starting material was replaced with 2-hydroxy-3, 4-dimethoxyacetophenone and 3, 4-dimethoxybenzoyl chloride, and the product 2- (3, 4-dimethoxy) -7, 8-dimethoxy-4H-benzopyran-4-one was obtained as pale white solid in accordance with the procedures of steps (4) and (5) in example 1, yield: 82 percent.1H NMR(400MHz,CDCl3)δ7.57(s,1H),7.54(dd,J＝8.5,1.8Hz,1H),7.37(d,J＝1.8Hz,1H),6.98(d,J＝9.3Hz,2H),6.73(s,1H),4.03(s,3H),3.99(s,6H),3.97(s,3H)。
EXAMPLE 10 Synthesis of Compound C9
(1) Synthesis of Compound C9
The starting material, 2-hydroxy-3, 4-dimethoxyacetophenone, was reacted with 3-methoxybenzoyl chloride in the same manner as in steps (4) and (5) of example 1 to give the product, 2- (3-methoxy) -7, 8-dimethoxy-4H-chromen-4-one, as a green solid, in a yield: 82 percent.1H NMR(400MHz,CDCl3)δ7.58(s,1H),7.50(d,J＝7.8Hz,1H),7.44(dd,J＝9.0,6.8Hz,2H),7.08(dd,J＝8.0,2.3Hz,1H),7.01(s,1H),6.79(s,1H),4.04(s,3H),4.01(s,3H),3.91(s,3H)。
EXAMPLE 11 Synthesis of Compound C10
(1) Synthesis of Compound C10
The raw material 2-hydroxy-3, 4-dimethoxyacetophenone and 4-methoxybenzoyl chloride were reacted according to the procedures of (4) and (5) in example 1 to obtain the product 2- (4-methoxy) -7, 8-dimethoxy-4H-benzopyran-4-one as brick red solid with the yield: 82 percent.1H NMR(500MHz,CDCl3)δ7.86(d,J＝8.8Hz,2H),7.56(s,1H),7.02(d,J＝8.7Hz,2H),6.99(s,1H),6.71(s,1H),4.02(s,3H),3.99(s,3H),3.89(s,3H)。
EXAMPLE 12 Synthesis of Compound C11
(1) Synthesis of Compound C11
The raw materials of 2-hydroxy-3, 4,5, 6-tetramethoxyacetophenone and 2-methoxy-4-picolinic acid are reacted according to the steps (4) and (5) in example 1 to obtain 5,6,7, 8-tetramethoxy-2- (2-methoxypyridin-4-ethyl) -4H-benzopyran-4-one as brick red solid with the following yields: 60 percent.1H NMR(400MHz,CDCl3)δ8.32(d,J＝4.9Hz,1H),7.30(d,J＝5.2Hz,1H),6.72(s,1H),5.35(t,J＝3.8Hz,1H),4.11(s,3H),4.02(s,2H),4.01(s,3H),3.95(s,6H)。
EXAMPLE 13 Synthesis of Compound C12
(1) Synthesis of Compound C12
The raw materials 2-hydroxy-3, 4,5, 6-tetramethoxyacetophenone and 6-methoxynicotinic acid are mixed according to the steps (4) and (5) in the example 1 to obtain the product 5,6,7, 8-tetramethoxy-2- (6-methoxypyridine-3-ethyl) -4H-benzopyran-4-one, pink solid, and the yield is as follows: 61 percent.1H NMR(500MHz,CDCl3)δ8.80(d,J＝2.3Hz,1H),8.03(dd,J＝8.7,2.5Hz,1H),6.88(d,J＝8.7Hz,1H),6.59(s,1H),4.11(s,3H),4.03(s,3H),4.01(s,3H),3.95(s,6H)。
EXAMPLE 14 Synthesis of Compound C13
(1) Synthesis of Compound C13
The starting materials, 2-hydroxy-3, 4,5, 6-tetramethoxyacetophenone and 5-methoxynicotinic acid, were reacted as described in steps (4) and (5) of example 1 to give 5,6,7, 8-tetramethoxy-2- (5-methoxypyridin-3-ethyl) -4H-benzopyran-4-one as a yellow solid in the following yields: and 55 percent.1H NMR(400MHz,CDCl3)δ8.80(s,1H),8.46(s,1H),7.65(d,J＝2.1Hz,1H),6.70(s,1H),4.11(s,3H),4.02(s,3H),3.96(s,9H)。
EXAMPLE 15 Synthesis of Compound C14
(1) Synthesis of Compound C14
The raw materials of 2-hydroxy-3, 4,5, 6-tetramethoxyacetophenone and 5, 6-dimethoxynicotinic acid are mixed to obtain the product 5,6,7, 8-tetramethoxy-2- (5, 6-dimethoxypyridine) according to the steps (4) and (5) in the example 1-3-ethyl) -4H-benzopyran-4-one, yellow solid, yield: and 55 percent.1H NMR(400MHz,CDCl3)δ8.40(d,J＝1.9Hz,1H),7.44(d,J＝1.9Hz,1H),6.60(s,1H),4.11(s,6H),4.02(s,3H),3.97(s,3H),3.96(s,6H)。
