CN102807566A - 1,7-diaryl-1,6-trans-diene-3,5-diketone as well as preparation method and application thereof - Google Patents
1,7-diaryl-1,6-trans-diene-3,5-diketone as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a 1,7-diaryl-1,6-trans-diene-3,5-diketone compound, namely a compound 6(a-i) represented by a general formula I as well as a preparation method of the 1,7-diaryl-1,6-trans-diene-3,5-diketone compound and an application of the 1,7-diaryl-1,6-trans-diene-3,5-diketone compound to preparation of a medicament for treating tumor. The tumor resistant activity of the 1,7-diaryl-1,6-trans-diene-3,5-diketone compound is evaluated on a mouse S180 model; and the experiment result shows that the compound 6(a-i) has an excellent tumor resisting action and can be applied to production of preparing a tumor-resistant medicament.
Description
Technical field
The present invention relates to a kind of compound of synthetic, particularly relate to one type 1,7-diaryl-1,6-trans diene-3, the 5-dione compounds the invention still further relates to its preparation method and the application in preparation medicine for treating tumor thing.
Background technology
Malignant tumour is a kind of common disease and frequently-occurring disease of serious threat human health, and the mortality ratio that the mankind cause because of malignant tumour is second of all disease death rates, is only second to cardiovascular and cerebrovascular diseases.The tumor treatment method has operative treatment, radiotherapy and pharmacological agent (chemotherapy).At present, chemotherapy remains the main means of clinical treatment tumour, and seeking antitumor drug is one of focus of new drug research.Curcumine is the natural product with anti-tumor activity.The contriver recognizes through the transformation to natural product, can find the better natural product verivate of new anti-tumor activity.See 1 from Structural Interrelationship, 7-diaryl-1,6-trans diene-3,5-diketone are the analogs of curcumine, possibly expand the anti-tumor activity of curcumine.According to this conception, the contriver proposes the present invention.
Summary of the invention
First technical problem that the present invention will solve is that the compound (6a-i) of general formula I is provided:
In the formula, R
1Be 3-indyl, R
2Be 2,3,4,9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl, R
1Be 3-indyl, R
2Be 9H-pyridine-3-[3,4-b] indyl, R
1Be 3-indyl, R
2Be 3-indyl, R
1Be 4-hydroxy 3-methoxybenzene base, R
2Be 2,3,4,9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl, R
1Be 4-hydroxy 3-methoxybenzene base, R
2Be 9H-pyridine-3-[3,4-b] indyl, R
1Be 4-hydroxy 3-methoxybenzene base, R
2Be 3-indyl, R
1Be 3,5-dimethoxy-4 '-hydroxy phenyl, R
2Be 2,3,4,9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl, R
1Be 3,5-dimethoxy-4 '-hydroxy phenyl, R
2Be 9H-pyridine-3-[3,4-b] indyl, R
1Be 3-pyridyl, R
2Be 2,3,4,9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl.
Compound (6a-i) to the representative of synthetic general formula I is numbered: R among the 6a
1Be 3-indyl, R
2Be 2,3,4, R among 9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl, the 6b
1Be 3-indyl, R
2Be R among 9H-pyridine-3-[3,4-b] indyl, the 6c
1Be 3-indyl, R
2Be R among 3-indyl, the 6d
1Be 4-hydroxy 3-methoxybenzene base, R
2Be 2,3,4, R among 9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl, the 6e
1Be 4-hydroxy 3-methoxybenzene base, R
2Be R among 9H-pyridine-3-[3,4-b] indyl, the 6f
1Be 4-hydroxy 3-methoxybenzene base, R
2Be R among 3-indyl, the 6g
1Be 3,5-dimethoxy-4 '-hydroxy phenyl, R
2Be 2,3,4, R among 9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl, the 6h
1Be 3,5-dimethoxy-4 '-hydroxy phenyl, R
2Be R among 9H-pyridine-3-[3,4-b] indyl, the 6i
1Be 3-pyridyl, R
2Be 2,3,4,9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl.
More than numbering is just described for ease, does not have any limited significance to invention.
