CN101914084B - Biphenylpyrone nitrogen heterocyclic derivatives and its preparation method and application - Google Patents

Abstract

The invention discloses a derivative of a diphenylpyrone nitrogen heterocyclic ring with a general formula shown in the specification as well as a preparation method and application thereof. In the formula, R is heterocyclic radical and substituted phenyl piperazinyl, the number of R1 and R2 is 1-5, and R1 and R2 are one or combination of halogen, C1-6 alkyl, cyano group, nitryl, trifluoromethyl, methoxyl and ethoxyl. The derivative of the diphenylpyrone nitrogen heterocyclic ring has stronger inhibition activity to cervical-cancer cells and hepatic cancer cells and can be used for preparing medicaments for treating cervical cancer or hepatic cancer.

Description

Biphenylpyrone nitrogen heterocyclic derivatives and its preparation method and application

technical field

The invention relates to the field of medicine, in particular to an anti-tumor active compound bisphenylpyrone nitrogen heterocyclic derivative and its preparation method and application.

Background technique

Tumor is one of the diseases that seriously endanger human health. According to data from the Chinese Medical Association in 2007, malignant tumors have become the number one killer among various diseases that endanger the lives of Chinese residents. Every year, 2 million people in China die of tumors. Chemotherapy is one of the three major methods of cancer treatment. After years of hard work, some cancers can now be cured by drug chemotherapy.

The skeleton of diphenylpyrone is a simple tricyclic structure, and the tricyclic rings are in the same plane, forming π-π conjugation, which is similar to the chemical structure of anthrone antitumor drugs, and has significant antitumor activity. However, the derivatives obtained by introducing different nitrogen heterocycles at the 7-position using diphenylpyrone as the basic core have not been reported so far.

Contents of the invention

The first object of the present invention is to provide a bisphenylpyrone nitrogen heterocyclic derivative

The second object of the present invention is to provide a preparation method of the derivative.

The third object of the present invention is to provide the application of the derivative.

The bisphenylpyrone nitrogen heterocyclic derivatives provided by the present invention have a general structural formula of

where R is:

(1) heterocyclic group, said heterocyclic group is piperidinyl, piperazinyl, methylpiperazinyl, morpholinyl, imidazolyl or triazolyl;

(II) Substituted phenylpiperazinyl, the substituted phenyl is a single-substituted phenyl or multi-substituted phenyl, and at each position of the benzene ring, the substituents are halogen, C ₁ ~C ₄ alkyl, cyano, nitro group, trifluoromethyl, methoxy, ethoxy, or amino;

(III) has the general formula

In the formula, R ₁ is located at each position of the benzene ring, and can be mono-substituted or multi-substituted, the number is 1-5, and it is halogen, C ₁ -C ₆ alkyl, cyano, nitro, One or a combination of trifluoromethyl, methoxy, and ethoxy;

or (IV) has the general formula

The substituents, wherein, R ₂ is located at each position of the benzene ring, can be mono-substituted or multi-substituted, the number is 1-5, and it is halogen, C ₁ -C ₆ alkyl, cyano, nitro, One or a combination of trifluoromethyl, methoxy, and ethoxy.

The preparation method of the bisphenylpyrone nitrogen heterocyclic derivative provided by the present invention, the general formula

R is a heterocyclic group or a substituted phenylpiperazinyl group, and the heterocyclic group is piperidinyl, piperazinyl, methylpiperazinyl, morpholinyl, imidazolyl, or triazolyl, and the substituted Phenyl is monosubstituted phenyl or polysubstituted phenyl, and the substituents are halogen, C ₁ ~C ₄ alkyl, cyano, nitro, trifluoromethyl, methoxy, ethoxy at each position of the benzene ring When base or amino group; reaction scheme is:

Include the following steps:

(A): With 5-bromosalicylic acid and 1,3,5-trimethoxybenzene as raw materials, react in Eaton's reagent to obtain 1,3-dimethoxy-7-bromo-bisphenylpyrone;

(B) 1,3-dimethoxy-7-bromo-bisphenylpyrone and substituted amine in 1,4-dioxane under the action of Pd ₂ (dba) ₃ , Xphos, Cs ₂ CO ₃ In a solvent, react under the protection of argon to obtain the derivative, and the substituted amine is selected from piperidine, piperazine, methylpiperazine, morpholine, imidazole, triazole, or substituted phenylpiperazine.