Example 16
In the compound shown in the formula (I), when X is N, the specific synthetic route is as follows:
the preparation method comprises the following specific steps:
(1) synthesis of Compound 20
2-hydroxy-3, 4, 5-trimethoxyacetophenone (2.3g,10mmol) was added to 40mL of DMF. Potassium carbonate (2.1g,15mmol) and iodomethane (679. mu.L, 1.1mmol) were added. The reaction mixture was stirred at room temperature for 2 hours, and after completion of the reaction, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give 2,3,4, 5-tetramethoxyacetophenone as compound 20 as a tan oil (2.3g,9.6 mmol). Yield: 96 percent.1H NMR(500MHz,CDCl3)δ7.07(s,1H),3.96(s,3H),3.92(s,3H),3.92(s,3H),3.86(s,3H),2.64(s,3H)。
(2) Synthesis of Compound 21
70% nitric acid (798. mu.L, 18mmol) was added dropwise to Compound 20 (2.3g,9.6mmol) and reacted at 0 ℃ for 15 minutes. The reaction was quenched with water and extracted with ethyl acetate. Washing the organic phase with saturated brine, drying over anhydrous sodium sulfate, concentrating, spin-drying most of the solvent, and purifying by silica gel column chromatography (5: 1 petroleum ether/ethyl acetate) to obtain 2,3,4, 5-tetra-ethyl acetateMethoxy-6-nitro-acetophenone, compound 21(1.9g,6.7mmol), as a pale yellow solid, yield: 70 percent.1H NMR(400MHz,CDCl3)δ4.00(s,3H),3.97(s,3H),3.95(s,3H),3.88(s,3H),2.59(s,3H)。
(3) Synthesis of Compound 22
Compound 21(1.9g,6.7mmol) was added to 134mL of tetrahydrofuran solution, and palladium on carbon (285mg, 15%) was added, followed by reaction at 40 ℃ for 15 hours under a hydrogen atmosphere. After completion of the reaction, it was cooled to room temperature, filtered through celite, and washed with ethyl acetate. The organic phase was concentrated and the bulk of the solvent was spin dried and purified by silica gel column chromatography (petroleum ether/ethyl acetate 2:1) to give the product 2,3,4, 5-tetramethoxy-6-amino-acetophenone compound 22(1.6g,6.3mmol) as a tan oil with a 95% yield.1H NMR(400MHz,CDCl3)δ4.12(s,3H),4.03(s,3H),4.02(s,3H),3.88(s,3H),2.83(s,3H)。
(4) Synthesis of Compound 23
Compound 22(0.57g,2.2mmol) was added to a solution of 11mL of dichloromethane, triethylamine (915. mu.L, 6.6mmol) was added thereto at 0 ℃, and 3, 4-dimethoxybenzoyl chloride (0.88g,4.4mmol) was added thereto. The system was stirred to room temperature at 0 ℃ and after 3 hours, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (petroleum ether/ethyl acetate ═ 5:1) to give compound 23(738mg, 1.8mmol) as a white solid. Yield: 80 percent.1H NMR(400MHz,CDCl3)δ8.24(s,1H),7.46(d,J＝1.9Hz,1H),7.44(dd,J＝8.2,2.1Hz,1H),6.92(d,J＝8.2Hz,1H),3.97(s,3H),3.95(s,3H),3.95(s,3H),3.93(s,3H),3.90(s,3H),3.84(s,3H),2.65(s,3H)。
(5) Synthesis of Compound 24
