CN110498784A - A kind of Nobiletin derivative or its pharmaceutically acceptable salt and its preparation method and application - Google Patents
A kind of Nobiletin derivative or its pharmaceutically acceptable salt and its preparation method and application Download PDFInfo
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- CN110498784A CN110498784A CN201910657044.4A CN201910657044A CN110498784A CN 110498784 A CN110498784 A CN 110498784A CN 201910657044 A CN201910657044 A CN 201910657044A CN 110498784 A CN110498784 A CN 110498784A
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Abstract
The invention discloses a kind of Nobiletin derivative or its pharmaceutically acceptable salts and its preparation method and application.Shown in the structure such as formula (I) of the Nobiletin derivative；Wherein, R1、R2、R3And R4It is respectively selected from hydrogen, halogen, hydroxyl, amino, C1‑6Substituted or non-substituted alkoxy, C1‑6Substituted or non-substituted ester group, C1‑6Substituted or non-substituted alkylamino radical, C1‑6Substituted or non-substituted amide groups；R5Selected from C3‑9Substituted or non-substituted aromatic rings, C3‑9Substituted or non-substituted aromatic heterocycle；X is selected from O or NR6.Nobiletin derivative of the present invention or its pharmaceutically acceptable salt structure novel, and compound shows P-gp excellent inhibiting effect, it can be prepared as P-gp inhibitor to carry out using the related disease that treatment and/or prevention are caused by P-gp, the especially relevant disease of tumor drug resistance；Or be used in combination with other drugs, it is applied as reversal of drug resistance agent, reversal index is high, can improve to conspicuousness the drug effect of drug.
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology, more particularly, to a kind of Nobiletin derivative or its pharmaceutically
Acceptable salt and its preparation method and application.
Background technique
Tumor multi-medicine drug-resistant (Multiple drug resistance, MDR), refers to tumour cell to a kind of antineoplastic
While object develops drug resistance, it is anti-that a kind of drug resistant intersection is also generated to the other structures anti-tumor drug different with mechanism of action
Pharmacological property is the one of the major reasons for leading to chemotherapy of tumors failure.Find multidrug resistance reversal agent and anti-tumor drug share with
Restoring multidrug resistance tumor cells is to overcome one of the main path of multidrug resistance to the sensibility of anticancer drug.
The overexpression of P- glycoprotein (P-gp) is one of the main mechanism for causing tumour cell to generate multidrug resistance, existing to grind
The P-gp protein inhibitor such as Verapamil studied carefully, the chemistry reversal agent such as cyclosporine are limited in clinical use because being more toxic
System.The efficient multidrug-resistance reversal agent of exploitation low toxicity is of great significance.Since natural products has less toxic, resourceful, work
Sight is turned to natural drug by the advantages that more with target spot, many scholars, is screened out from it the natural activity with anti-multidrug resistance
Ingredient.
Nobiletin derives from Rutaceae river tangerine, has anti-cell cohesion, antithrombus formation, antimycotic, anti-inflammatory, anti-mistake
Quick, anticholinesterase and anti-epileptic, while the still multiple pharmacological effects such as promotor of carbohydrate metabolism, therefore be with it
Parent compound carries out the compound that more bioactivity are provided in research and development, with biggish application prospect.
Summary of the invention
The purpose of the present invention is to provide a kind of Nobiletin derivative or its pharmaceutically acceptable salts.It is of the present invention
Compound carries out structural modification using Nobiletin as precursor structure, to it, and obtained compound structure is novel；And compound for
P- glycoprotein (P-gp) shows excellent inhibiting effect, can be used as P-gp inhibitor and carries out using and then being prepared into
The related disease that drug, treatment and/or prevention are caused by P-gp, the especially relevant disease of tumor drug resistance；Or and other drugs
It is used in combination, is applied as reversal of drug resistance agent, improve the drug effect of drug.
Another object of the present invention is to provide the preparations of the Nobiletin derivative or its pharmaceutically acceptable salt
Method.
A further object of the present invention is to provide the Nobiletin derivative or its pharmaceutically acceptable salt or river are old
The application of Pi Su.
Above-mentioned purpose of the invention is achieved by following scheme:
A kind of Nobiletin derivative or its pharmaceutically acceptable salt, the structure such as formula of the Nobiletin derivative
(I) shown in:
Wherein, R1、R2、R3And R4It is respectively selected from hydrogen, halogen, hydroxyl, amino, C1-6Substituted or non-substituted alkoxy, C1-6It takes
Generation or non-substituted ester group, C1-6Substituted or non-substituted alkylamino radical, C1-6Substituted or non-substituted amide groups；
R5Selected from C3-9Substituted or non-substituted aromatic rings, C3-9Substituted or non-substituted aromatic heterocycle；The aromatic heterocycle be containing
There is the aromatic rings of N, O or S atom；
X is selected from O or NR6；The R6Selected from hydrogen, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Substituted or non-substituted alkoxy or
C1-6Substituted or non-substituted alkylamino radical；
The C1-6Substituted or non-substituted alkoxy, C1-6Substituted or non-substituted ester group, C1-6Substituted or non-substituted alkylamino radical,
C1-6Substituted or non-substituted amide groups, C3-9Substituted or non-substituted aromatic rings and C3-9Substitution in substituted or non-substituted aromatic heterocycle
For halogen, hydroxyl, amino, C1-4Alkyl or C1-4Alkoxy is replaced.
Preferably, the R1、R2、R3And R4It is respectively selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, methoxyl group, ethyoxyl, third
Oxygroup, isopropoxy, methylamino, dimethylamino, ethylamino-, Propylamino, isopropylamino.
Preferably, the R5Selected from substituted or non-substituted phenyl, substituted or non-substituted phenylpyridine or substituted or non-substituted
Phenyl benzo [d] [1,3] dioxin；It is therein to be substituted by C1-4Alkyl or C1-4Alkoxy is replaced.
Preferably, the R6For hydrogen or C1-6Substituted or non-substituted alkyl, wherein C1-6Taking in substituted or non-substituted alkyl
In generation, refers to that halogen, hydroxyl or amino are replaced.
Preferably, the R5It is selected from
Preferably, the R6For methyl, propyl, isopropyl, 2- methox-etlayl or N, N- dimethyl ethyl.
It is highly preferred that described in the following any structure of structure of the Nobiletin derivative:
Preferably, its described pharmaceutically acceptable salt is that Nobiletin derivative shown in formula (I) is reacted with acid
Product.
Preferably, it is described acid be hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, methanesulfonic acid, salicylic acid,
Trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalene sulfonic acids, maleic acid, fumaric acid, citric acid, acetic acid, tartaric acid, succinic acid, malic acid or paddy
Propylhomoserin.