In the general formula, R is

In the formula, R ₂ is located at each position of the benzene ring, and can be monosubstituted or polysubstituted, the number is 1 to 5, and it is halogen, C ₁ ~C ₆ alkyl, cyano, nitro, trifluoromethyl , methoxyl group, ethoxyl group or their combination, the reaction scheme is:

Preparation methods include:

(A) Using 5-nitrosalicylic acid and 1,3,5-trimethoxybenzene as raw materials, react in Eaton's reagent to obtain 1,3-dimethoxy-7-nitro-bisphenylpyrone ;

(B) 1,3-dimethoxy-7-nitro-bisphenylpyrone and hydrazine hydrate react under the action of Raney nickel in an alcohol solvent to obtain 1,3-dimethoxy-7- Amino-diphenylpyrone;

(C) 1,3-dimethoxy-7-amino-diphenylpyrone and propyne bromide are refluxed in alkali and acetone solvent to obtain 1,3-dimethoxy-7-(2-alkynyl Alanine)-diphenylpyrone;

(D) Reaction of sodium azide and benzyl bromide derivatives in DMSO for 12h, adding 1,3-dimethoxy-7-(2-alkynylpropylamine)-diphenylpyrone, in copper sulfate pentahydrate , under the effect of ascorbic acid, reaction obtains described derivative, and the general formula of described benzyl bromide derivative is:

Wherein R ₂ is located at each position of the benzene ring, and can be monosubstituted or polysubstituted, the number is 1 to 5, and it is halogen, C ₁ ~C ₆ alkyl, cyano, nitro, trifluoromethyl, One of methoxy, ethoxy, or a combination thereof.

In the general formula, R is

In the formula, R ₁ is located at each position of the benzene ring, and can be monosubstituted or polysubstituted, the number is 1 to 5, and it is halogen, C ₁ ~C ₆ alkyl, cyano, nitro, trifluoromethyl , one of methoxy, ethoxy or their combination, the reaction scheme is:

Preparation methods include:

(A) take 5-hydroxysalicylic acid and 1,3,5-trimethoxybenzene as raw materials, react in Eaton's reagent to obtain 1,3-dimethoxy-7-hydroxyl-bisphenylpyrone;

(B) 1,3-dimethoxy-7-hydroxyl-bisphenylpyrone and propyne bromide are refluxed in alkali and acetone solvent to obtain 1,3-dimethoxy-7-(2-propargyl Oxygen)-diphenylpyrone;

(C) Reaction of sodium azide and benzyl bromide derivatives in DMSO for 12h, adding 1,3-dimethoxy-7-(2-propargyloxy)-bisphenylpyrone, in copper sulfate pentahydrate , under the effect of ascorbic acid, reaction obtains described derivative, and the general formula of described benzyl bromide derivative is:

Among them, R ₁ is located at each position of the benzene ring, and can be monosubstituted or polysubstituted, the number is 1 to 5, and it is halogen, C ₁ ~C ₆ alkyl, cyano, nitro, trifluoromethyl , methoxy, ethoxy or a combination thereof.

The bisphenylpyrone nitrogen heterocycle derivative provided by the invention is used for preparing medicine for treating cervical cancer or liver cancer.

Detailed ways

The present invention will be further described below in conjunction with specific embodiments. It should be understood that the following examples are only used to illustrate the present invention but not to limit the scope of the present invention.

Embodiment 1 raw material is synthesized

1.1 Synthesis of 1,3-dimethoxy-7-bromo-bisphenylpyrone

10.9g (0.5mol) of 5-bromosalicylic acid and 8.5g (0.53mol) of 1,3,5-trimethoxybenzene were dissolved in 100ml of Eaton's reagent, stirred at 110°C for 4 hours, the reaction was complete, cooled to room temperature, Add an appropriate amount of ice water, stir for 2.0 hours, filter, wash with water until neutral, and recrystallize from methanol to obtain 10 g of the product with a yield of 70.5%. ¹ HNMR (300MHz, DMSO-d ₆ , TMS) data: δ8.38 (1H, s, Ar), 7.70 (1H, d, Ar), 7.25 (1H, d, Ar), 6.49 (1H, s, Ar), 6.35 (1H, s, Ar), 4.12 (s, 3H, _OCH3 ), 3.96 (3H, s, _OCH3 ).

1.2 Synthesis of 1,3-dimethoxy-7-nitro-bisphenylpyrone

Dissolve 9.1 g (0.05 mol) of 5-nitrosalicylic acid and 8.5 g (0.055 mol) of 1,3,5-trimethoxybenzene in 100 ml of Eaton's reagent, stir and react at 110°C for 4 hours, the reaction is complete, and cool to At room temperature, an appropriate amount of ice water was added, stirred for 2 hours, filtered, washed with water until neutral, and recrystallized from methanol to obtain 12 g of the product with a yield of 79.2%. ¹ HNMR (300MHz, DMSO-d ₆ , TMS): δ9.14 (1H, s, Ar), 8.47 (1H, d, Ar), 7.50 (1H, d, Ar), 6.55 (1H, s, Ar) , 6.42 (1H, s, Ar), 4.01 (3H, s, OCH ₃ ), 3.95 (3H, s, OCH ₃ ).M+H+, 302.90