Compound 23(738mg, 1.8mmol) was added to 60mL of an anhydrous tetrahydrofuran solution, and potassium tert-butoxide (0.61g,5.4mmol) was added and reacted at 75 ℃ for 18 hours under an argon atmosphere. After the reaction was completed, the reaction mixture was cooled to room temperature, and then water was added to terminate the reaction, followed by acidification with 2.0M aqueous hydrochloric acid. And (5) extracting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and purified by silica gel column chromatography (petroleum ether/ethyl acetate ═ 3:1) to give product 24(592mg, 1.5mmol) as a white solid in yield: 82 percent. 1H NMR (400MHz, CDCl)3)δ7.35(d,J＝6.6Hz,2H),7.02(d,J＝8.9Hz,1H),6.72(s,1H),4.12(s,3H),4.09(s,3H),4.03(s,3H),4.00(s,6H),3.98(s,3H)。
(6) Synthesis of target Compound 25
Compound 24(0.2mmol) was added to anhydrous N, N-dimethylformamide (2.0mL) and sodium hydride (60% dispersed in mineral oil, 80mg,2.0mmol) was added. After a reaction time of 30 minutes at 90 ℃ chloroalkanes (0.6mmol) containing different substituents were added. The reaction mixture was stirred at 90 ℃ for 2 hours, after the solution was cooled to room temperature, poured into water and acidified by addition of 2.0M aqueous hydrochloric acid. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and purified by silica gel column chromatography (petroleum ether/ethyl acetate 3:1) to give product 25 containing various substituents.
EXAMPLE 17 Synthesis of Compound C15
(1) Synthesis of Compound C15
The starting 2- (3, 4-dimethoxy) -5,6,7, 8-tetramethoxy-quinolin-4 (1H) -one (24) and 2-chloroethylmethyl ether were reacted by the method described in the (6) th step of example 16 to give 2- (3, 4-dimethoxy-quinoline-4 (1H) -onePhenyl) -5,6,7, 8-tetramethoxy-1- (2-methoxyethyl) -quinolin-4 (1H) -one. Light yellow oil, yield: 70 percent.1H NMR(400MHz,MeOD–d4)δ7.90(d,J＝2.1Hz,1H),7.71(dd,J＝8.4,2.1Hz,1H),7.28(s,1H),7.07(d,J＝8.4Hz,1H),4.43(t,J＝4.4Hz,2H),4.11(s,3H),4.07(s,3H),3.97(s,3H),3.97(s,3H),3.93(t,J＝4.4Hz,2H),3.91(s,3H),3.89(s,3H),3.49(s,3H)。
EXAMPLE 18 Synthesis of Compound C16
(1) Synthesis of Compound C16
The starting material 2- (3, 4-dimethoxy) -5,6,7, 8-tetramethoxy-quinolin-4 (1H) -one (24) (80mg, 0.2mmol) was dissolved in 3mL of DMF solution, followed by the addition of potassium carbonate (41mg,0.3mmol) and iodomethane (14. mu.L, 0.22 mmol). After reacting for 1 hour at room temperature, extracting by ethyl acetate, extracting by saturated saline solution, drying by anhydrous sodium sulfate, concentrating and drying the solvent, and then carrying out silica gel column chromatography to obtain the product 2- (3, 4-dimethoxy) -5,6,7, 8-tetramethoxy-1-methyl-quinoline-4 (1H) -ketone. Light yellow oil, yield: 70 percent.1H NMR(400MHz,CDCl3)δ7.94(d,J＝2.0Hz,1H),7.65(dd,J＝8.4,2.0Hz,1H),7.14(s,1H),6.98(d,J＝8.4Hz,1H),4.20(s,3H),4.13(s,3H),4.11(s,3H),4.04(s,3H),4.01(s,3H),3.96(s,3H),3.91(s,3H)。
EXAMPLE 19 Synthesis of Compound C17
(1) Synthesis of Compound C17
The starting material, 2- (3, 4-dimethoxy) -5,6,7, 8-tetramethoxy-quinolin-4 (1H) -one (24), was reacted with 1-chloropropane in the same manner as in the step (6) in example 16 to give 2- (3, 4-dimethoxy) -5,6,7, 8-tetramethoxy-1-propyl-quinolin-4 (1H) -one. Light yellow oil, yield: 62 percent.1H NMR(400MHz,MeOD–d4)δ7.89(d,J＝2.1Hz,1H),7.68(dd,J＝8.4,2.1Hz,1H),7.24(s,1H),7.06(d,J＝8.4Hz,1H),4.25(t,J＝6.4Hz,2H),4.11(s,3H),4.06(s,3H),3.97(s,3H),3.96(s,3H),3.90(s,3H),3.88(s,3H),2.01(dd,J＝13.9,6.5Hz,2H),1.19(t,J＝7.4Hz,3H).