The present invention also protects the preparation method of the Nobiletin and its derivative simultaneously, includes the following steps:
S1. in -30~25 DEG C of solvents dissolved with alkaline matter, formula 1 is mixed with compound shown in formula 2, and is gradually heated up
It is reacted to 25~100 DEG C, compound shown in formula 3 can be obtained；
S2. compound shown in formula 3 is dissolved with the molten of alkaline matter or alkaline matter and triethyl group silicon substrate triflate
In agent, it is warming up to 40~100 DEG C of reactions after first room temperature, target product can be obtained；
Wherein, R1、R2、R3And R4It is respectively selected from hydrogen, halogen, hydroxyl, amino, C1-6Substituted or non-substituted alkoxy, C1-6It takes
Generation or non-substituted ester group, C1-6Substituted or non-substituted alkylamino radical, C1-6Substituted or non-substituted amide groups；
R5Selected from C3-9Substituted or non-substituted aromatic rings, C3-9Substituted or non-substituted aromatic heterocycle；The aromatic heterocycle be containing
There is the aromatic rings of N, O or S atom；
X is selected from O or NR6；The R6Selected from hydrogen, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Substituted or non-substituted alkoxy or
C1-6Substituted or non-substituted alkylamino radical；
The C1-6Substituted or non-substituted alkoxy, C1-6Substituted or non-substituted ester group, C1-6Substituted or non-substituted alkylamino radical,
C1-6Substituted or non-substituted amide groups, C3-9Substituted or non-substituted aromatic rings and C3-9Substitution in substituted or non-substituted aromatic heterocycle
For halogen, hydroxyl, amino, C1-4Alkyl or C1-4Alkoxy is replaced.
Preferably, step S1, in S2, the alkaline matter is independently selected from diisopropyl ethyl amine, triethylamine, diethyl
Amine, 4-dimethylaminopyridine, piperidines, pyrroles, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride,
One of sodium tert-butoxide or potassium tert-butoxide are a variety of.
Preferably, step S1, in S2, the solvent independently selected from methylene chloride, 1,2- dichloroethanes, chloroform, ether,
Benzene, toluene, ethyl acetate, tetrahydrofuran, 1,4- dioxane, acetonitrile, propionitrile, acetone, N,N-dimethylformamide, N, N- bis-
One of methylacetamide or dimethyl sulfoxide are a variety of.
Preferably, the preparation process of the Nobiletin are as follows:
(1) it reacts, is obtained described in formula 6 in the solvent of compound described in formula 5 and acetylation reagent in the presence of a basic
Compound；
(2) it is reacted in the solvent of compound in the presence of a lewis acid described in formula 6, obtains compound described in formula 7；
(3) it is reacted in the solvent of compound described in formula 7 and N- N-iodosuccinimide (NIS) in the presence of acidic materials,
Obtain compound described in formula 8；
(4) it is reacted in the solvent of compound described in formula 8 and stannous chloride in the presence of sodium methoxide, obtains chemical combination described in formula 9
Object；
(5) compound and 3 described in formula 9 is reacted in the solvent of 4- dimethoxy-benzoyl chloride in the presence of a basic, is obtained
To compound described in formula 10；
(6) compound described in formula 10 is dissolved with the molten of alkaline matter or alkaline matter and triethyl group silicon substrate triflate
It is reacted in agent, compound Nobiletin can be obtained.
Preferably, in step (1), the acetylation reagent is acetic anhydride or chloroacetic chloride.
Preferably, in step (1), the molar ratio of compound described in formula 5 and acetylation reagent is 1:1~1:20；More preferably
Ground is 1:1~1:2.
Preferably, in step (1), the solvent be selected from methylene chloride, 1,2- dichloroethanes, chloroform, ether, benzene, toluene,
Ethyl acetate, tetrahydrofuran, 1,4- dioxane, acetonitrile, propionitrile, acetone, acetic acid, N,N-dimethylformamide, N, N- diformazan
One of yl acetamide or dimethyl sulfoxide are a variety of.
Preferably, in step (1), the alkaline matter is selected from diisopropyl ethyl amine, triethylamine, diethylamine, 4- diformazan
Aminopyridine, piperidines, pyrroles, sodium acetate, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, uncle
One of sodium butoxide or potassium tert-butoxide are a variety of.
Preferably, in step (1), the temperature of the reaction is -10~150 DEG C, and the reaction time is 1~40 hour；It is more excellent
Selection of land, temperature are 0~100 DEG C, and the reaction time is 1~4 hour.
Preferably, in step (2), the lewis acid is selected from boron trifluoride, alchlor, trifluoromethanesulfonic acid aluminium, trichlorine
Change one of iron, tin tetrachloride or titanium tetrachloride or a variety of.
Preferably, in step (2), compound described in formula 6 and lewis acidic molar ratio are 1:1~1:30；More preferably
For 1:2~1:25.
Preferably, in step (2), the solvent is selected from methylene chloride, 1,2- dichloroethanes, chloroform, ether, benzene, toluene
Or one of acetic acid or a variety of.
Preferably, in step (2), reaction temperature is -10~150 DEG C, and the reaction time is 1~40 hour；It is highly preferred that warm
Degree is 0~100 DEG C, and the reaction time is 1~4 hour.
Preferably, in step (3), the molar ratio of compound described in formula 7 and NIS are 1:1~10；More preferably 1:1~
2。
Preferably, in step (3), the solvent be selected from methylene chloride, 1,2- dichloroethanes, chloroform, ether, benzene, toluene,
One of ethyl acetate, tetrahydrofuran, 1,4- dioxane, acetonitrile or propionitrile are a variety of.
Preferably, in step (3), the acidic materials are selected from p-methyl benzenesulfonic acid, benzene sulfonic acid, acetic acid, trifluoroacetic acid, trifluoro
One of methanesulfonic acid, hydrochloric acid or sulfuric acid are a variety of.
Preferably, in step (3), the temperature of the reaction is 0~50 DEG C, and the reaction time is 1~24 hour；More preferably
Ground, temperature are 15~35 DEG C, and the reaction time is 1~4 hour.
Preferably, in step (4), the molar ratio of compound described in formula 8 and sodium methoxide is 1:1~30；More preferably 1:5
~15.
Preferably, in step (4), the solvent is selected from tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, methanol, ethyl alcohol, N, N- diformazan
One of base formamide, DMAC N,N' dimethyl acetamide or dimethyl sulfoxide are a variety of.
Preferably, in step (4), the temperature of the reaction is 25~120 DEG C, and the reaction time is 1~24 hour；More preferably
Ground, temperature are 60~100 DEG C, and the reaction time is 1~4 hour.
Preferably, in step (5), compound described in formula 9 and 3, the molar ratio of 4- dimethoxy-benzoyl chloride is 1:1~3；
More preferably 1:1~1.5.
Preferably, in step (5), the solvent be selected from methylene chloride, 1,2- dichloroethanes, chloroform, ether, benzene, toluene,
One of ethyl acetate, tetrahydrofuran, 1,4- dioxane or acetonitrile are a variety of.
Preferably, in step (5), the alkaline matter is selected from diisopropyl ethyl amine, triethylamine, diethylamine, 4- diformazan
Aminopyridine, piperidines, pyrroles, sodium acetate, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, uncle
One of sodium butoxide or potassium tert-butoxide are a variety of.