1.3 Synthesis of 1,3-dimethoxy-7-amino-diphenylpyrone

Add 20 ml of methanol to 3.01 g (0.01 mol) of 1,3-dimethoxy-7-nitro-bisphenylpyrone prepared according to the method in Example 1.2, then add 0.5 g of Raney nickel, and slowly add hydrazine hydrate dropwise 2 mL, stirred at room temperature for 4 hours, filtered, concentrated, and recrystallized from methanol. 1.9 g of the product was obtained, yield: 69.2%. ¹ HNMR (300MHz, DMSO-d ₆ , TMS): δ7.52 (1H, s, Ar), 7.22 (1H, d, Ar), 7.00 (1H, d, Ar), 6.47 (1H, s, Ar) , 6.32 (1H, s, Ar), 3.98 (3H, s, OCH ₃ ), 3.91 (3H, s, OCH ₃ ), 3.77 (2H, br, NH). 2M+Na+, 565.19

1.4 Synthesis of 1,3-dimethoxy-7-(2-alkynylpropylamine)-bisphenylpyrone

1,3-dimethoxy-7-amino-diphenylpyrone 1g (3.7mmol) prepared according to the method of Example 1.3 was dissolved in acetone, and then 1.5g (10.9mmol) of potassium carbonate and 0.42 propyne bromide were added. g (3.6 mmol), refluxed for 6 hours, poured into water, a large amount of precipitate formed, filtered, ether and methanol washed the filter cake to obtain 900 mg of product, yield: 53.6%. ¹ HNMR (300MHz, DMSO-d ₆ , TMS): δ7.22 (1H, s, Ar), 7.12 (1H, d, Ar), 7.05 (1H, d, Ar), 6.61 (1H, s, Ar) , 6.42 (1H, s, Ar), 6.28 (1H, t, NH), 4.21 (2H, s, CH ₂ ), 3.98 (3H, s, OCH ₃ ), 3.91 (3H, s, OCH ₃ ), 3.19 (1H, s, CH).

1.5 Synthesis of 1,3-dimethoxy-7-hydroxyl-bisphenylpyrone

Dissolve 7.7g (0.5mol) of 5-hydroxysalicylic acid and 8.5g (0.53mol) of 1,3,5-trimethoxybenzene in 100ml of Eatons reagent, stir at 110°C for 4 hours, the reaction is complete, and cool to room temperature , add an appropriate amount of ice water, stir for 2 hours, filter, wash with water until neutral, and recrystallize from methanol to obtain 10 g of product with a yield of 75%. ¹ HNMR (300MHz, DMSO-d ₆ , TMS): δ9.81 (1H, s, OH), 7.93-7.35 (3H, m, Ar), 6.70 (1H, s, Ar), 6.50 (1H, s, Ar), 3.89 (3H, s, OCH ₃ ), 3.85 (3H, s, OCH ₃ ). M-H+: 271.64

1.6 Synthesis of 1,3-dimethoxy-7-(2-propargyloxy)-bisphenylpyrone

Dissolve 1 g of 1,3-dimethoxy-7-hydroxy-bisphenylpyrone prepared according to the method in Example 1.5 in 15 ml of acetone, then add 1.5 g of potassium hydroxide and 0.42 g of propyne bromide, and reflux for 6 hours , was poured into water, a large amount of precipitate was produced, filtered, and the filter cake was washed with diethyl ether and methanol to obtain 900 mg of the product, yield: 79%. ¹ HNMR (300MHz, DMSO-d ₆ , TMS): δ7.57-7.37 (3H, m, Ar), 6.67 (1H, s, Ar), 6.50 (1H, s, Ar), 4.90 (2H, s, _CH2 ), 3.90 (3H, s, _OCH3 ), 3.84 (3H, s, _OCH3 ), 3.60 (1H, s, CH).

Example 2 Synthesis of 1,3-dimethoxy-7-azacyclic-bisphenylpyrone

The reaction scheme of embodiment 2.1～2.6 is:

The reaction scheme of embodiment 2.7～2.9 is:

The reaction scheme of embodiment 2.10～2.14 is:

2.1 Synthesis of 1,3-dimethoxy-7-R-bisphenylpyrone

100mg of 1,3-dimethoxy-7-bromo-bisphenylpyrone prepared according to the method of Example 1.1 and 50ml of piperidine, Pd ₂ (dba) ₃ (catalytic amount), ligand Xphos (2-bicyclo Hexylphosphine-2′, 4′, 6′-triisopropylbiphenyl (catalytic amount), cesium carbonate (200mg) was dissolved and suspended in 1,4-dioxane (5ml), under argon protection, 115 After stirring at ℃ for 15 hours, filter, concentrate, and recrystallize from ether to obtain 89 mg of the product, yield: 65%. ¹ HNMR (300MHz, DMSO-d ₆ , TMS) data: δ7.62 (1H, s, Ar), 7.31 (2H, d, Ar), 6.49 (1H, d, Ar), 6.34 (1H, d, Ar), 3.98 (3H, s, OCH ₃ ), 3.92 (3H, s, OCH ₃ ), 3.88 (3H, m, OCH ₃ ), 3.71 (4H, br, CH ₂ ), 1.79-1.56 (6H, m , CH ₂ ).

