CN102807566B - 1,7-diaryl-1,6-trans diene-3,5-diketone, its preparation method and application - Google Patents

Abstract

The invention discloses the compound 6a-i of 1,7-diaryl-1,6-trans diene-3,5-dione compounds and general formula I representative, the invention also discloses its preparation method and the application in preparation tumor, the present invention is at mouse S ₁₈₀model is evaluated the anti-tumor activity of the compounds of this invention, experimental result shows that compound 6a-i of the present invention has outstanding antitumor action, can be applicable to prepare in the production of antitumor drug.

Description

1,7-diaryl-1,6-trans-diene-3,5-dione, its preparation method and application

technical field

The present invention relates to a kind of synthetic compound and its preparation method and application, especially relate to a kind of 1,7-diaryl-1,6-trans diene-3,5-dione compound, the present invention also relates to Its preparation method and its application in the preparation of drugs for treating tumors.

Background technique

Malignant tumor is a common and frequently-occurring disease that seriously threatens human health. The mortality rate of human beings caused by malignant tumors is the second highest among all diseases, second only to cardiovascular and cerebrovascular diseases. Tumor treatments include surgery, radiation therapy, and drug therapy (chemotherapy). At present, chemotherapy is still the main means of clinical treatment of tumors, and finding anti-tumor drugs is one of the hotspots in new drug research. Curcumin is a natural product with antitumor activity. The inventors realized that by modifying natural products, new natural product derivatives with better anti-tumor activity can be found. 1,7-diaryl-1,6-trans-diene-3,5-dione is a structural analogue of curcumin from the structural relationship, which may expand the antitumor activity of curcumin. Based on this idea, the inventors came up with the present invention.

Contents of the invention

The first technical problem to be solved in the present invention is to provide the compound (6a-i) of general formula I:

In the formula, R1 is ₃ -indolyl, R2 is 2,3,4,9 _- tetrahydro-1H-pyridine-3-[3,4-b]indolyl, R1 is ₃ -indole Base, R ₂ is 9H-pyridine-3-[3,4-b]indolyl, R ₁ is 3-indolyl, R ₂ is 3-indolyl, R ₁ is 4-hydroxy-3-methyl _Oxyphenyl , R2 is 2,3,4,9-tetrahydro-1H-pyridine-3-[3,4-b]indolyl, R1 is ₄ -hydroxyl-3-methoxyphenyl , R ₂ is 9H-pyridine-3-[3,4-b]indolyl, R ₁ is 4-hydroxy-3-methoxyphenyl, R ₂ is 3-indolyl, R ₁ is 3, 5-dimethoxy-4-hydroxyphenyl, R ₂ is 2,3,4,9-tetrahydro-1H-pyridine-3-[3,4-b]indolyl, R ₁ is 3,5 -Dimethoxy-4-hydroxyphenyl, R ₂ is 9H-pyridine-3-[3,4-b]indolyl, R ₁ is 3-pyridyl, R ₂ is 2,3,4,9 -tetrahydro-1H-pyridine-3-[3,4-b]indolyl.

The compound (6a-i) represented by the general formula I synthesized is numbered: in 6a R ₁ is 3-indolyl, R ₂ is 2,3,4,9-tetrahydro-1H-pyridine-3-[3 , 4-b]indolyl, R in 6b is ₃ -indolyl, R is 9H _- pyridine-3-[3,4-b]indolyl, R in 6c is ₃ -indolyl , R ₂ is 3-indolyl, R ₁ in 6d is 4-hydroxy-3-methoxyphenyl, R ₂ is 2,3,4,9-tetrahydro-1H-pyridine-3-[3, 4-b] indolyl, R ₁ in 6e is 4-hydroxy-3-methoxyphenyl, R ₂ is 9H-pyridine-3-[3,4-b] indolyl, R ₁ in 6f is 4-Hydroxy-3-methoxyphenyl, R2 is ₃ -indolyl, R1 in 6g is 3,5-dimethoxy- _{4 -} hydroxyphenyl, R2 is 2,3,4, 9-tetrahydro-1H-pyridine-3-[3,4-b]indolyl, R ₁ in 6h is 3,5-dimethoxy-4-hydroxyphenyl, R ₂ is 9H-pyridine-3 -[3,4-b]indolyl, R ₁ in 6i is 3-pyridyl, R ₂ is 2,3,4,9-tetrahydro-1H-pyridine-3-[3,4-b]indyl Indolyl.

The above numbering is only for convenience of description, and does not have any limiting meaning to the invention.

The second technical problem to be solved in the present invention is to provide a preparation method for the compound of general formula 6a-i, the method comprising:

(1) In the presence of 12-I-53-acetoxy periodate (DMP) and sodium bicarbonate, (S)-2,3,4,9-tetrahydro-1H- Oxidation of pyridin[3,4-b]indole-3-carbinol to (S)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-3-carbaldehyde;

(2) In the presence of 12-I-53-acetoxy periodate (DMP) and sodium bicarbonate, tetrahydrofuran (THF) was used as solvent to oxidize 9H-pyridine[3,4-b]indole-3-methanol 9H-pyridin[3,4-b]indole-3-carbaldehyde;

(3) (S)-2,3,4,9-tetrahydro-1H-pyridin[3,4-b]indole-3-carbaldehyde, 9H-pyridine[3,4-b]indole-3 -Formaldehyde and 1H-indole-3-carbaldehyde and 4-hydroxy-3-methoxybenzaldehyde, 1H-indole-3-carbaldehyde, 3,5-dimethoxy-4-hydroxybenzaldehyde, pyridine- 3-formaldehyde is coupled through pentanedione to prepare 1,7-diaryl-1,6-trans-diene-3,5-dione, namely.