Preferably, in step (5), the temperature of the reaction is -10~100 DEG C, and the reaction time is 1~24 hour；It is more excellent
Selection of land, temperature are 0~40 DEG C, and the reaction time is 1~4 hour.
Preferably, in step (6), the solvent of the reaction be selected from methylene chloride, 1,2- dichloroethanes, chloroform, ether,
One of benzene, toluene, ethyl acetate, tetrahydrofuran, 1,4- dioxane or acetonitrile are a variety of.
Preferably, in step (6), the alkaline matter is selected from diisopropyl ethyl amine, triethylamine, diethylamine, 4- diformazan
Aminopyridine, piperidines, pyrroles, sodium acetate, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, uncle
One of sodium butoxide or potassium tert-butoxide are a variety of.
Preferably, in step (6), the temperature of the reaction is -10~120 DEG C, and the reaction time is 1~24 hour；It is more excellent
Selection of land, temperature are 20~100 DEG C, and the reaction time is 1~12 hour.
The Nobiletin derivative or its pharmaceutically acceptable salt or Nobiletin are in preparation P-gp inhibitor medicaments
In application also in protection scope of the present invention etc.
Preferably, the Nobiletin derivative or its pharmaceutically acceptable salt or Nobiletin are being prepared into treatment
Application in P-gp related disease drug.
The present invention also protects the Nobiletin derivative or its pharmaceutically acceptable salt or Nobiletin making simultaneously
Application in standby tumor multi-drug resistance reversal agents.
Preferably, the Nobiletin derivative or its pharmaceutically acceptable salt or Nobiletin and anti-tumor drug are mixed
With application.
Preferably, the P-gp inhibitor medicaments or tumor multi-drug resistance reversal agents can add that customary adjuvant is prepared into can
The dosage form that clinic receives.
It is highly preferred that the P-gp inhibitor medicaments or tumor multi-drug resistance reversal agents can be prepared as oral type tablet,
Pill, capsule, injection injection or powder needle.
Compared with prior art, the invention has the following advantages:
Nobiletin derivative of the present invention or its pharmaceutically acceptable salt structure novel, and compound is for P-gp
Excellent inhibiting effect is shown, P-gp inhibitor is can be prepared as and carries out using treatment and/or prevention are caused by P-gp
The relevant disease of related disease, especially tumor drug resistance；Or be used in combination with other drugs, it is answered as reversal of drug resistance agent
With reversal index is high, can improve to conspicuousness the drug effect of drug.
Detailed description of the invention
Fig. 1 is that Nobiletin and its derivative are combined administering paclitaxel and moved in taxol resistance A549/T tumour cell nude mice
Plant the antitumaous effect in model.
Specific embodiment
The present invention is made combined with specific embodiments below and further being elaborated, the embodiment is served only for explaining this
Invention, is not intended to limit the scope of the present invention.Test method as used in the following examples is normal unless otherwise specified
Rule method；Used material, reagent etc., unless otherwise specified, for the reagent and material commercially obtained.
Embodiment 1
In compound shown in formula (I), when X is O, specific synthetic route is as follows:
(1) synthesis of compound 12
At room temperature, compound 3,4,5- trimethoxy phenol and sodium acetate, sequentially add in acetic anhydride and mix, at 110 DEG C
Lower heating 2 hours.After the reaction was completed, reaction system is concentrated under reduced pressure, ethyl acetate extracts three times.Saturated common salt water washing, nothing
Aqueous sodium persulfate is dry.Concentration of organic layers obtains the phenylacetate containing different substituents, i.e. compound 12.
(2) synthesis of compound 13
Compound 12 is added in glacial acetic acid solution, is added boron trifluoride ether solution (about 48%).Reaction mixture is 70
It is stirred 2 hours at DEG C, thin-layer chromatographic analysis monitoring reaction is completed.Then reaction system, ethyl acetate extraction, saturation is quenched with water
Brine It, anhydrous sodium sulfate are dry, and silica gel column chromatography (petroleum ether: ethyl acetate=10:1) purifying obtains taking containing difference
The hydroxy acetophenone of Dai Ji, i.e. compound 13.
(3) synthesis of compound 17
2,3- dimethoxy-pyridine (1.04g, 7.5mmol) is added in 30mL dichloromethane solution, bromine is then added
(1.12g, 7.0mmol) is reacted at room temperature 48 hours.After fully reacting, concentration removes most of solvent, and column chromatographs (petroleum ether: second
Acetoacetic ester=10:1), obtain product 2,3- dimethoxy -5- bromopyridine (i.e. compound 15,1.5g), white solid, yield
93%.1H NMR(400MHz,CDCl3) δ 7.80 (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) is added in 5mL n,N-Dimethylformamide solution,
It is added cuprous cyanide (179.2mg, 4.0mmol), under argon gas protection, is warming up to 160 DEG C, fully reacting after reaction 8 hours.It is cooling
It to room temperature, is diluted with water, after ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate is dry, and concentration removes solvent, column
It chromatographs (petroleum ether: ethyl acetate=10:1), acquisition product 2,3- dimethoxy -5- cyanopyridine (i.e. compound 16,
164.2mg, 1.0mmol), white solid, yield 50%.1H NMR(400MHz,CDCl3) δ 8.10 (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) is added in 5.0mL ethanol solution, at room temperature
The sodium hydroxide solution (1.67mL, 10mmol) of 6M is added, is warming up to 90 DEG C and reacts 16 hours.After fully reacting, concentration is removed
Solvent obtains product 5,6- dimethoxy niacin (i.e. compound 17,133mg, 0.73mmol), Beige powder, yield 73%.1H
NMR(400MHz,CDCl3) δ 8.53 (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
5.0mL will be added containing different substituents 2- hydroxy acetophenone (1.0mmol) in the general synthetic method of compound 18
In methylene chloride.At 0 DEG C, after triethylamine (1.5mmol) is added, by the chlorobenzoyl chloride (1.2mmol) containing different substituents
In addition system.Mixture is stirred at 0 DEG C to room temperature, and after 3 hours, reaction system, ethyl acetate extraction is quenched with water.It is organic
Saturated common salt water washing is mutually used, anhydrous sodium sulfate is dry, and silica gel column chromatography (petroleum ether: ethyl acetate=5:1) purifying is contained
There is the compound 18 of different substituents.
It will be added in 5mL methylene chloride containing different substituents 2- hydroxy acetophenone (1.0mmol).At 0 DEG C, it is added
It, will be in pyridine carboxylic acid (1.2mmol) addition system containing different substituents after DMAP (1.5mmol).Mixture stirs at 0 DEG C
It mixes to room temperature, after 3 hours, reaction system, ethyl acetate extraction is quenched with water.Organic phase saturated common salt water washing, anhydrous sulphur
Sour sodium is dry, and silica gel column chromatography (petrol ether/ethyl acetate=5:1) purifying obtains the compound 18 containing different substituents.