2.2 Synthesis of 1,3-dimethoxy-7-morpholine-bisphenylpyrone

100 mg of 1,3-dimethoxy-7-bromo-bisphenylpyrone prepared according to the method of Example 1.1 and 65 ml of morpholine, Pd ₂ (dba) ₃ (catalytic amount), ligand Xphos (catalytic amount), Cesium carbonate (200mg) was dissolved and suspended in 1,4-dioxane (5ml), under the protection of argon, stirred at 115°C for 15 hours, the reaction was complete, filtered, concentrated, and recrystallized from ether to obtain 100mg of the product. The yield was : 70.8%. ¹ HNMR (300MHz, DMSO-d ₆ , TMS) data: δ7.70 (1H, s, Ar), 7.30 (2H, m, Ar), 6.48 (1H, d, Ar), 6.33 (1H, d, Ar), 3.98 (3H, s, _OCH3 ), 3.91 (4H, m, _CH2 ), 3.88 (3H, m, _OCH3 ), 3.22 (4H, m, _CH2 ).

2.3 Synthesis of 1,3-dimethoxy-7-(4-methylpiperazine)-diphenylpyrone

100mg of 1,3-dimethoxy-7-bromo-bisphenylpyrone and 65ml of 4-methylpiperazine prepared according to the method of Example 1.1, Pd ₂ (dba) ₃ (catalytic amount), ligand Xphos ( Catalytic amount), cesium carbonate (200mg) was dissolved and suspended in 1,4-dioxane (5ml), under the protection of argon, stirred at 115°C for 15 hours, filtered, concentrated, and recrystallized from ether to obtain 105mg of the product. Rate: 71.8%. ¹ HNMR (300MHz, DMSO-d ₆ , TMS) data: δ7.71 (1H, s, Ar), 7.31 (2H, d, Ar), 6.48 (1H, d, Ar), 6.33 (1H, d, Ar), 3.98 (3H, s, OCH ₃ ), 3.92 (3H, s, OCH ₃ ), 3.88 (3H, m, OCH ₃ ), 3.27 (4H, m, CH ₂ ), 2.61 (4H, m, CH ₂ ), 2.38 (3H, s, _CH3 ).

2.4 Synthesis of 1,3-dimethoxy-7-(1,2,4-triazole)-biphenylpyrone

100 mg of 1,3-dimethoxy-7-bromo-bisphenylpyrone and 55 ml of 1,2,4-triazole, Pd ₂ (dba) ₃ (catalytic amount), and Xphos (catalytic amount), cesium carbonate (200mg) was dissolved and suspended in 1,4-dioxane (5ml), under the protection of argon, stirred at 115°C for 15 hours, filtered, concentrated, and recrystallized from ether to obtain 95mg Product, yield: 68.8%. ¹ HNMR (300MHz, DMSO-d ₆ , TMS) data: δ8.38 (1H, s, Ar), 8.23 (1H, s, Ar), 7.72 (1H, s, Ar), 7.30 (2H, m, Ar), 6.50 (1H, d, Ar), 6.36 (1H, d, Ar), 4.05 (3H, s, _OCH3 ), 3.92 (3H, m, _OCH3 ).

2.5 Synthesis of 1,3-dimethoxy-7-imidazole-biphenylpyrone

100 mg of 1,3-dimethoxy-7-bromo-bisphenylpyrone prepared according to the method of Example 1.1 and 55 ml of imidazole, Pd ₂ (dba) ₃ (catalytic amount), ligand Xphos (catalytic amount), carbonic acid Cesium (200mg) was dissolved and suspended in 1,4-dioxane (5ml), under the protection of argon, stirred at 115°C for 15 hours, filtered, concentrated, and recrystallized from ether to obtain 90mg of the product, yield: 65.8%. ¹ HNMR (300MHz, DMSO-d ₆ , TMS) data: δ8.11 (2H, m, Ar), 7.92-7.50 (4H, m, Ar), 6.69 (1H, d, Ar), 652 (1H, d, Ar), 4.05 (3H, s, _OCH3 ), 3.92 (3H, m, _OCH3 ).