This preparation method can be generalized with the route of Fig. 1, Fig. 2.

The third technical problem to be solved by the present invention is to provide the application of the compound in the preparation of drugs for treating tumors.

The fourth technical problem to be solved by the present invention is to evaluate the antitumor activity of the compound of the present invention on the mouse _S180 model.

Description of drawings

Figure 1 is (S)-2,3,4,9-tetrahydro-1H-pyridin[3,4-b]indole-3-carbaldehyde (4a) and 9H-pyridine[3,4-b]indole - a synthetic route map of 3-formaldehyde (4b);

i) dilute sulfuric acid, formaldehyde, H ₂ O; ii) SOCl ₂ , MeOH; iii) KMnO ₄ , DMF; iv) NaBH ₄ , THF; v) DMP, NaHCO ₃ , THF

Figure 2 is a synthetic route diagram of 1,7-diaryl-1,6-trans-diene-3,5-dione (6a-i).

4c is indole-3-carbaldehyde, 4d is vanillin, 4e is syringaldehyde, and 4f is pyridine-3-carbaldehyde;

i) B ₂ O ₃ , (nBuO) ₃ B, nBu-NH ₂ , 1NHCl; ii) B ₂ O ₃ , (nBuO) ₃ B, nBu-NH ₂ , 1NHCl;

Detailed ways

The following examples and test data illustrate the above-mentioned and other technical characteristics and advantages of the present invention in more detail.

Example 1 Preparation of (S)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-3-carboxylic acid (1)

Add 800ml of water, 0.4ml of concentrated sulfuric acid and 10g (49mmol) of L-tryptophan into a 1000ml eggplant bottle, stir until the L-tryptophan is completely dissolved, then add 15ml of formaldehyde solution, after 6-7 reactions, a white solid precipitates out, Adjust pH to 7 with concentrated ammonia water, filter after standing. Obtained 10.440 g (98%) of the title product as a colorless solid.

Example 2 Preparation of (S)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-3-carboxylic acid methyl ester (2a)

Add 100ml of methanol to a 250ml eggplant bottle and add 13ml of thionyl chloride dropwise in an ice-salt bath. After stirring for 30min, slowly add 10g (45.8mmol) of (S)-2,3,4,9-tetrahydro-1H- Pyridine[3,4-b]indole-3-carboxylic acid (1), after 9-10h reaction (S)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole Indole-3-carboxylic acid (1) was completely dissolved, and the reaction liquid was pumped dry, added ether and filtered. The filter cake was suspended with ethyl acetate, and then saturated aqueous sodium bicarbonate solution was added to adjust the pH to 8 for extraction. The ester layer was washed with water to neutrality, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, separated and purified by column chromatography (petroleum ether: acetone = 2:1) to obtain 3.982 g (36%) of the target product as a colorless solid.

Example 3 Preparation of 9H-pyridine [3,4-b] indole-3-carboxylic acid methyl ester (2b)

Add 4g (17.2mmol) (S)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-3-carboxylic acid methyl ester (2a) in 250ml eggplant bottle, ice Add DMF (NN-dimethylformamide) in the salt bath to dissolve it, add 3.804g (24.1mmol) potassium permanganate several times in small amounts, react for 30min, add 50ml of ethanol and stir for 30min, pour the reaction solution into a watch glass blow dry. Rinse with THF (tetrahydrofuran), collect the washings, concentrate the washings to dryness under reduced pressure, wash with diethyl ether, and filter to obtain 1.477 g (38%) of the target product as a pale yellow solid.

Example 4 Preparation of (S)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-3-carbinol (3a)

In a 250ml eggplant bottle, add 4g (17.2mmol) (S)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-3-carboxylic acid methyl ester (2a) with THF 1. After the methanol was dissolved, 3.268 g (86 mmol) of sodium borohydride was added in small amounts and several times in an ice bath, and the reaction was carried out for 9-10 hours, monitored by TLC. After the reaction was completed, saturated potassium hydrogensulfate aqueous solution was added to adjust the pH to 5, the reaction solution was concentrated under reduced pressure to remove THF, the reaction solution was adjusted to pH = 8 with saturated sodium bicarbonate, and extracted with ethyl acetate. The ester layer was washed with water until neutral, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. 868 mg (25%) of the title product were obtained as a colorless solid.

Example 5 Preparation of 9H-pyrido[3,4-b]indole-3-carbinol (3b)

In 250ml eggplant bottle, add 4g (17.7mmol) 9H-pyridine [3,4-b] indole-3-carboxylate methyl ester (2b) after dissolving with THF, methanol, add 3.36g ( 88.5mmol) sodium borohydride, reacted for 9-10h, monitored by TLC. After the reaction was completed, saturated potassium hydrogensulfate aqueous solution was added to adjust the pH to 5, the reaction solution was concentrated under reduced pressure to remove THF, the reaction solution was adjusted to pH = 8 with saturated sodium bicarbonate, and extracted with ethyl acetate. The ester layer was washed with water until neutral, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. This gave 708 mg (20%) of the title product as a colorless solid.