(5) synthesis of target compound
The general synthetic method of target compound (i.e. compound 19), by the compound 18 containing different substituents
(1.0mmol) is added in dichloroethanes (5.0mL), and triethylamine (3.0mmol) and trimethyl silicon substrate trifluoro-methanyl sulfonate is added
(6.0mmol).It is reacted at 95 DEG C 4 hours, then uses methanol quenching reaction system, ethyl acetate extraction.Organic phase saturation
Brine It, anhydrous sodium sulfate is dry, and silica gel column chromatography (petrol ether/ethyl acetate=2:1) purifying obtains taking containing difference
The compound 19 of Dai Ji.
Referring to above-mentioned route, compound C1~C7 is synthesized.
The preparation of 2 compound C1 of embodiment
(1) synthesis of compound 13a
At room temperature, 3,4,5- trimethoxy phenol, that is, compound 11a (9.2g, 50mmol) and sodium acetate (8.2g,
Mixing in acetic anhydride (47mL, 500mmol) 100mmol) is sequentially added, is heated 2 hours at 110 DEG C.It after the reaction was completed, will be anti-
System is answered to be concentrated under reduced pressure, ethyl acetate extracts three times.Saturated common salt water washing, anhydrous sodium sulfate are dry.Concentration of organic layers obtains
3,4,5- trimethoxy phenethyl esters, i.e. compound 12a (11.2g, 49.5mmo).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) is added in glacial acetic acid (37.5mL), boron trifluoride ether solution (48%,
250mL) in addition system.Reaction system stirs 4 hours at 70 DEG C, thin-layer chromatographic analysis (petrol ether/ethyl acetate=2:1)
Monitor reaction effect.After the reaction was completed, reaction system is quenched with water, ethyl acetate extracts three times.It is saturated common salt water washing, anhydrous
Sodium sulphate is dry.Silica gel column chromatography (petrol ether/ethyl acetate=5:1) purifying, obtains 2,3,4- trimethoxy -6- hydroxy benzenes second
Ketone, that is, compound 13a (10.2g, 45.1mmol), yellow oily, yield 91%.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
16mL methylene chloride is added in 2,3,4- trimethoxy -6- hydroxy acetophenone, that is, compound 13a (904mg, 4.0mmol)
In solution, at 0 DEG C, triethylamine (1.47mL, 12mmol) and 3 are sequentially added, 4- dimethoxy-benzoyl chloride (1.04g,
5.2mmol).Reaction system is warmed to room temperature lower reaction 2 hours from 0 DEG C, system is quenched with water after the reaction was completed, ethyl acetate is three times
Extraction.Saturated common salt water washing, anhydrous sodium sulfate are dry.Silica gel column chromatography (petrol ether/ethyl acetate=5:1) purifying, obtains
Product 2- acetyl group -3,4,5- trimethoxy -3,4- Dimethoxy-benzoic acid methyl esters (1.3g, 3.4mmol), white solid produce
Rate: 85%.1H NMR(400MHz,CDCl3) δ 7.81 (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)。
2- acetyl group -3,4,5- trimethoxy -3,4- Dimethoxy-benzoic acid methyl esters (1.17g, 3.0mmol) is added
In 18mL dichloroethane solution, be added triethylamine (1.2mL, 9.0mmol) and trimethyl silicon substrate trifluoro-methanyl sulfonate (3.3mL,
18mmol), it is stirred 2 hours at 95 DEG C.Methanol quenching reaction mixture is used after the reaction was completed, and ethyl acetate extracts three times.It is full
It is dry with brine It, anhydrous sodium sulfate.Silica gel column chromatography (petrol ether/ethyl acetate=2:1) purifying, obtains product 2-
(3,4- Dimethoxyphenyl) -5,6,7- trimethoxy -4H- benzopyran-4-one (905mg, 2.4mmol), brown solid produce
Rate: 81%.1H NMR(500MHz,CDCl3) δ 7.51 (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)。
The preparation of 3 compound C2 of embodiment
(1) synthesis of compound 13b
Raw material is replaced with into 2,3,4- trimethoxy -6- hydroxy acetophenones and nitric acid reaction, according in embodiment 2
(2) method of step obtains product to get to 2,3,4- trimethoxy -5- nitro 6- hydroxy acetophenones, yellow solid, yield:
79%.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 2,3,4- trimethoxy -6- hydroxy acetophenone, 15mmol triethylamine, 6.0mmol 3,4- dimethoxy
Chlorobenzoyl chloride, methylene chloride (25mL) solution.Acetyl group -3,4 product 2- are obtained according to the method for (4) step in embodiment 1,
5- trimethoxy -6- nitrobenzophenone -3,4- Dimethoxy-benzoic acid methyl esters, beige solid, yield: 90%.1H NMR
(500MHz,CDCl3) δ 7.73 (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 2- acetyl group -3,4,5- trimethoxy -6- nitrobenzophenone -3,4- Dimethoxy-benzoic acid methyl esters,
13mmol triethylamine, 25.6mmol trimethyl silicon substrate trifluoro-methanyl sulfonate, 26mL dichloroethane solution.According in embodiment 1
The method of (5) step obtain product, -5,6,7- trimethoxy -8- nitro -4H- benzopyrene of 2- (3,4- Dimethoxyphenyl)
It mutters -4- ketone, brown solid, yield: 84%.1H NMR(400MHz,CDCl3) δ 7.42 (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)。
By raw material 2- (3,4- Dimethoxyphenyl) -5,6,7- trimethoxy -8- nitro -4H- benzopyran-4-one with
The reaction of palladium/carbon obtains product according to the method for (3) step in embodiment 2,8- amino -2- (3,4- Dimethoxyphenyl) -5,
6,7- trimethoxy -4H- benzopyran-4-ones, yellow solid, yield: 95%.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)。
The preparation of 4 compound C3 of embodiment
(1) synthesis of compound 13c
Glacial acetic acid is added in 2,3,4- trimethoxy -6- hydroxy acetophenone, that is, compound 13a (4.436g, 19.6mmol)
In (15mL), it is added in sodium acetate (1.77g, 21.6mmol).Then at 0 DEG C, the diluted Br of glacial acetic acid will be used2(1.5mL,
29.4mmol) it is added drop-wise in reaction system.It is transferred to and stirs 12 hours at room temperature, pour into ice water (150mL), filter, obtain
Product 2,3, the bromo- 6- hydroxy acetophenone, that is, compound 13c of 4- trimethoxy -5-, yellow solid, yield: 81%.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
Raw material is replaced with into the bromo- 6- hydroxy acetophenone of 2,3,4- trimethoxy -5-, and 3,4- dimethoxy-benzoyl chloride,
The bromo- 2- of product 8- (3,4- Dimethoxyphenyl) -5,6,7- is obtained according to (4) step, the method for (5) step in embodiment 1
Trimethoxy -4H- benzopyran-4-one.White solid, yield: 59%.1H NMR(400MHz,CDCl3) δ 7.64 (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)。
The preparation of 5 compound C4 of embodiment
(1) synthesis of compound 13d
Raw material is replaced with into 2,3,4- trimethoxy phenol, is obtained according to (1) step, the method for (2) step in embodiment 1
Product 2- hydroxyl -3,4,5- trimethoxy acetophenone.Yellow solid, yield: 89%.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
Raw material is replaced with into 2- hydroxyl -3,4,5- trimethoxy acetophenone, and 3,4- dimethoxy-benzoyl chloride, according to reality
It applies (4) step, the method for (5) step in example 1 and obtains product 2- (3,4- Dimethoxyphenyl) -7,8- dimethoxy-4 ' H- benzo
Pyrans -4- ketone, light yellow solid, yield: 82%.1H NMR(400MHz,CDCl3) δ 7.57 (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)。
The preparation of 6 compound C5 of embodiment
(1) synthesis of compound 13e
By raw material 2- hydroxyl -3,4,5- trimethoxy acetophenone (1.1g, 5.0mmol) is dissolved in 50mL acetonitrile solution, so
NIS (1.4g, 6.0mmol) and p-methyl benzenesulfonic acid (950mg, 5.0mmol) are added afterwards, reacts 2 hours at room temperature.Reaction is completed
Afterwards, concentration removes most of solvent, and ethyl acetate extracts three times.Saturated common salt water washing, anhydrous sodium sulfate are dry.Concentration is spin-dried for
After solvent, product 2- hydroxyl -3,4, the iodo- acetophenone of 5- trimethoxy 6-, yield: 73% are obtained.1H NMR(500MHz,CDCl3)
δ 14.00 (s, 1H), 4.02 (d, J=4.6Hz, 3H), 4.01 (s, 3H), 3.80 (s, 3H), 2.70 (s, 3H).