2.6 Synthesis of 1,3-dimethoxy-7-(4-(2-methoxyphenyl)-piperazine)-diphenylpyrone

1,3-dimethoxy-7-bromo-bisphenylpyrone 100mg and 4-(2-methoxyphenyl) piperazine 75ml, Pd ₂ (dba) ₃ (catalytic amount), ligand Xphos (catalytic amount), cesium carbonate (200mg) suspended in 1,4-dioxane (5ml), under the protection of argon, stirred at 115°C for 15 hours, the reaction was complete, filtered, concentrated, diethyl ether Recrystallization gave 121 mg of product, yield: 80.8%. ¹ HNMR (300MHz, DMSO-d ₆ , TMS): δ7.60-6.77 (7H, m, Ar), 6.59-6.45 (2H, m, Ar), 3.87 (3H, s OCH ₃ ), 3.85 (3H, s, OCH ₃ ), 3.73 (3H, s, OCH ₃ ), 3.58-3.43 (8H, m, CH ₂ ).

2.7 Synthesis of 1,3-dimethoxy-7-((1-(2-methylbenzyl)-1,2,3-triazole)-4-methylaminobisphenylpyrone

Dissolve 40 mg (0.6 mmol) of sodium azide in DMSO, add 115 mg (0.57 mmol) of o-methylbenzyl bromide and stir at room temperature for 12 hours, then add 1,3-dimethoxy-7 -(2-alkynylpropylamine)-diphenylpyrone 130mg (0.42mmol), then dissolve copper sulfate pentahydrate (catalytic amount) in 1ml of water, add sodium ascorbate (catalytic amount), and quickly drop into the reaction solution , stirred at room temperature for 16 hours, poured into dilute ammonia water, extracted with dichloromethane, concentrated, and column chromatography (dichloromethane:methanol=100:1). 150 mg of product was obtained, yield: 74.6%. ¹ HNMR (300MHz, DMSO-d ₆ , TMS): δ7.85 (1H, s, CH=C-), 7.30-6.97 (7H, m, Ar), 6.59-6.42 (2H, m, Ar), 6.36 (1H, br, NH), 5.52 (2H, s, CH ₂ ), 4.34 (2H, d, CH ₂ ), 3.87 (3H, s, OCH ₃ ), 3.83 (3H, s, OCH ₃ ), 2.24 ( 3H, s, CH ₃ ).

2.8 Synthesis of 1,3-dimethoxy-7-((1-(4-fluorobenzyl)-1,2,3-triazole)-4-methylaminobisphenylpyrone

Dissolve 40 mg (0.6 mmol) of sodium azide in DMSO, add 110 mg (0.57 mmol) of 4-fluorobenzyl bromide and stir at room temperature for 12 hours, then add 1,3-dimethoxy-7 -(2-alkynylpropylamine)-diphenylpyrone 130mg (0.42mmol), then dissolve copper sulfate pentahydrate (catalytic amount) in 1ml of water, add sodium ascorbate (catalytic amount), and quickly drop into the reaction solution , stirred at room temperature for 16 hours, poured into dilute ammonia water, extracted with dichloromethane, concentrated, and column chromatography (dichloromethane:methanol=100:1). 140 mg of product was obtained, yield: 70%. 1HNMR (300MHz, DMSO-d6, TMS): δ8.02(1H, s, CH=C-), 7.35-7.11(7H, m, Ar), 6.62-6.46(2H, m, Ar), 6.45(1H , br, NH), 5.55 (2H, s, CH ₂ ), 4.36-4.34 (2H, br, CH ₂ ), 3.90 (3H, s, OCH ₃ ), 3.86 (3H, s, OCH ₃ ).

2.9 Synthesis of 1,3-dimethoxy-7-((1-(2-nitrobenzyl)-1,2,3-triazole)-4-methylaminobisphenylpyrone

Dissolve 40mg (0.6mmol) of sodium azide in DMSO, add 118mg (0.57mmol) of o-nitrobenzyl bromide, add 115mg (0.57mmol) of 2-methylbenzyl bromide, and stir at room temperature for 12 hours, then add it all at once according to the method in Example 1.4 Prepared 130mg (0.42mmol) of 1,3-dimethoxy-7-(2-alkynylpropylamine)-diphenylpyrone, then dissolved copper sulfate pentahydrate (catalytic amount) in 1ml of water, and added ascorbic acid Sodium (catalytic amount) was quickly dropped into the reaction solution, stirred at room temperature for 16 hours, poured into dilute ammonia water, extracted with dichloromethane, concentrated, and column chromatographed (dichloromethane:methanol=100:1). 110 mg of product was obtained, yield: 64.6%. ¹ HNMR (300MHz, DMSO-d ₆ , TMS): δ8.12-8.01 (2H, m, Ar), 7.69-7.11 (5H, m, Ar), 6.87-6.43 (4H, m, Ar), 5.92 ( 2H, s, _CH2 ), 4.38 (2H, br, _CH2 ), 3.86 (6H, s, _OCH3 ).