Example 6 Preparation of (S)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-3-carbaldehyde (4a)

Add 2g (9.9mmol) (S)-2,3,4,9-tetrahydro-1H-pyridine[3,4-b]indole-3-carbinol (3a), 998mg (11.8mmol ) Sodium bicarbonate was dissolved in THF, and 5.876g (13.7mmol) DMP (dess-martin oxidant) was slowly added under ice bath, and the reaction was carried out for 9-10h, monitored by TLC. After the reaction, filter. The filtrate was concentrated to dryness under reduced pressure and separated on a preparative TLC plate. Obtained 594 mg (30%) of the title product as a dark yellow solid.

Example 7 Preparation of 9H-pyridine [3,4-b] indole-3-carbaldehyde (4b)

Add 2g (10mmol) 9H-pyridin[3,4-b]indole-3-carbinol (3b), 1.008g (12mmol) sodium bicarbonate in THF to dissolve in 250ml eggplant bottle, slowly add 5.936g ( 14mmol) DMP (dess-martin oxidant), reacted for 9-10h, monitored by TLC. After the reaction, filter. The filtrate was concentrated to dryness under reduced pressure, and separated and purified by silica gel column chromatography (petroleum ether: acetone = 6:1) to obtain 803 mg (41%) of the target compound as a pale yellow solid.

Example 8 Preparation of 4-(3-indolyl)-5,6-hexene-2,4-dione (5a)

Add 10.58ml (102.9mmol) of acetylacetone, 5.0g (72.1mmol) of boron oxide and 50.0mL of ethyl acetate into a 150mL three-necked flask, install a reflux condenser, and stir in an oil bath at a constant temperature of 70°C for 1h. Then add 4.973g (34.3mmol) indole 3-carboxaldehyde and 4.8ml (34.3mmol) tributyl borate, stir in an oil bath at a constant temperature of 85°C for 30min; continue to dilute 1.8mL (41.1mmol) of Slowly add butylamine dropwise into the three-necked flask within 30 minutes, react at a constant temperature of 100°C in an oil bath for 1h, then cool to room temperature; Set, fully separated, and the aqueous layer was extracted 3 times with ethyl acetate. The ethyl acetate layers were combined, washed with water until neutral, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, separated and purified by silica gel column chromatography (petroleum ether: acetone = 5:1), and 1.713 g (22%) was obtained Yellow solid object.

Example 9 Preparation of 6-(4-hydroxyl-3-methoxyphenyl)-5,6-hexene-2,4-dione (5b)

Add 10.58ml (102.9mmol) of acetylacetone, 5.0g (72.1mmol) of boron oxide and 50.0mL of ethyl acetate into a 150mL three-necked flask, install a reflux condenser, and stir in an oil bath at a constant temperature of 70°C for 1h. Then add 5.2g (34.3mmol) vanillin and 4.8ml (34.3mmol) tributyl borate, stir in an oil bath at a constant temperature of 85°C for 30min; continue to dilute 1.8mL (41.1mmol) n-butylamine in 10mL ethyl acetate Slowly add it dropwise to the three-necked flask within 30 minutes, react at a constant temperature of 100°C in an oil bath for 1 hour, then cool to room temperature; add 36mL (1mol/L) hydrochloric acid dropwise to the reaction flask, stir at a constant temperature of 50°C for 30min, stand still, and fully The layers were separated, and the aqueous layer was extracted 3 times with ethyl acetate. The ethyl acetate layers were combined, washed with water until neutral, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, separated and purified by silica gel column chromatography (petroleum ether: acetone = 5:1), and 3.66 g (48%) was obtained Yellow solid object.

Example 10 Preparation of 6-(4-hydroxyl-3,5-dimethoxyphenyl)-5,6-hexene-2,4-dione (5c)

Add 10.58ml (102.9mmol) of acetylacetone, 5.0g (72.1mmol) of boron oxide and 50.0mL of ethyl acetate into a 150mL three-necked flask, install a reflux condenser, and stir in an oil bath at a constant temperature of 70°C for 1h. Then add 6.2g (34.3mmol) syringaldehyde and 4.8ml (34.3mmol) tributyl borate, stir in an oil bath at a constant temperature of 85°C for 30min; continue to dilute (1.8mL, 41.1mmol) n-butylamine Slowly add it dropwise into the three-necked flask within 30 minutes, react at a constant temperature of 100°C in an oil bath for 1 hour, and then cool to room temperature; add 36mL (1mol/L) of hydrochloric acid dropwise into the reaction flask, stir at a constant temperature of 50°C for 30min under reflux, and let stand. The layers were separated thoroughly, and the aqueous layer was extracted 3 times with ethyl acetate. The ethyl acetate layers were combined, washed with water until neutral, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, separated and purified by silica gel column chromatography (petroleum ether: acetone = 4:1) to obtain 2.77g (31%) Yellow solid object.