Second technical problem that the present invention will solve provides the preparation method of general formula compound 6a-i, and this method comprises:
(1) in the presence of 12-I-53-acetoxyl periodate (DMP) and sodium hydrogencarbonate, makes solvent with (S)-2,3,4 with THF (THF); 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) in the presence of 12-I-53-acetoxyl periodate (DMP) and sodium hydrogencarbonate, make solvent 9H-pyridine [3,4-b] indole-3-carbinol is oxidized to 9H-pyridine [3,4-b] indole-3-formaldehyde with THF (THF);
(3) with (S)-2,3,4; 9-tetrahydrochysene-1H-pyridine [3,4-b] indole-3-formaldehyde, 9H-pyridine [3,4-b] indole-3-formaldehyde and 1H-indole-3-formaldehyde and 4-hydroxy 3-methoxybenzene formaldehyde, 1H-indole-3-formaldehyde, 3; 5-dimethoxy-4 '-hydroxy benzaldehyde, pyridine-3-formaldehyde prepare 1,7-diaryl-1 through the diacetylmethane coupling; 6-trans diene-3, the 5-diketone promptly gets.
This preparation method can use the route of Fig. 1, Fig. 2 to summarize.
The 3rd technical problem that the present invention will solve provided the application of said compound in preparation medicine for treating tumor thing.
The 4th technical problem that the present invention will solve is at mouse S
180Estimate the anti-tumor activity of The compounds of this invention on the model.
Description of drawings
Fig. 1 is (S)-2,3,4, the synthetic route chart of 9-tetrahydrochysene-1H-pyridine [3,4-b] indole-3-formaldehydes (4a) and 9H-pyridine [3,4-b] indole-3-formaldehydes (4b);
I) dilute sulphuric acid, formaldehyde, H
2O; Ii) SOCl
2, MeOH; Iii) KMnO
4, DMF; Iv) NaBH
4, THF; V) DMP, NaHCO
3, THF
Fig. 2 is 1,7-diaryl-1,6-trans diene-3, the synthetic route chart of 5-diketone (6a-i).
4c is an indole-3-formaldehyde, and 4d is a Vanillin, and 4e is a syringic aldehyde, and 4f is pyridine-3-formaldehyde;
i)B
2O
3，(nBuO)
3B，nBu-NH
2，1NHCl；ii)B
2O
3，(nBuO)
3B，nBu-NH
2，1NHCl；
Embodiment
Following examples and testing data are done more detailed explanation to the present invention is above-mentioned with other technical characterictic and advantage.
Embodiment 1 preparation (S)-2,3,4,9-tetrahydrochysene-1H-pyridine [3,4-b] Indole-3-Carboxylic Acids (1)
In 1000ml eggplant bottle, add 800ml water, the 0.4ml vitriol oil and 10g (49mmol) L-tryptophane, be stirred to the L-tryptophane and all dissolve back adding formaldehyde solution 15ml, behind the reaction 6-7, the adularescent solid is separated out, and transfers PH=7 with strong aqua, leaves standstill after-filtration.Obtain 10.440g (98%) colorless solid target compound.
Embodiment 2 preparation (S)-2,3,4,9-tetrahydrochysene-1H-pyridine [3,4-b] indole-3-carboxylic acid methyl esters (2a)
Adding 100ml methyl alcohol cryosel dropwise drips the 13ml thionyl chloride under bathing in 250ml eggplant bottle, behind the stirring 30min, slowly adds 10g (45.8mmol) (S)-2,3; 4,9-tetrahydrochysene-1H-pyridine [3,4-b] Indole-3-Carboxylic Acids (1), (S)-2 behind the reaction 9-10h; 3,4,9-tetrahydrochysene-1H-pyridine [3; 4-b] all dissolvings of Indole-3-Carboxylic Acid (1), reaction solution is drained, add ether and filter.The aqueous solution modulation PH=8 that adds saturated sodium bicarbonate after filter cake suspends with ETHYLE ACETATE, extraction.The washing of ester layer is extremely neutral, anhydrous sodium sulfate drying, and filtration, filtrate decompression are concentrated into dried, column chromatographic isolation and purification (sherwood oil: acetone=2: 1) obtain 3.982g (36%) colorless solid target compound.