2.10 Synthesis of 1,3-dimethoxy-7-((1-(2-methylbenzyl)-1,2,3-triazole)-4-methoxybisphenylpyrone

Dissolve 40 mg (0.6 mmol) of sodium azide in DMSO, add 116 mg (0.57 mmol) of 2-methylbenzyl bromide and stir at room temperature for 12 hours, then add 1,3-dimethoxy- 7-(2-propargyloxy)-diphenylpyrone 135mg (0.43mmol), then dissolve copper sulfate pentahydrate (catalytic amount) in 1ml of water, add sodium ascorbate (catalytic amount), and quickly drop into the reaction solution , stirred at room temperature for 16 hours, poured into dilute ammonia water, extracted with dichloromethane, concentrated, and column chromatography (dichloromethane:methanol=100:1). 150 mg of product was obtained, yield: 74.6%. ¹ HNMR (300MHz, DMSO-d ₆ , TMS): δ8.18 (1H, s, CH=C-), 7.59-7.05 (7H, m, Ar), 6.67 (1H, d, Ar), 6.50 (1H , d, Ar), 5.61 (2H, s, CH ₂ ), 5.23 (2H, s, CH ₂ ), 3.90 (3H, s, OCH ₃ ), 3.87 (3H, s, OCH ₃ ), 2.30 (3H, s, CH ₃ ).

2.11 Synthesis of 1,3-dimethoxy-7-((1-(2-fluorobenzyl)-1,2,3-triazole)-4-methoxybisphenylpyrone

Dissolve 40 mg (0.6 mmol) of sodium azide in DMSO, add 110 mg (0.55 mmol) of o-fluorobenzyl bromide and stir at room temperature for 12 hours, then add 1,3-dimethoxy-7- (2-propargyloxy)-diphenylpyrone 135mg (0.43mmol), then copper sulfate pentahydrate (catalytic amount) was dissolved in 1ml water, sodium ascorbate (catalytic amount) was added, and quickly dropped into the reaction solution, Stir at room temperature for 16 hours, pour into dilute ammonia water, extract with dichloromethane, concentrate, and perform column chromatography (dichloromethane:methanol=100:1). 125 mg of product was obtained, yield: 68.6%. ¹ HNMR (300MHz, DMSO-d ₆ , TMS): δ8.28 (1H, s, CH=C-), 7.60-7.18 (7H, m, Ar), 6.67 (1H, d, Ar), 6.49 (1H , d, Ar), 5.71 (2H, d, CH ₂ ), 5.23 (2H, s, CH ₂ ), 3.90 (3H, s, OCH ₃ ), 3.87 (3H, s, OCH ₃ ).

2.12 Synthesis of 1,3-dimethoxy-7-((1-(4-bromobenzyl)-1,2,3-triazole)-4-methoxybisphenylpyrone

Dissolve 40 mg (0.6 mmol) of sodium azide in DMSO, add 120 mg (0.55 mmol) of p-bromobenzyl bromide and stir at room temperature for 12 hours, then add 1,3-dimethoxy-7- (2-propargyloxy)-diphenylpyrone 130mg (0.42mmol), then copper sulfate pentahydrate (catalytic amount) was dissolved in 1ml of water, sodium ascorbate (catalytic amount) was added, and quickly dropped into the reaction solution, Stir at room temperature for 16 hours, pour into dilute ammonia water, extract with dichloromethane, concentrate, and perform column chromatography (dichloromethane:methanol=100:1). 130 mg of product was obtained, yield: 68.6%. ¹ HNMR (300MHz, DMSO-d ₆ , TMS): δ8.31 (1H, s, CH=C-), 7.58-7.24 (7H, m, Ar), 6.68 (1H, d, Ar), 6.50 (1H , d, Ar), 5.61 (2H, d, CH ₂ ), 5.24 (2H, s, CH ₂ ), 3.90 (3H, s, OCH ₃ ), 3.87 (3H, s, OCH ₃ ).

2.13 Synthesis of 1,3-dimethoxy-7-((1-(4-nitrobenzyl)-1,2,3-triazole)-4-methoxybisphenylpyrone

Dissolve 40 mg (0.6 mmol) of sodium azide in DMSO, add 118 mg (0.57 mmol) of p-nitrobenzyl bromide and stir at room temperature for 12 hours, then add 1,3-dimethoxy-7 -(2-propargyloxy)-diphenylpyrone 130mg (0.42mmol), then dissolve copper sulfate pentahydrate (catalytic amount) in 1ml of water, add sodium ascorbate (catalytic amount), and quickly drop into the reaction solution , stirred at room temperature for 16 hours, poured into dilute ammonia water, extracted with dichloromethane, concentrated, and column chromatography (dichloromethane:methanol=100:1). 130 mg of product was obtained, yield: 77.6%. ¹ HNMR (300MHz, DMSO-d ₆ , TMS): δ8.38 (1H, s, CH=C-), 8.21 (2H, m, Ar), 7.75-7.42 (5H, m, Ar), 6.66 (1H , d, Ar), 6.49 (1H, d, Ar), 5.80 (2H, s, CH ₂ ), 5.24 (2H, s, CH ₂ ), 3.89 (3H, s, OCH ₃ ), 3.86 (3H, s , OCH ₃ ).