Example 11 Preparation of 6-(3-pyridyl)-5,6-hexene-2,4-dione (5d)

Add 10.58ml (102.9mmol) of acetylacetone, 5.0g (72.1mmol) of boron oxide and 50.0mL of ethyl acetate into a 150mL three-necked flask, install a reflux condenser, and stir in an oil bath at a constant temperature of 70°C for 1h. Then add 3.7g (34.3mmol) pyridine 3-carboxaldehyde and 4.8ml (34.3mmol) tributyl borate, stir in an oil bath at a constant temperature of 85°C for 30min; continue to dilute 1.8mL (41.1mmol) n-butyl Slowly add the amine dropwise into the three-necked flask within 30 minutes, react at a constant temperature of 100°C for 1 hour in an oil bath, then cool to room temperature; add 36mL (1mol/L) of hydrochloric acid dropwise into the reaction flask, stir at a constant temperature of 50°C for 30min under reflux, and let stand , fully separated layers, and the aqueous layer was extracted 3 times with ethyl acetate. The ethyl acetate layers were combined, washed with water until neutral, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, separated and purified by silica gel column chromatography (petroleum ether: acetone = 6:1), and 0.59 g (9.2%) was obtained Yellow solid object.

Example 12 Preparation of 1-(3-indolyl)-7-(2,3,4,9-tetrahydro-1H-pyridine-3-[3,4-b]indolyl)-1,6- Heptadiene-3,5-dione (6a)

Add 1.191g (5.25mmol) 4-(3-indolyl)-5,6-hexene-2,4-dione (5a), 254mg (3.68mmol) boron oxide and 30.0mL Equipped with a reflux condensing device, stirred and reacted for 1 h at a constant temperature of 70° C. in an oil bath. Then 500 mg (2.5 mmol) of (S)-2,3,4,9-tetrahydro-1H-pyridin[3,4-b]indole-3-carbaldehyde (4a) and 575 mg (2.5 mmol) of tributyl borate were added For ester, stir in an oil bath at a constant temperature of 85°C for 30min; slowly add 0.1ml (2.5mmol) of n-butylamine diluted in 10mL of ethyl acetate into the three-necked bottle within 30min, and continue to react for 1h in an oil bath at a constant temperature of 100°C, then Cool to room temperature; the reaction mixture was refluxed with 5 mL (1 mol/L) of hydrochloric acid and stirred at a constant temperature of 50°C for 30 min, allowed to stand, and the layers were fully separated, and the aqueous layer was extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with water until neutral, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, separated and purified by column chromatography (dichloromethane:methanol=25:1), and 94 mg (9%) of yellow Solid target compound.

Mp 116°C; (c=0.14, CH ₃ OH); ESI/MS (m/e) 409[MH] ^- ; IR (KBr): 3218, 1618, 1567, 1449, 1328, 1264, 1217, 1057, 963; ¹ HNMR ( 300MHz, DMSO-d6): δ=11.65(s, 1H), 11.03(s, 1H), 7.96(d, J=7.2Hz, 1H), 7.82(d, J=2.7Hz, 1H), 7.46(t , J=9Hz, 3H), 7.34(d, J=7.8Hz, 1H), 7.27(s, 1H), 7.23～7.15(m, 3H), 7.09(t, J=7.8Hz, 1H), 7.00( t, J=7.2Hz, 1H), 5.26(s, 1H), 5.20(t, J=5.7Hz, 1H), 4.97(f, J=12Hz, 1H), 4.62(d, J=3.6Hz, 1H ), 3.52(d, J=6Hz, 2H), 2.96(s, 2H), 2.84(d, J=3.3Hz, 1H).

Example 13 Preparation of 1-(3-indolyl)-7-(9H-pyridine-3-[3,4-b]indolyl)-1,6-heptadiene-3,5-dione ( 6b)

Add 1.191g (5.25mmol) 4-(3-indolyl)-5,6-hexene-2,4-dione (5a), 254mg (3.68mmol) boron oxide and 30.0mL Equipped with a reflux condensing device, stirred and reacted for 1 h at a constant temperature of 70° C. in an oil bath. Then add 490mg (2.5mmol) 9H-pyridine[3,4-b]indole-3-carboxaldehyde (4b) and 575mg (2.5mmol) tributyl borate, stir in an oil bath at a constant temperature of 85°C for 30min; dilute in 10mL acetic acid 0.1ml (2.5mmol) of n-butylamine in ethyl ester was slowly added dropwise to the three-necked flask within 30min, and the reaction was continued at 100°C oil bath for 1h, and then cooled to room temperature; the reaction mixture was washed with 5mL (1mol/L) of hydrochloric acid , reflux at a constant temperature of 50° C. and stir for 30 minutes, let stand, separate layers sufficiently, and extract the aqueous layer with ethyl acetate three times. The ethyl acetate layers were combined, washed with water until neutral, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, separated and purified by column chromatography (petroleum ether: acetone = 3:1), and 124 mg (12%) of a red solid was obtained target compound.

Mp 87.1～87.9℃; (c=0.13, CH ₃ OH); ESI/MS (m/e) 404.4 [MH] ⁻ ; IR (KBr): 3210, 1614, 1567, 1499, 1430, 1341, 1245, 1126, 953, 740; ¹ HNMR (300MHz, DMSO-d6): δ=11.92(s, 2H), 8.99(s, 1H), 8.48(s, 1H), 8.26(d, J=7.8Hz, 1H), 8.02(t, J= 9.3Hz, 3H), 7.79(d, J=15.3Hz, 1H), 7.66~7.43(m, 4H), 7.33~7.15(m, 5H), 6.81(d, J=15.6Hz, 1H).