EXAMPLE 20 Synthesis of Compound C18
(1) Synthesis of Compound C18
Compound 23(738mg, 1.8mmol) was added to 60mL of an anhydrous tetrahydrofuran solution, and potassium tert-butoxide (0.61g,5.4mmol) was added under argon atmosphere and reacted at 75 ℃ for 18 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and then water was added to terminate the reaction, followed by acidification with 2.0M aqueous hydrochloric acid. And (5) extracting with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and purified by silica gel column chromatography (petroleum ether/ethyl acetate 3:1) to give the product 2- (3, 4-dimethoxy) -5,6,7, 8-tetramethoxy-quinolin-4 (1H) -one (592mg, 1.5mmol) as a white solid. Yield: 82 percent. 1H NMR (400MHz, CDCl)3)δ7.35(d,J＝6.6Hz,2H),7.02(d,J＝8.9Hz,1H),6.72(s,1H),4.12(s,3H),4.09(s,3H),4.03(s,3H),4.00(s,6H),3.98(s,3H)。
EXAMPLE 21 Synthesis of Compound C19
(1) Synthesis of Compound C19
The starting material, 2- (3, 4-dimethoxy) -5,6,7, 8-tetramethoxy-quinolin-4 (1H) -one (24), and dimethylaminoethyl chloride hydrochloride were reacted as described in step (6) of example 16 to give the product, 2- (3, 4-dimethoxy) -5,6,7, 8-tetramethoxy-1- (2- (dimethylamino) -ethyl) quinolin-4 (1H) -one. Light yellow oil, yield: 71 percent.1H NMR(500MHz,MeOD–d4)δ7.94(s,1H),7.74(d,J＝8.4Hz,1H),7.32(s,1H),7.08(d,J＝8.4Hz,1H),4.44(t,J＝5.6Hz,2H),4.13(s,3H),4.08(s,3H),3.99(s,6H),3.92(s,3H),3.90(s,3H),3.03(t,J＝5.5Hz,2H),2.48(s,6H)。
Example 22 Compound (I)Substance C1-C19 paclitaxel IC in experiment for reversing HCT8/T drug-resistant cells50Testing
Testing of the IC of the Compounds prepared in examples 1 to 21 on paclitaxel in an experiment to reverse HCT8/T resistant cells50The test data are shown in table 1. Nobiletin and derivatives thereof can reduce IC of paclitaxel in drug-resistant HCT8/T cells50The anti-tumor effect of the paclitaxel is enhanced, and the cytotoxicity is obviously lower than that of the paclitaxel; wherein the IC of C7, C12, C6 and C1 is combined with paclitaxel50The values were 185-fold, 87-fold, 81-fold, and 66-fold lower than paclitaxel alone.
TABLE 1 IC of nobiletin derivatives paclitaxel in experiments reversing HCT8/T drug resistance cells50Test results
aThe cytotoxicity of the compound;bIC of P-gp inhibitor in combination with paclitaxel50；cMultiple of reversal as IC50(paclitaxel)/IC50(P-gp inhibitor in combination with paclitaxel).
From table 1,4 compounds C1, C6, C7 and C19 with higher fold reversal were identified, wherein C6 has higher cytotoxicity, so compounds C1, C7 and C19 were selected as subjects to test their solubility and animal experiments.
1. And (3) testing the solubility: the solubility of three compounds, C1, C7 and C19, was measured by high performance liquid chromatography in sodium dihydrogen phosphate buffer at room temperature and found to be: 3.67 + -0.52 μ g/mL, 5.58 + -1.17 μ g/mL, and 1.58 + -0.13 mg/mL; wherein the water solubility of compound C19 is 283 times higher than that of C7.