By 2- hydroxyl -3,4, the iodo- acetophenone of 5- trimethoxy -6- (3.6g, 10.2mmol) is dissolved in 30mL DMF, then
It is added stannous chloride (359mg, 3.6mmol), under protection of argon gas, the methanol solution (25mL) for the 4M sodium methoxide newly prepared is added
Enter in system, react after twenty minutes, poured into ice water at 90 DEG C, is acidified with 5.0M HCl.Then ethyl acetate extraction three times, is satisfied
And brine It, anhydrous sodium sulfate are dry.Silica gel column chromatography (petrol ether/ethyl acetate=10:1) purifying obtains product 2- hydroxyl
Base -3,4,5,6- tetramethoxy acetophenones, that is, compound 13e (1.5g), pale yellow-green liquid, yield: 59%.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
Raw material is replaced with into 2- hydroxyl -3,4,5,6- tetramethoxy acetophenones, and piperonyl cyclonene chlorobenzoyl chloride, according to embodiment
(4) step, the method for (5) step obtain product 2- (piperonyl cyclonene) -5 in 1,6,7,8- tetramethoxy -4H- benzopyran-4-ones,
White solid, yield: 79%.1H NMR(400MHz,MeOD–d4) δ 7.62 (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)。
The preparation of 7 compound C6 of embodiment
The synthesis of compound C6:
Raw material is replaced with into 2- hydroxyl -3,4,5,6- tetramethoxy acetophenones, and 3,4,5- trimethoxy-benzoyl chlorides are pressed
Product 2- (3,4,5- trimethoxy) -5,6,7,8- tetramethoxy-is obtained according to (4) step, the method for (5) step in embodiment 1
4H- benzopyran-4-one, white solid, yield: 80%.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)。
The preparation of 8 compound C7 of embodiment
The synthesis of compound C7:
Raw material is replaced with into 2- hydroxyl -3,4,5,6- tetramethoxy acetophenones, and 3,4,-dimethoxy-benzoyl chloride is pressed
Product 2- (3,4- dimethoxy) -5,6,7,8- tetramethoxy -4H- is obtained according to (4) step, the method for (5) step in embodiment 1
Benzopyran-4-one, white solid, yield: 78%.1H NMR(500MHz,CDCl3) δ 7.57 (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)。
The synthesis of 9 compound C8 of embodiment
(1) synthesis of compound 13f
Raw material is replaced with into 2,3- syringol, is produced according to (1) step, the method for (2) step in embodiment 1
Object 2- hydroxyl -3,4- dimethoxy-acetophenone.Brown solid, yield: 95%.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
Raw material is replaced with into 2- hydroxyl -3,4 dimethoxy-acetophenone, and 3,4- dimethoxy-benzoyl chloride, according to implementation
(4) step, the method for (5) step obtain-7,8-dimethoxy-4 ' H- chromene of product 2- (3,4- dimethoxy)-in example 1
4- ketone, shallow white solid, yield: 82%.1H NMR(400MHz,CDCl3) δ 7.57 (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)。
The synthesis of 10 compound C9 of embodiment
(1) synthesis of compound C9
By raw material 2- hydroxyl -3,4 dimethoxy-acetophenone, and 3- methoxy benzoyl chloride, in embodiment 1 (4)
Step, the method for (5) step obtain-7,8-dimethoxy-4 ' H- benzopyran-4-one of product 2- (3- methoxyl group), green solid,
Yield: 82%.1H NMR(400MHz,CDCl3) δ 7.58 (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)。
The synthesis of 11 compound C10 of embodiment
(1) synthesis of compound C10
By raw material 2- hydroxyl -3,4 dimethoxy-acetophenone, and 4- methoxy benzoyl chloride, in embodiment 1 (4)
Step, the method for (5) step obtain-7,8-dimethoxy-4 ' H- benzopyran-4-one of product 2- (4- methoxyl group), brick-red solid
Body, yield: 82%.1H NMR(500MHz,CDCl3) δ 7.86 (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)。
The synthesis of 12 compound C11 of embodiment
(1) synthesis of compound C11
By raw material 2- hydroxyl -3,4,5,6- tetramethoxy acetophenones, and 2- methoxyl group-Isonicotinic acid, according to embodiment 1
In (4) step, the method for (5) step obtain product 5,6,7,8- tetramethoxy -2- (2- methoxypyridine -4- ethyl) -4H- benzene
And pyrans -4- ketone, brick-red solid, yield: 60%.1H NMR(400MHz,CDCl3) δ 8.32 (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)。
The synthesis of 13 compound C12 of embodiment
(1) synthesis of compound C12
By raw material 2- hydroxyl -3,4,5,6- tetramethoxy acetophenones, and 6- methoxyl group niacin, in embodiment 1 (4)
Step, the method for (5) step obtain product 5,6,7,8- tetramethoxy -2- (6- methoxypyridine -3- ethyl) -4H- chromene -
4- ketone, pink solid, yield: 61%.1H NMR(500MHz,CDCl3) δ 8.80 (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)。
The synthesis of 14 compound C13 of embodiment
(1) synthesis of compound C13
By raw material 2- hydroxyl -3,4,5,6- tetramethoxy acetophenones, and 5- methoxyl group niacin, in embodiment 1 (4)
Step, the method for (5) step obtain product 5,6,7,8- tetramethoxy -2- (5- methoxypyridine -3- ethyl) -4H- chromene -
4- ketone, yellow solid, yield: 55%.1H NMR(400MHz,CDCl3) δ 8.80 (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)。
The synthesis of 15 compound C14 of embodiment
(1) synthesis of compound C14
By raw material 2- hydroxyl -3,4,5,6- tetramethoxy acetophenones, and 5,6- dimethoxy niacin, according in embodiment 1
(4) step, the method for (5) step obtain product 5,6,7,8- tetramethoxy -2- (5,6- dimethoxy-pyridine -3- ethyl) -4H-
Benzopyran-4-one, yellow solid, yield: 55%.1H NMR(400MHz,CDCl3) δ 8.40 (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).