2.14 Synthesis of 1,3-dimethoxy-7-((1-(3-cyanobenzyl)-1,2,3-triazole)-4-methoxybisphenylpyrone

Dissolve 40 mg (0.6 mmol) of sodium azide in DMSO, add 116 mg (0.57 mmol) of 2-cyanobenzyl bromide and stir at room temperature for 12 hours, then add 1,3-dimethoxy- 130 mg (0.42 mmol) of 7-(2-propargyloxy)-bisphenylpyrone, then dissolve copper sulfate pentahydrate (catalytic amount) in 1 ml of water, add sodium ascorbate (catalytic amount), and quickly drop into the reaction solution , stirred at room temperature for 16 hours, poured into dilute ammonia water, extracted with dichloromethane, concentrated, and column chromatography (dichloromethane:methanol=100:1). 130 mg of product was obtained, yield: 78.6%. 1HNMR (300MHz, DMSO-d6, TMS): δ8.35 (1H, s, CH=C-), 7.82-7.42 (7H, m, Ar), 6.66 (1H, d, Ar), 6.49 (1H, d , Ar), 5.69 (2H, s, CH ₂ ), 5.24 (2H, s, CH ₂ ), 3.90 (3H, s, OCH ₃ ), 3.87 (3H, s, OCH ₃ ).

All the reagents used in the above examples are commercially available analytically pure. The implementation of the present invention is not limited to the above examples. The rest of the target compounds can be synthesized by using different benzyl bromide derivatives and substituted amines as raw materials and repeating the steps in the above examples to synthesize the required bisphenylpyrone derivatives. The chemical structures and NMR data of some preferred derivatives of the present invention are shown in Table 1 and Table 2. Table 1 is the NMR data of derivatives when R is a heterocyclic group or a substituted phenylpiperazine group, and Table 2 is that R is

时衍生物的核磁数据。

NMR data of time derivatives.

Table 1 NMR data of bisphenylpyrone nitrogen heterocyclic derivatives

Table 2 NMR data of bisphenylpyrone nitrogen heterocyclic derivatives

Embodiment 3 pharmacological experiment

(1) Experimental materials

After the test samples were dissolved in DMSO (Merck), PBS (-) was added to make a 1000 μg/ml solution or a uniform suspension, and then diluted with DMSO-containing PBS (-).

The cell lines are Hela (human cervical cancer cells) and Bel7402 (human liver cancer cells).

Other materials and main instruments are:

Culture medium: RPMI1640 + 15% NBS + double antibody; MTT: purchased from Sigma Company (St.Louis, MO, USA); other reagents are of domestic analytical grade. Fully automatic microplate reader WellscanMK-2 (Labsystems Company), CO ₂ constant temperature incubator (Japan Sanyo Company), imported 96-well culture plate, etc.

Table 3 Derivative half cell death inhibitor concentration or _IC50 value

^a Doxorubicin positive control (Doxorubicin, positive control)

(2) Experimental method

MTT (tetrazolium salt) method: 100 μl of cell suspension with a concentration of 4-6×10 ⁴ cells/ml was added to each well of a 96-well plate, and placed in a 37° C., 5% CO ₂ incubator. After 24 hours, add sample solution (diluted 100 times), 10 μl/well, set up duplicate wells, and act at 37° C., 5% CO ₂ for 72 hours. Add 20 μl of 5 mg/ml MTT solution to each well, add DMSO solution after 4 hours of action, 100 μl/well, put it in an incubator, measure the 570nm OD value with MK-2 automatic microplate reader after dissolution.

(3) Experimental results

The synthesized compounds were tested for the inhibitory effect of cell lines in vitro, and 20 compounds with better activity were selected from the preliminary screening results for re-screening, and the concentration of the inhibitor that caused half of the cells to die was calculated, that is, the IC ₅₀ value (μM) , and the results are shown in Table 3.

The above results show that the derivatives prepared by the present invention have better tumor cell proliferation inhibitory activity, and most of the compounds have in vitro activity, especially derivatives A1, A5, A7, and A10 have stronger inhibitory effects on Hela cells Bel7402 cells Cell proliferation, the derivatives can be used to prepare medicines for cervical cancer and liver cancer.