2. Animal experiments: all animal experiments were approved by the animal care and use committee of the university of traditional Chinese medicine, Guangzhou (code: ZYYL 20150807).
Tumor mice were randomized into 9 groups (n ═ 6): a control group (CTR), a 15mg/kg PTX administration group, a 50mg/kg nobiletin (C7) administration group, a 50mg/kg C1 administration group, a 50mg/kg C19 administration group, a 50mg/kg nobiletin (C7) +15mg/kg PTX administration group, a 25mg/kg C1+15mg/kg PTX administration group, a 50mg/kg C1+15mg/kg PTX administration group, a 25mg/kg C19+15mg/kg PTX administration group, and a 50mg/kg C19+15mg/kg PTX administration group. Resuspend 5X 10 with 50. mu.L of RPMI 1640 medium and 50. mu.L of matrigel6A549/T cells were injected subcutaneously into right forelimb axillary tumors (A549/T xenograft tumors) of 8-week nude mice. After 5 days, the tumor-forming mice are administrated by intraperitoneal injection once every 3 days, the tumor volume is recorded every three days, and the calculation formula is as follows: volume (width squared length)/2, recorded by day 30, all nude mice were sacrificed, tumors excised, then weighed on an electronic balance, and the weight of each group of tumors recorded.
On the basis of the previous studies, the tumors that have developed resistance, were injected intraperitoneally with an effective dose (15mg/kg) of Paclitaxel (PTX) alone, and had no significant therapeutic effect on the resistant tumors compared to the non-administered blank group (Cancer Chemother Pharmacol 2007,60, 907-914). Thus, test compounds C1, C7, C19 of the present invention were combined with PTX, respectively, and test compounds C1, C7, C19 were tested for their reversal effect on tumor resistance to PTX, as shown in fig. 1.
As can be seen from FIG. 1, compound C19 was administered in combination with PTX at doses of 25mg/kg and 50mg/kg, respectively, with a significant reduction in tumor volume compared to the PTX group administered alone; in addition, all nude mice had no significant weight loss, indicating that the combination did not cause additional toxicity; in the A549/T xenograft tumor transplantation model, the PTX combined with C19(50mg/kg) can remarkably reduce the tumor volume by 57 percent and is more effective than equivalent dose of nobiletin (C7) (P < 0.05); similarly, C1 also enhanced the therapeutic effect of PTX in a549/T xenograft model, with similar inhibitory effect to that of nobiletin.
As can be seen from the above results, the solubility of the nobiletin derivative of the present invention is significantly improved compared to nobiletin, wherein the water solubility of C19 is 283 times that of C7; meanwhile, after the nobiletin derivative and Paclitaxel (PTX) are jointly administered, the paclitaxel concentration in a tumor cell body is obviously improved, the drug resistance of the tumor cell in the tumor cell body is reversed, the effect of the paclitaxel on inhibiting the tumor growth is improved, and the nobiletin derivative can be prepared into a drug-resistant tumor multi-drug resistance reversal agent for application and mixed with other anti-tumor drugs for application, so that the prevention and treatment effect of the tumor is improved.
It should be finally noted that the above examples are only intended to illustrate the technical solutions of the present invention, and not to limit the scope of the present invention, and that other variations and modifications based on the above description and thought may be made by those skilled in the art, and that all embodiments need not be exhaustive. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (6)
1. A nobiletin derivative or a pharmaceutically acceptable salt thereof is characterized in that the nobiletin derivative has any one of the following structures:
2. the nobiletin derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt thereof is a product obtained by reacting the nobiletin derivative with an acid.
3. The nobiletin derivative or a pharmaceutically acceptable salt thereof according to claim 2, wherein the acid is hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, methanesulfonic acid, salicylic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, fumaric acid, citric acid, acetic acid, tartaric acid, succinic acid, malic acid, or glutamic acid.
4. The use of the nobiletin derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 in the preparation of a P-gp inhibitor medicament.
5. The use of the nobiletin derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 in the preparation of a multidrug resistance reversal agent for tumors.
6. The use according to claim 4 or 5, wherein the nobiletin derivative or the pharmaceutically acceptable salt thereof is mixed with an antitumor drug.
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