Embodiment 16
In compound shown in formula (I), when X is N, specific synthetic route is as follows:
The specific preparation step of the above process is as follows:
(1) synthesis of compound 20
2- hydroxyl -3,4,5- trimethoxy acetophenone (2.3g, 10mmol) is added in 40mL DMF.Potassium carbonate is added
(2.1g, 15mmol) and iodomethane (679 μ L, 1.1mmol).Reaction mixture is stirred at room temperature 2 hours, after the reaction was completed plus
Water dilution, ethyl acetate extraction.Organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, after concentration is spin-dried for solvent, obtains
At 2,3,4,5- tetramethoxy acetophenones (i.e. compound 20), brown yellow oil (2.3g, 9.6mmol).Yield: 96%.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
(2.3g, 9.6mmol) is added dropwise in compound 20 in 70% nitric acid (798 μ L, 18mmol), it is anti-at 0 DEG C
It answers 15 minutes.Reaction system, ethyl acetate extraction is quenched with water.Organic phase saturated common salt water washing, anhydrous sodium sulfate is dry,
After concentration is spin-dried for most of solvent, silica gel column chromatography (petrol ether/ethyl acetate=5:1) purifying obtains 2,3,4,5- tetra- methoxies
Base -6- nitro-acetophenone, that is, compound 21 (1.9g, 6.7mmol), faint yellow solid, yield: 70%.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
It is molten that compound 21 (1.9g, 6.7mmol) is added in 134mL tetrahydrofuran solution, addition palladium/carbon (285mg,
15%) it, in atmosphere of hydrogen, 40 DEG C, reacts 15 hours.Reaction is completed, and after being cooled to room temperature, is filtered with diatomite, acetic acid second
Ester washing.Organic phase concentration is spin-dried for most of solvent, silica gel column chromatography (petrol ether/ethyl acetate=2:1) purifying is produced
2,3,4,5- tetramethoxy -6- amino-acetophenone of object, that is, compound 22 (1.6g, 6.3mmol), brown yellow oil, yield:
95%.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) is added in 11mL dichloromethane solution, at 0 DEG C, triethylamine (915 μ are added
L, 6.6mmol) after, it is added 3,4- dimethoxy-benzoyl chloride (0.88g, 4.4mmol).System is stirred at 0 DEG C to room temperature, and 3
After hour, reaction system, ethyl acetate extraction is quenched with water.Organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, silicon
Plastic column chromatography (petrol ether/ethyl acetate=5:1) purifying, obtains compound 23 (738mg, 1.8mmol), white solid.Yield:
80%.1H NMR(400MHz,CDCl3) δ 8.24 (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) is added in 60mL anhydrous tetrahydrofuran solution, potassium tert-butoxide is added
(0.61g, 5.4mmol) reacts 18 hours at 75 DEG C under argon gas protection.After the reaction was completed, it is cooled to after room temperature plus water terminates
Reaction, the acidification of 2.0M aqueous hydrochloric acid solution.Ethyl acetate extraction.Organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, warp
Silica gel column chromatography (petrol ether/ethyl acetate=3:1) purifying obtain product 24 (592mg, 1.5mmol) be white solid, yield:
82%.1H NMR(400MHz,CDCl3) δ 7.35 (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) is added in anhydrous n,N-Dimethylformamide (2.0mL), sodium hydride (60% is added
It is scattered in mineral oil, 80mg, 2.0mmol).After 90 DEG C are reacted 30 minutes, the chloralkane containing different substituents is added
(0.6mmol).Reaction mixture stirs 2 hours at 90 DEG C, after solution is cooled to room temperature, is poured into water, and 2.0M salt is added
Aqueous acid acidification.Organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, through silica gel column chromatography (petroleum ether/acetic acid second
Ester=3:1) purifying obtain the product 25 containing different substituents.
The synthesis of 17 compound C15 of embodiment
(1) synthesis of compound C15
By raw material 2- (3,4- dimethoxy) -5,6,7,8- tetramethoxy -4H- benzopyran-4-one and 2- chloroethyl first
Base ether obtains product 2- (3,4- Dimethoxyphenyl) -5,6,7,8- tetramethoxy-according to the method for (6) step in embodiment 2
1- (2- methoxy ethyl)-quinoline -4 (1H) -one.Faint yellow oily, yield: 70%.1H NMR(400MHz,MeOD–d4)δ
7.90 (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)。
The synthesis of 18 compound C16 of embodiment
(1) synthesis of compound C16
By -5,6,7,8- tetramethoxy -4H- benzopyran-4-one of raw material 2- (3,4- dimethoxy) (80mg,
0.2mmol) be dissolved in 3mL DMF solution, be then added potassium carbonate (41mg, 0.3mmol) and iodomethane (14 μ L,
0.22mmol).After room temperature reaction 1 hour, ethyl acetate extraction, saturated salt solution extraction, anhydrous sodium sulfate is dry, concentration rotation
Through silica gel column chromatography after dry solvent, -5,6,7,8- tetramethoxy -1- methyl -4H- benzo of product 2- (3,4- dimethoxy) is obtained
Pyrans -4- ketone.Faint yellow oily, yield: 70%.1H NMR(400MHz,CDCl3) δ 7.94 (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)。
The synthesis of 19 compound C17 of embodiment
(1) synthesis of compound C17
Raw material 2- (3,4- dimethoxy) -5,6,7,8- tetramethoxy -4H- benzopyran-4-one is pressed with n-propyl chloride
Product 2- (3,4- dimethoxy) -5,6,7,8- tetramethoxy -1- propyl -4H- is obtained according to the method for (6) step in embodiment 2
Benzopyran-4-one.Faint yellow oily, yield: 62%.1H NMR(400MHz,MeOD–d4) δ 7.89 (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)
The synthesis of 20 compound C18 of embodiment
(1) synthesis of compound C18
Compound 27 (738mg, 1.8mmol) is added in 60mL anhydrous tetrahydrofuran solution, potassium tert-butoxide is added
(0.61g, 5.4mmol), argon gas protection, reacts 18 hours at 75 DEG C.After the reaction was completed, it is cooled to after room temperature plus water terminates instead
It answers, the acidification of 2.0M aqueous hydrochloric acid solution.Ethyl acetate extraction.Organic phase saturated common salt water washing, anhydrous sodium sulfate is dry, through silicon
Plastic column chromatography (petrol ether/ethyl acetate=3:1) purifying obtains product 2- (3,4- dimethoxy) -5,6,7,8- tetramethoxy -
4H- benzopyran-4-one (592mg, 1.5mmol) is white solid.Yield: 82%.1H NMR(400MHz,CDCl3)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)。
The synthesis of 21 compound C19 of embodiment
(1) synthesis of compound C19
By raw material 2- (3,4- dimethoxy) -5,6,7,8- tetramethoxy -4H- benzopyran-4-one and dimethylamino chlorine
Ethane hydrochloride obtains four methoxy of product 2- (3,4- dimethoxy) -5,6,7,8- according to the method for (6) step in embodiment 2
Base -1- (2- (dimethylamino)-ethyl) 4H- benzopyran-4-one.Faint yellow oily, yield: 71%.1H NMR(500MHz,
MeOD–d4) δ 7.94 (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).