Embodiment 3 preparation 9H-pyridine [3,4-b] indole-3-carboxylic acid methyl esters (2b)
In 250ml eggplant bottle, add 4g (17.2mmol) (S)-2,3,4; 9-tetrahydrochysene-1H-pyridine [3; 4-b] indole-3-carboxylic acid methyl ester (2a), cryosel is bathed down and is added DMF (NN-N) with its dissolving, repeatedly adds 3.804g (24.1mmol) potassium permanganate on a small quantity; Adding ethanol 50ml stirs 30min behind the reaction 30min, reaction solution is poured in the watch-glass dry up.Wear away with THF (THF), collect washing lotion, washing lotion is evaporated to dried, washes with the ether bubble, filters and obtains 1.477g (38%) faint yellow solid target compound.
Embodiment 4 preparation (S)-2,3,4,9-tetrahydrochysene-1H-pyridine [3,4-b] indole-3-carbinols (3a)
In 250ml eggplant bottle, add 4g (17.2mmol) (S)-2,3,4,9-tetrahydrochysene-1H-pyridine [3,4-b] indole-3-carboxylic acid methyl esters (2a) with THF, dissolve with methanol after, repeatedly add 3.268g (86mmol) Peng Qinghuana under the ice bath on a small quantity, reaction 9-10h, TLC monitoring.After reaction finishes, add saturated aqueous potassium hydrogen sulfate and transfer PH=5, reaction solution is evaporated to removes THF, and reaction solution transfers to PH=8 with saturated sodium bicarbonate again, ethyl acetate extraction.The washing of ester layer is extremely neutral, anhydrous sodium sulfate drying, and filtration, filtrate decompression are concentrated into dried.Obtain 868mg (25%) colorless solid target compound.
Embodiment 5 preparation 9H-pyridine [3,4-b] indole-3-carbinols (3b)
In 250ml eggplant bottle, add 4g (17.7mmol) 9H-pyridine [3,4-b] indole-3-carboxylic acid methyl esters (2b) with THF, dissolve with methanol after, repeatedly add 3.36g (88.5mmol) Peng Qinghuana under the ice bath on a small quantity, reaction 9-10h, TLC monitoring.After reaction finishes, add saturated aqueous potassium hydrogen sulfate and transfer PH=5, reaction solution is evaporated to removes THF, and reaction solution transfers to PH=8 with saturated sodium bicarbonate again, ethyl acetate extraction.The washing of ester layer is extremely neutral, anhydrous sodium sulfate drying, and filtration, filtrate decompression are concentrated into dried.Obtain 708mg (20%) colorless solid target compound.
Embodiment 6 preparation (S)-2,3,4,9-tetrahydrochysene-1H-pyridine [3,4-b] indole-3-formaldehydes (4a)
In 250ml eggplant bottle, add 2g (9.9mmol) (S)-2; 3,4,9-tetrahydrochysene-1H-pyridine [3; 4-b] indole-3-carbinol (3a), 998mg (11.8mmol) sodium hydrogencarbonate dissolve with THF; Ice bath slowly adds 5.876g (13.7mmol) DMP (dess-martin oxygenant), reaction 9-10h, TLC monitoring down.After reaction finishes, filter.Filtrate decompression is concentrated into dried, separates with preparation type TLC plate.Obtain 594mg (30%) deep yellow solid target thing.
Embodiment 7 preparation 9H-pyridine [3,4-b] indole-3-formaldehydes (4b)
In 250ml eggplant bottle, add 2g (10mmol) 9H-pyridine [3; 4-b] indole-3-carbinol (3b), 1.008g (12mmol) sodium hydrogencarbonate dissolve with THF; Ice bath slowly adds 5.936g (14mmol) DMP (dess-martin oxygenant), reaction 9-10h, TLC monitoring down.After reaction finishes, filter.Filtrate decompression is concentrated into dried, silica gel column chromatography separating purification (sherwood oil: acetone=6: 1), obtain 803mg (41%) faint yellow solid target compound.