Example 14 Preparation of 1,7-bis(3-indolyl)-1,6-heptadiene-3,5-dione (6c)

Add 5g (50mmol) of acetylacetone, 2.415g (35mmol) of boron oxide and 250.0mL of ethyl acetate into a 500mL three-necked flask, install a reflux condenser, and stir for 1 hour at a constant temperature of 70°C in an oil bath. Then add 15.95g (110mmol) indole 3-carboxaldehyde and 25.3g (110mmol) tributyl borate, and stir in an oil bath at a constant temperature of 85°C for 30min; continue to dilute 4.4ml (110mmol) n-butylamine in 10mL ethyl acetate Slowly add it dropwise to the three-necked bottle within 30 minutes, react at a constant temperature of 100°C for 1 hour in an oil bath, and then cool to room temperature; add 220mL (1mol/L) hydrochloric acid dropwise to the reaction bottle, stir at a constant temperature of 50°C for 30min, stand still, and fully The layers were separated, and the aqueous layer was extracted 3 times with ethyl acetate. The ethyl acetate layers were combined, washed with water until neutral, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, separated and purified by silica gel column chromatography (petroleum ether: acetone = 3:1), and 503 mg (3%) of red Solid target compound.

Mp 74～75℃; (c=0.30, CH ₃ OH); ESI/MS (m/e) 353.4 [MH] ^- ; IR (KBr): 3735, 3391, 2360, 11610, 1572, 1509, 1419, 1293, 1245, 1131, 1104 , 959, 740; ¹ HNMR (300MHz, DMSO-d6): δ=11.83(s, 1H), 8.01(d, J=5Hz, 2H), 7.96(d, J=6Hz, 2H), 7.88(d, J=9Hz, 2H), 7.51(d, J=5Hz, 2H), 7.27～7.21(m, 4H), 6.75(d, J=12Hz, 2H).

Example 15 Preparation of (S)-1-(4-hydroxy-3-methoxyphenyl)-7-(2,3,4,9-tetrahydro-1H-pyridine-3-[3,4-b ]indolyl)-1,6-heptadiene-3,5-dione (6d)

Add 1.228g (5.25mmol) 6-(4-hydroxyl-3-methoxyphenyl)-5,6-hexene-2,4-dione (5b), 254mg (3.68mmol) in 150mL three-necked flask Boron oxide and 30.0 mL of ethyl acetate were installed with a reflux condensing device, and the reaction was stirred for 1 h at a constant temperature of 70°C in an oil bath. Then 500 mg (2.5 mmol) of (S)-2,3,4,9-tetrahydro-1H-pyridin[3,4-b]indole-3-carbaldehyde (4a) and 575 mg (2.5 mmol) of tributyl borate were added For ester, stir in an oil bath at a constant temperature of 85°C for 30min; slowly add 0.1ml (2.5mmol) of n-butylamine diluted in 10mL of ethyl acetate into the three-necked bottle within 30min, and continue to react for 1h in an oil bath at a constant temperature of 100°C, then Cool to room temperature; the reaction mixture was refluxed with 5 mL (1 mol/L) of hydrochloric acid and stirred at a constant temperature of 50°C for 30 min, allowed to stand, and the layers were fully separated, and the aqueous layer was extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with water until neutral, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, separated and purified by column chromatography (dichloromethane:methanol=25:1), and 208 mg (20%) of yellow Solid target compound.

Mp 103～104℃; (c=0.75, CH ₃ OH); ESI/MS (m/e) 415.5 [MH] ^- ; IR (KBr): 3238, 2363, 1703, 1590, 1512, 1451, 1331, 1277, 1215, 1160, 1124 , 1061, 969, 814, 742; ¹ HNMR (300MHz, DMSO-d6): δ=11.00(s, 1H), 9.43(s, 1H), 7.45(d, J=7.5Hz, 1H), 7.33(d , J=8.1Hz, 1H), 7.25(s, 1H), 7.15～7.06(m, 4H), 6.99(t, J=7.5Hz, 2H), 6.82(d, J=8.1Hz, 1H), 5.16 (s, 1H), 5.09(s, 1H), 4.52(s, 1H), 3.84(s, 3H), 3.45(d, J=6Hz, 2H), 2.94(s, 2H), 2.85(d, J =3.9Hz, 1H).