22 compound C1~C19 of embodiment taxol IC in reversing the experiment of HCT8/T mdr cell50Test
Compound prepared by testing example 1 to 21 is to the IC for reversing taxol in the experiment of HCT8/T mdr cell50, test
Data are as shown in table 1.Nobiletin and its derivative are by reducing IC of the taxol in drug resistance HCT8/T cell50, enhance
The antitumor action of taxol, and cytotoxicity is significantly lower than taxol；Wherein with taxol associated with C7, C12, C6, C1
IC50Value reduces 185 times, 87 times, 81 times, 66 times compared with taxol is used alone respectively.
The IC of 1 Nobiletin analog derivative of table taxol in reversing the experiment of HCT8/T mdr cell50Test result
aThe cytotoxicity of compound；bIC when P-gp inhibitor and taxol are combined50；cReversal index=IC50(Japanese yew
Alcohol)/IC50(P-gp inhibitor and taxol are combined).
As can be known from Table 1, reversal index higher 4 are compound C1, C6, C7 and C19, the wherein cytotoxicity of C6
It is larger, therefore subsequently selected compound C1, C7, C19 are object, carry out testing its solubility and zoopery.
1, solubility test: room temperature tests C1, C7 using high performance liquid chromatography in sodium dihydrogen phosphate buffer,
The solubility of these three compounds of C19 measures result and is respectively as follows: 3.67 ± 0.52 μ g/mL, 5.58 ± 1.17 μ g/mL and 1.58
±0.13mg/mL；Wherein the water solubility of compound C19 is 283 times of C7.
2, zoopery: all zooperies (are compiled through Traditional Chinese Medicine University Of Guangzhou's animal care and using committee's approval
Number: ZYYL20150807).
Mice with tumor is randomly divided into 9 groups (n=6): control group (CTR), 15mg/kg PTX administration group, the river 50mg/kg dried orange peel
Plain (C7) administration group, 50mg/kg C1 administration group, 50mg/kg C19 administration group, 50mg/kg Nobiletin (C7)+15mg/kg
PTX administration group, 25mg/kg C1+15mg/kg PTX administration group, 50mg/kg C1+15mg/kg PTX administration group, 25mg/kg
C19+15mg/kg PTX administration group and 50mg/kg C19+15mg/kg PTX administration group.With 1640 culture medium of RPMI of 50 μ L
5 × 10 are resuspended with 50 μ L matrigels6A549/T cell, being subcutaneously injected into the right fore armpit kind tumors of 8 weeks nude mices, (A549/T xenogenesis is swollen
Tumor).After 5 days, the every 3 days intraperitoneal injections of tumor formation mouse are primary, record gross tumor volume, calculation formula every three days are as follows: volume=(wide
Square * length of degree)/2, when record was to the 30th day, all nude mices are put to death, then tumor resection is weighed with electronic balance, record
The weight of each group tumour.
On the basis of studying the past, drug resistant tumour is generated, only through the purple of effective dose (15mg/kg) is injected intraperitoneally
China fir alcohol (PTX) does not have apparent therapeutic effect (Cancer Chemother to drug-resistant tumor compared with the blank group not being administered
Pharmacol 2007,60,907-914).Therefore, the present invention tests compound C1, and C7, C19 combine with PTX respectively, testization
Object C1 is closed, C7, C19 are for tumour to the reversing effect of PTX drug resistance, and test results are shown in figure 1.
As can be known from Fig. 1, after compound C19 and PTX being administered in combination, dosage is respectively 25mg/kg and 50mg/kg, with
Single to compare to PTX group, gross tumor volume is obviously reduced；In addition, all nude mices illustrate drug combination without obvious weight loss
Additional toxicity will not be brought；In A549/T xenograft tumor transplantation model, PTX joint C19 (50mg/kg) can make gross tumor volume
57% is substantially reduced, it is more more effective (P < 0.05) than the same dose of Nobiletins (C7)；Equally, C1 also enhances PTX in A549/
Therapeutic effect in T xenograft tumor transplantation model, inhibitory effect are similar to Nobiletin effect.
It can be seen that by the above results, for Nobiletin derivative of the present invention is compared to Nobiletin, solubility
It is significantly improved, wherein the water solubility of C19 is 283 times of C7；Meanwhile Nobiletin derivative and taxol (PTX) join
After closing administration, the intracorporal paclitaxel concentration of tumour cell is significantly improved, the drug resistance of tumour cell, improves Japanese yew in reverse
Alcohol inhibits the effect of tumour growth, can be prepared as resistant tumors multidrug-resistance reversal agent application, with other anti-tumor drugs
Mixture application, improves the control efficiency of tumour.
Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than protects to the present invention
The limitation of shield range can also be made on the basis of above description and thinking for those of ordinary skill in the art
Other various forms of variations or variation, there is no necessity and possibility to exhaust all the enbodiments.It is all of the invention
Made any modifications, equivalent replacements, and improvements etc., should be included in the protection of the claims in the present invention within spirit and principle
Within the scope of.
Claims (10)
1. a kind of Nobiletin derivative or its pharmaceutically acceptable salt, which is characterized in that the Nobiletin derivative
Shown in structure such as formula (I):
Wherein, R1、R2、R3And R4It is respectively selected from hydrogen, halogen, hydroxyl, amino, C1-6Substituted or non-substituted alkoxy, C1-6Replace or
Non-substituted ester group, C1-6Substituted or non-substituted alkylamino radical, C1-6Substituted or non-substituted amide groups；
R5Selected from C3-9Substituted or non-substituted aromatic rings, C3-9Substituted or non-substituted aromatic heterocycle；The aromatic heterocycle is to contain N, O
Or the aromatic rings of S atom；
X is selected from O or NR6；The R6Selected from hydrogen, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Substituted or non-substituted alkoxy or C1-6It takes
Generation or non-substituted alkylamino radical；
The C1-6Substituted or non-substituted alkoxy, C1-6Substituted or non-substituted ester group, C1-6Substituted or non-substituted alkylamino radical, C1-6It takes
Generation or non-substituted amide groups, C3-9Substituted or non-substituted aromatic rings and C3-9Halogen is substituted by substituted or non-substituted aromatic heterocycle
Element, hydroxyl, amino, C1-4Alkyl or C1-4Alkoxy is replaced.