Claims (5)

1. A bisphenylpyrone nitrogen heterocyclic derivative, the general structural formula is

where R is: (1) heterocyclic group, said heterocyclic group is piperidinyl, piperazinyl, methylpiperazinyl, morpholinyl, imidazolyl or triazolyl; (II) substituted phenylpiperazinyl, the substituted phenylpiperazinyl is selected from: R is

(III) has the general formula

In the formula, the number of R ₁ is 1 to 5, which is one of halogen, C ₁ to C ₆ alkyl, cyano, nitro, trifluoromethyl, methoxy, ethoxy or their combination; or (IV) has the general formula

wherein, the number of R ₂ is 1 to 5, which is one of halogen, C ₁ to C ₆ alkyl, cyano, nitro, trifluoromethyl, methoxy, ethoxy or their combination. 2. a kind of preparation method of bisphenylpyrone nitrogen heterocycle derivative as claimed in claim 1, the structural general formula of described derivative is

Wherein R is a heterocyclic group or a substituted phenylpiperazinyl group, the heterocyclic group is piperidinyl, piperazinyl, methylpiperazinyl, morpholinyl, imidazolyl, or triazolyl, and the substituted Phenyl is monosubstituted phenyl or polysubstituted phenyl, and substituent is halogen, C ₁ alkyl, trifluoromethyl, methoxy; It is characterized in that, comprises the following steps: (A): With 5-bromosalicylic acid and 1,3,5-trimethoxybenzene as raw materials, react in Eaton's reagent to obtain 1,3-dimethoxy-7-bromo-bisphenylpyrone; (B) 1,3-dimethoxy-7-bromo-bisphenylpyrone and substituted amine in 1,4-dioxane under the action of Pd ₂ (dba) ₃ , Xphos, Cs ₂ CO ₃ In a solvent, react under the protection of argon to obtain the derivative, and the substituted amine is selected from piperidine, piperazine, methylpiperazine, morpholine, imidazole, triazole, or substituted phenylpiperazine. 3. a kind of preparation method of bisphenylpyrone nitrogen heterocycle derivative as claimed in claim 1, the structural general formula of described derivative is

where R is

In the formula, the number of R ₂ is 1 to 5, and it is one of halogen, C ₁ -C ₆ alkyl, cyano, nitro, trifluoromethyl, methoxy, ethoxy or a combination thereof, It is characterized by including: (A) Using 5-nitrosalicylic acid and 1,3,5-trimethoxybenzene as raw materials, react in Eaton's reagent to obtain 1,3-dimethoxy-7-nitro-bisphenylpyrone ; (B) 1,3-dimethoxy-7-nitro-bisphenylpyrone and hydrazine hydrate react under the action of Raney nickel in an alcohol solvent to obtain 1,3-dimethoxy-7- Amino-diphenylpyrone; (C) 1,3-dimethoxy-7-amino-diphenylpyrone and propyne bromide are refluxed in alkali and acetone solvent to obtain 1,3-dimethoxy-7-(2-alkynyl Alanine)-diphenylpyrone; (D) Reaction of sodium azide and benzyl bromide derivatives in DMSO for 12h, adding 1,3-dimethoxy-7-(2-alkynylpropylamine)-diphenylpyrone, in copper sulfate pentahydrate , under the effect of ascorbic acid, reaction obtains described derivative, and the general formula of described benzyl bromide derivative is: The number of R ₂ is 1-5, and it is one of halogen, C ₁ -C ₆ alkyl, cyano, nitro, trifluoromethyl, methoxy, ethoxy or a combination thereof. 4. a kind of preparation method of bisphenylpyrone nitrogen heterocycle derivative as claimed in claim 1, the structural general formula of described derivative is

where R is

In the formula, the number of R ₁ is 1 to 5, and it is one of halogen, C ₁ -C ₆ alkyl, cyano, nitro, trifluoromethyl, methoxy, ethoxy or a combination thereof, It is characterized by including: (A) take 5-hydroxysalicylic acid and 1,3,5-trimethoxybenzene as raw materials, react in Eaton's reagent to obtain 1,3-dimethoxy-7-hydroxyl-bisphenylpyrone; (B) 1,3-dimethoxy-7-hydroxyl-bisphenylpyrone and propyne bromide are refluxed in alkali and acetone solvent to obtain 1,3-dimethoxy-7-(2-propargyl Oxygen)-diphenylpyrone; (C) Reaction of sodium azide and benzyl bromide derivatives in DMSO for 12h, adding 1,3-dimethoxy-7-(2-propargyloxy)-bisphenylpyrone, in copper sulfate pentahydrate , under the effect of ascorbic acid, reaction obtains described derivative, and the general formula of described benzyl bromide derivative is:

The number of R ₁ is 1-5, which is one of halogen, C ₁ -C ₆ alkyl, cyano, nitro, trifluoromethyl, methoxy, ethoxy or a combination thereof. 5. The application of the bisphenylpyrone nitrogen heterocyclic derivative as claimed in claim 1, characterized in that it is used for the preparation of medicines for treating cervical cancer or liver cancer.