Example 16 Preparation of 1-(4-hydroxy-3-methoxyphenyl)-7-(9H-pyridine-3-[3,4-b]indolyl)-1,6-heptadiene-3 , 5-diketone (6e)

Add 1.228g (5.25mmol) 6-(4-hydroxyl-3-methoxyphenyl)-5,6-hexene-2,4-dione (5b), 254mg (3.68mmol) in 150mL three-necked flask Boron oxide and 30.0 mL of ethyl acetate were installed with a reflux condensing device, and the reaction was stirred for 1 h at a constant temperature of 70°C in an oil bath. Then add 490mg (2.5mmol) 9H-pyridine[3,4-b]indole-3-carboxaldehyde (4b) and 575mg (2.5mmol) tributyl borate, stir in an oil bath at a constant temperature of 85°C for 30min; dilute in 10mL acetic acid 0.1ml (2.5mmol) of n-butylamine in ethyl ester was slowly added dropwise to the three-necked flask within 30min, and the reaction was continued at 100°C oil bath for 1h, and then cooled to room temperature; the reaction mixture was washed with 5mL (1mol/L) of hydrochloric acid , reflux at a constant temperature of 50° C. and stir for 30 minutes, let stand, separate layers sufficiently, and extract the aqueous layer with ethyl acetate three times. The ethyl acetate layers were combined, washed with water until neutral, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, separated and purified by column chromatography (petroleum ether: acetone = 3:1), and 210 mg (20.4%) of a red solid was obtained target compound.

Mp 91°C; (c=0.14, CH ₃ OH); ESI/MS (m/e) 413.3 [M+H] ⁺ ; IR (KBr): 3750, 3285, 2361, 1629, 1574, 1512, 1454, 1372, 1338, 1273 , 1242, 1207, 1159, 1134, 1011, 957, 838, 733; ¹ HNMR (300MHz, DMSO-d6): δ=11.94(s, 1H), 9.71(s, 1H), 8.98(s, 1H), 8.50(s, 1H), 8.26(d, J=7.8Hz, 1H), 7.81(d, J=15.6Hz, 1H), 7.66～7.58(m, 3H), 7.32(f, J=6.6Hz, 2H ), 7.19(t, J=7.5Hz, 2H), 6.83(f, J=5.4Hz, 2H), 6.20(s, 1H), 3.85(s, 3H).

Example 17 Preparation of 1-(4-hydroxyl-3-methoxyphenyl)-7-(3-indolyl)-1,6-heptadiene-3,5-dione (6f)

Add 1.228g (5.25mmol) 6-(4-hydroxyl-3-methoxyphenyl)-5,6-hexene-2,4-dione (5b), 254mg (3.68mmol) in 150mL three-necked flask Boron oxide and 30.0 mL of ethyl acetate were installed with a reflux condensing device, and the reaction was stirred for 1 h at a constant temperature of 70°C in an oil bath. Then add 362.5mg (2.5mmol) indole-3-carboxaldehyde and 575mg (2.5mmol) tributyl borate, stir in an oil bath at a constant temperature of 85°C for 30min; dilute 0.1ml (2.5mmol) n-butyl The amine was slowly added dropwise to the three-necked flask within 30 minutes, and the reaction was continued for 1 hour at a constant temperature of 100°C oil bath, and then cooled to room temperature; the reaction mixture was reacted with 5mL (1mol/L) of hydrochloric acid at a constant temperature of 50°C for 30 minutes with reflux stirring, left to stand, fully The layers were separated, and the aqueous layer was extracted 3 times with ethyl acetate. The ethyl acetate layers were combined, washed with water until neutral, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, separated and purified by column chromatography (petroleum ether: acetone = 3:1), and 212.7 mg (25%) of red Solid target compound.

Mp 66～67℃; (c=0.45, CH ₃ OH); ESI/MS (m/e) 360 [MH] ^- ; IR (KBr): 3313, 2362, 1573, 1511, 1459, 1424, 1266, 1244, 1129, 1029, 961 , 741, 533; ¹ HNMR (300MHz, DMSO-d6): δ=11.85(s, 1H), 9.59(s, 1H), 8.01(t, J=2.4Hz, 1H), 7.91(d, J=15.9 Hz, 2H), 7.54(s, 1H), 7.49(f, J=4.5Hz, 1H), 7.31(d, J=1.8Hz, 1H), 7.23(m, 2H), 7.14(f, J=6.6 Hz, 1H), 6.85～6.69(m, 3H), 6.11(s, 1H), 3.85(s, 3H).

Example 18 Preparation of (S)-1-(3,5-dimethoxy-4-hydroxyphenyl)-7-(2,3,4,9-tetrahydro-1H-pyridine-3-[3, 4-b]indolyl)-1,6-heptadiene-3,5-dione (6g)

Add 1.386g (5.25mmol) 6-(4-hydroxyl-3,5-dimethoxyphenyl)-5,6-hexene-2,4-dione (5c), 254mg ( 3.68 mmol) of boron oxide and 30.0 mL of ethyl acetate were installed with a reflux condensing device, and stirred and reacted for 1 h at a constant temperature of 70° C. in an oil bath. Then 500 mg (2.5 mmol) of (S)-2,3,4,9-tetrahydro-1H-pyridin[3,4-b]indole-3-carbaldehyde (4a) and 575 mg (2.5 mmol) of tributyl borate were added For ester, stir in an oil bath at a constant temperature of 85°C for 30min; slowly add 183mg (2.5mmol) n-butylamine diluted in 10mL of ethyl acetate into the three-necked flask dropwise within 30min, continue the reaction in an oil bath at a constant temperature of 100°C for 1h, and then cool to room temperature; the reaction mixture was refluxed with 5 mL (1 mol/L) of hydrochloric acid and stirred at a constant temperature of 50°C for 30 min, allowed to stand, and the layers were fully separated, and the aqueous layer was extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with water until neutral, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, separated and purified by column chromatography (dichloromethane:methanol=25:1), and 267 mg (25.4%) of yellow Solid target compound.