2. Nobiletin derivative or its pharmaceutically acceptable salt according to claim 1, which is characterized in that the R1、
R2、R3And R4It is respectively selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, methylamino, two
Methylamino, ethylamino-, Propylamino, isopropylamino；
The R5Selected from substituted or non-substituted phenyl, substituted or non-substituted phenylpyridine or substituted or non-substituted phenyl benzo [d]
[1,3] dioxin；It is therein to be substituted by C1-4Alkyl or C1-4Alkoxy is replaced；
The R6For hydrogen or C1-6Substituted or non-substituted alkyl, wherein C1-6Substitution in substituted or non-substituted alkyl refers to halogen, hydroxyl
Base or amino are replaced.
3. Nobiletin derivative or its pharmaceutically acceptable salt according to claim 2, which is characterized in that the R5Choosing
From
The R6For methyl, propyl, isopropyl, 2- methox-etlayl or N, N- dimethyl ethyl.
4. Nobiletin derivative or its pharmaceutically acceptable salt according to claim 3, which is characterized in that its described medicine
Acceptable salt is the product that Nobiletin derivative shown in formula (I) is reacted with acid on.
5. Nobiletin derivative or its pharmaceutically acceptable salt according to claim 4, which is characterized in that 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, naphthalene sulphur
Acid, maleic acid, fumaric acid, citric acid, acetic acid, tartaric acid, succinic acid, malic acid or glutamic acid.
6. the preparation method of any Nobiletin of Claims 1 to 5 and its derivative, which is characterized in that including walking as follows
It is rapid:
S1. in -30~25 DEG C of solvents dissolved with alkaline matter, formula 1 is mixed with compound shown in formula 2, and is gradually warming up to 25
~100 DEG C of reactions, can be obtained compound shown in formula 3；
S2. compound shown in formula 3 is in the solvent dissolved with alkaline matter or alkaline matter and triethyl group silicon substrate triflate,
It is warming up to 40~100 DEG C of reactions after first room temperature, target product can be obtained；
Wherein, R1、R2、R3And R4It is respectively selected from hydrogen, halogen, hydroxyl, amino, C1-6Substituted or non-substituted alkoxy, C1-6Replace or
Non-substituted ester group, C1-6Substituted or non-substituted alkylamino radical, C1-6Substituted or non-substituted amide groups；
R5Selected from C3-9Substituted or non-substituted aromatic rings, C3-9Substituted or non-substituted aromatic heterocycle；The aromatic heterocycle is to contain N, O
Or the aromatic rings of S atom；
X is selected from O or NR6；The R6Selected from hydrogen, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Substituted or non-substituted alkoxy or C1-6It takes
Generation or non-substituted alkylamino radical；
The C1-6Substituted or non-substituted alkoxy, C1-6Substituted or non-substituted ester group, C1-6Substituted or non-substituted alkylamino radical, C1-6It takes
Generation or non-substituted amide groups, C3-9Substituted or non-substituted aromatic rings and C3-9Halogen is substituted by substituted or non-substituted aromatic heterocycle
Element, hydroxyl, amino, C1-4Alkyl or C1-4Alkoxy is replaced.
7. prepared by any Nobiletin derivative of Claims 1 to 5 or its pharmaceutically acceptable salt or Nobiletin
Application in P-gp inhibitor medicaments.
8. applying according to claim 7, which is characterized in that the Nobiletin derivative or its pharmaceutically acceptable salt
Or Nobiletin is in the application being prepared into treatment P-gp related disease drug.
9. prepared by any Nobiletin derivative of Claims 1 to 5 or its pharmaceutically acceptable salt or Nobiletin
Application in tumor multi-drug resistance reversal agents.
10. according to any application of claim 7~9, which is characterized in that the Nobiletin derivative or its pharmaceutically may be used
The salt or Nobiletin of receiving and the application of anti-tumor drug mixture.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110845466A (en) * | 2019-11-27 | 2020-02-28 | 中国科学院成都有机化学有限公司 | Oxacyclononadiene derivative, pharmaceutical composition thereof, preparation method and application thereof |
| CN114605273A (en) * | 2022-03-29 | 2022-06-10 | 南昌航空大学 | Method for synthesizing arylamino phenol compound by palladium-catalyzed CO-participated 1, 4-eneyne aromatization reaction |
| US11820747B2 (en) | 2021-11-02 | 2023-11-21 | Flare Therapeutics Inc. | PPARG inverse agonists and uses thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001302511A (en) * | 2000-02-15 | 2001-10-31 | Kyowa Hakko Kogyo Co Ltd | Medicine exhaustion suppressant |
| US20130096083A1 (en) * | 2010-03-01 | 2013-04-18 | Universite Joseph Fourier | Use of isoquinolones for preparing drugs, novel isoquinolones and method for synthesising same |
| CN104736144A (en) * | 2012-07-27 | 2015-06-24 | A·M·G·邦特 | Efflux inhibitor compositions and methods of treatment using the same |
| US20170027901A1 (en) * | 2015-07-29 | 2017-02-02 | Macau University Of Science And Technology | Use of nobiletin in cancer treatment |
| CN111825611A (en) * | 2019-04-19 | 2020-10-27 | 中央研究院 | 4(1H) -quinovone derivatives and uses thereof |
-
2019
- 2019-07-19 CN CN201910657044.4A patent/CN110498784B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001302511A (en) * | 2000-02-15 | 2001-10-31 | Kyowa Hakko Kogyo Co Ltd | Medicine exhaustion suppressant |
| US20130096083A1 (en) * | 2010-03-01 | 2013-04-18 | Universite Joseph Fourier | Use of isoquinolones for preparing drugs, novel isoquinolones and method for synthesising same |
| CN104736144A (en) * | 2012-07-27 | 2015-06-24 | A·M·G·邦特 | Efflux inhibitor compositions and methods of treatment using the same |
| US20170027901A1 (en) * | 2015-07-29 | 2017-02-02 | Macau University Of Science And Technology | Use of nobiletin in cancer treatment |
| CN111825611A (en) * | 2019-04-19 | 2020-10-27 | 中央研究院 | 4(1H) -quinovone derivatives and uses thereof |
Non-Patent Citations (9)
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110845466A (en) * | 2019-11-27 | 2020-02-28 | 中国科学院成都有机化学有限公司 | Oxacyclononadiene derivative, pharmaceutical composition thereof, preparation method and application thereof |
| 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 |
| US11820747B2 (en) | 2021-11-02 | 2023-11-21 | Flare Therapeutics Inc. | PPARG inverse agonists and uses thereof |
| CN114605273A (en) * | 2022-03-29 | 2022-06-10 | 南昌航空大学 | Method for synthesizing arylamino phenol compound by palladium-catalyzed CO-participated 1, 4-eneyne aromatization reaction |
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