Mp 114°C; (c=0.59, CH ₃ OH); ESI/MS (m/e) 445.5[MH] ^- ; IR (KBr): 3389, 1600, 1510, 1453, 1331, 1264, 1217, 1111, 743; ¹ HNMR ( 300MHz, DMSO-d6): δ=10.98(s, 1H), 8.74(s, 1H), 7.45(d, J=7.8Hz, 1H), 7.33(d, J=7.8Hz, 1H), 7.16～6.97 (m, 6H), 5.17(s, 1H), 5.06(t, J=5.7Hz, 1H), 4.90(f, J=15.6, 1H), 4.54(s, 1H), 3.83(s, 6H), 3.46(t, J=6.3, 2H), 2.95(s, 2H), 2.87(f, J=15.4, 1H).

Example 19 Preparation of 1-(3,5-dimethoxy-4-hydroxyphenyl)-7-(9H-pyridine-3-[3,4-b]indolyl)-1,6-heptanedi ene-3,5-dione (6h)

Add 1.386g (5.25mmol) 6-(4-hydroxyl-3,5-dimethoxyphenyl)-5,6-hexene-2,4-dione (5c), 254mg ( 3.68 mmol) of boron oxide and 30.0 mL of ethyl acetate were installed with a reflux condensing device, and stirred and reacted for 1 h at a constant temperature of 70° C. in an oil bath. Then add 490mg (2.5mmol) 9H-pyridine[3,4-b]indole-3-carboxaldehyde (4b) and 575mg (2.5mmol) tributyl borate, stir in an oil bath at a constant temperature of 85°C for 30min; dilute in 10mL acetic acid 0.1ml (2.5mmol) of n-butylamine in ethyl ester was slowly added dropwise to the three-necked flask within 30min, and the reaction was continued at 100°C oil bath for 1h, and then cooled to room temperature; the reaction mixture was washed with 5mL (1mol/L) of hydrochloric acid , reflux at a constant temperature of 50° C. and stir for 30 minutes, let stand, separate layers sufficiently, and extract the aqueous layer with ethyl acetate three times. The ethyl acetate layers were combined, washed with water until neutral, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, separated and purified by column chromatography (petroleum ether: acetone = 3:1), and 145 mg (13%) of a red solid was obtained target compound.

Mp 110°C; (c=0.65, CH ₃ OH); ESI/MS (m/e) 441.4[MH] ^- ; IR (KBr): 3351, 1598, 1509, 1457, 1333, 1214, 1112, 962, 824; ¹ HNMR ( 300MHz, DMSO-d6): δ=11.92(s, 1H), 9.01(d, J=14.7Hz, 2H), 8.50(s, 1H), 8.26(d, J=8.1Hz, 1H), 7.82(d , J=15.6Hz, 1H), 7.66～7.56(m, 3H), 7.31(t, J=7.2Hz, 1H), 7.19(d, J=15.3Hz, 1H), 7.06(s, 2H), 6.86 (d, J=15.9Hz, 1H), 6.21(s, 1H), 3.84(s, 6H).

Example 20 Preparation of 1-(3-pyridyl)-7-(2,3,4,9-tetrahydro-1H-pyridine-3-[3,4-b]indolyl)-1,6-heptyl Diene-3,5-dione (6i)

Add 496 mg (2.63 mmol) of 6-(3-pyridyl)-5,6-hexene-2,4-dione (5d), 127 mg (1.84 mmol) of boron oxide and 30.0 mL of acetic acid in a 150 mL three-necked flask Ethyl ester, equipped with a reflux condensing device, stirred and reacted for 1 h at a constant temperature of 70°C in an oil bath. Then 250 mg (1.25 mmol) of (S)-2,3,4,9-tetrahydro-1H-pyridin[3,4-b]indole-3-carbaldehyde (4a) and 288 mg (1.25 mmol) of tributyl borate were added For ester, stir in an oil bath at a constant temperature of 85°C for 30min; slowly add 0.1ml (2.5mmol) of n-butylamine diluted in 10mL of ethyl acetate into the three-necked bottle within 30min, and continue to react for 1h in an oil bath at a constant temperature of 100°C, then Cool to room temperature; the reaction mixture was refluxed with 2.5 mL (1 mol/L) of hydrochloric acid at a constant temperature of 50° C. and stirred for 30 min, allowed to stand, and the layers were fully separated. The aqueous layer was extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with water until neutral, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, separated and purified by column chromatography (dichloromethane:methanol=25:1), and 44 mg (9.5%) of yellow Solid target compound.

Mp 141～142℃; (c=0.71, CH ₃ OH); ESI/MS (m/e) 372.4 [M+H] ⁺ ; IR (KBr): 3054, 2875, 2360, 1591, 1512, 1452, 1326, 1298, 1265, 1164 , 1059, 742; ¹ HNMR (300MHz, DMSO-d6): δ=10.97(s, 1H), 8.85(s, 1H), 8.55(d, J=2.8Hz, 1H), 8.12(d, J=4.7 Hz, 1H), 7.54(s, 1H), 7.46(t, J=4.6Hz, 2H), 7.34(d, J=4.8Hz, 1H), 7.24(d, J=9.5Hz, 1H), 7.09( t, J=4.4Hz, 1H), 7.00(t, J=4.3Hz, 1H), 5.22(s, 1H), 5.04(t, J=6Hz, 1H), 4.95(f, J=8.6Hz, 1H ), 4.53(s, 1H), 3.44(t, J=4.3Hz, 2H), 2.93(s, 2H), 2.89(f, J=12.6Hz, 1H).

Example 21 Inhibition of tumor cell proliferation experiment

The compounds of the present invention were prepared in PBS containing 1% DMSO. A total of K562 (human chronic leukemia cells), HL60 (human promyelocytic leukemia cells), MCF-7 (human breast cancer cells), HepG2 (hepatocellular carcinoma cells), S180 (mouse ascites tumor cells), Mes -SA (human uterine sarcoma cells) six tumor cell lines.

HepG2, K562, MCF-7, HL60, S180, and Mes-SA cells in good growth state and in logarithmic growth phase were seeded in 96-well plates at a density of 2×10 ⁴ cells/mL, 100 μl per well. Cultivate in a 37° C., 5% CO ₂ incubator for 4 hours, add the sterilized compound of the present invention according to a preset concentration gradient, and add an equal volume of solvent for dissolving the sample in the control group. After continuing to culture for 48 hours, add 25 μl of MTT solution with a concentration of 5 mg/mL to each well, incubate at 37°C for 4 hours, carefully remove the supernatant (remove the supernatant after the suspended cells are centrifuged), and then add 100 μl DMSO (dimethylformazol) to each well. base sulfoxide), shake for about 15min to dissolve the precipitate. Immediately measure the OD (absorbance) value on a microplate reader at a wavelength of 570 nm. Calculate the tumor inhibition rate and IC ₅₀ . The results are listed in Table 1. The results show that the compounds of the present invention have a definite inhibitory effect on tumor cell proliferation, except for compound 6i which has no significant inhibitory effect on MCF-7 (IC ₅₀ greater than 100 μmol/L), all of them have cytotoxic activity on the above tumor cell lines.

Anti-tumor cell proliferation activity of Table 16a-i ( _IC50 ±SDμM) ^a

Doxorubicin is represented by A, Cur=curcumin, n=6.

Example 22 Antitumor activity of compound 6a-i on _S180 mouse model

Under sterile conditions, take the S180 sarcoma inoculated in ICR mice for 7-10 days, add appropriate amount of normal saline to prepare tumor cell suspension, the number of cells is 2×10 ⁷ /ml, and inoculate it under the skin of the forelimb armpit of healthy male ICR mice. Each mouse was injected with 0.2ml. 24 hours after tumor inoculation, the mice in the treatment group were intraperitoneally injected with 0.2 ml of the aqueous solution of the compound of the present invention daily at a dose of 2 μmol/kg. The mice in the blank group were intraperitoneally injected with 0.2 ml of normal saline daily. On the 8th day of the experiment, the mice were weighed, and the tumors of the mice in each group were dissected and weighed, and finally the tumor inhibition rate of the animals in each group was counted. The curative effect of solid tumor is expressed by tumor weight inhibition percentage, calculated as follows: tumor weight inhibition rate%=(1-tumor weight of administration group/tumor weight of blank group)×100%. The results are listed in Table 2. The results showed that compounds 6a, 6b, 6c, 6d, 6h, and 6i had obvious antitumor effects in vivo, and their tumor inhibition rates were 34.38%, 25.09%, 24.92%, 42.87%, 19.61%, and 23.89%, respectively.

Table 26a-i In vivo anti-tumor proliferation activity

tumor reuse Indicates, n=10; a) p<0.001 compared with normal saline; b) compared with normal saline

p<0.01 compared with water; c) p<0.001 compared with normal saline, p<0.05 compared with curcumin.

The above-mentioned embodiments are only descriptions of preferred implementations of the present invention, and are not intended to limit the scope of the present invention. Variations and improvements should fall within the scope of protection defined by the claims of the present invention.

Claims (3)

1. a general formula is the compound of I:

In formula,

R ₁for 3-indyl, R ₂it is 2,3,4,9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl;

R ₁for 4-hydroxy 3-methoxybenzene base, R ₂it is 2,3,4,9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl;

R ₁for 3-pyridyl, R ₂it is 2,3,4,9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl.

2. prepare a method for compound according to claim 1, it is characterized in that comprising the following steps:

(1) under 12-I-53-acetoxyl periodate (DMP) and sodium bicarbonate exist, solvent is made by (S)-2 with tetrahydrofuran (THF) (THF), 3,4,9-tetrahydrochysene-1H-pyridine [3,4-b] indole-3-carbinol is oxidized to (S)-2,3,4,9-tetrahydrochysene-1H-pyridine [3,4-b] indole-3-formaldehyde;

(2) by (S)-2,3,4,9-tetrahydrochysene-1H-pyridine [3,4-b] indole-3-formaldehyde and 3-methoxy-4-hydroxybenzaldehyde, 1H-indole-3-formaldehyde, pyridine-3-formaldehyde by diacetylmethane coupling, obtain compound according to claim 1.

3. the purposes of compound according to claim 1 in preparation tumor.