Embodiment 8 preparation 4-(3-indyl)-5,6-hexene-2,4-diketone (5a)
In the 150mL three-necked bottle, add the ETHYLE ACETATE of 10.58ml (102.9mmol) methyl ethyl diketone, 5.0g (72.1mmol) boron oxide and 50.0mL, load onto reflux condensate device, oil bath constant temperature stirs 1h down for 70 ℃.Add 4.973g (34.3mmol) indoles 3-formaldehyde and 4.8ml (34.3mmol) tributyl borate then, oil bath constant temperature stirs 30min for 85 ℃; 1.8mL (41.1mmol) n-Butyl Amine 99 that continuation will be diluted in the 10mL ETHYLE ACETATE slowly is added drop-wise in 30min in the three-necked bottle, and 100 ℃ of oil bath isothermal reaction 1h are cooled to room temperature then; In reaction flask, drip the hydrochloric acid of 36mL (1mol/L), 50 ℃ of refluxing and stirring 30min of constant temperature leave standstill, fully layering, and water layer is with ethyl acetate extraction 3 times.Merge the vinyl acetic monomer layer, washing is extremely neutral, anhydrous sodium sulfate drying, and filtration, filtrate decompression are concentrated into dried, silica gel column chromatography separating purification (sherwood oil: acetone=5: 1), obtain 1.713g (22%) yellow solid target compound.
Embodiment 9 preparation 6-(4-hydroxyl-3-methoxyphenyl)-5,6-hexene-2,4-diketone (5b)
In the 150mL three-necked bottle, add the ETHYLE ACETATE of 10.58ml (102.9mmol) methyl ethyl diketone, 5.0g (72.1mmol) boron oxide and 50.0mL, load onto reflux condensate device, oil bath constant temperature stirs 1h down for 70 ℃.Add 5.2g (34.3mmol) Vanillin and 4.8ml (34.3mmol) tributyl borate then, oil bath constant temperature stirs 30min for 85 ℃; 1.8mL (41.1mmol) n-Butyl Amine 99 that continuation will be diluted in the 10mL ETHYLE ACETATE slowly is added drop-wise in 30min in the three-necked bottle, and 100 ℃ of oil bath isothermal reaction 1h are cooled to room temperature then; In reaction flask, drip the hydrochloric acid of 36mL (1mol/L), 50 ℃ of refluxing and stirring 30min of constant temperature leave standstill, fully layering, and water layer is with ethyl acetate extraction 3 times.Merge the vinyl acetic monomer layer, washing is extremely neutral, anhydrous sodium sulfate drying, and filtration, filtrate decompression are concentrated into dried, silica gel column chromatography separating purification (sherwood oil: acetone=5: 1), obtain 3.66g (48%) yellow solid target compound.
Embodiment 10 preparation 6-(4-hydroxyl-3,5-dimethoxy phenyl)-5,6-hexene-2,4-diketone (5c)
In the 150mL three-necked bottle, add the ETHYLE ACETATE of 10.58ml (102.9mmol) methyl ethyl diketone, 5.0g (72.1mmol) boron oxide and 50.0mL, load onto reflux condensate device, oil bath constant temperature stirs 1h down for 70 ℃.Add 6.2g (34.3mmol) syringic aldehyde and 4.8ml (34.3mmol) tributyl borate then, oil bath constant temperature stirs 30min for 85 ℃; Continuation will be diluted in the 10mL ETHYLE ACETATE (1.8mL, 41.1mmol) n-Butyl Amine 99 slowly is added drop-wise in 30min in the three-necked bottle, 100 ℃ of oil bath isothermal reaction 1h are cooled to room temperature then; In reaction flask, drip the hydrochloric acid of 36mL (1mol/L), 50 ℃ of refluxing and stirring 30min of constant temperature leave standstill, fully layering, and water layer is with ethyl acetate extraction 3 times.Merge the vinyl acetic monomer layer, washing is extremely neutral, anhydrous sodium sulfate drying, and filtration, filtrate decompression are concentrated into dried, silica gel column chromatography separating purification (sherwood oil: acetone=4: 1), obtain 2.77g (31%) yellow solid target compound.
Embodiment 11 preparation 6-(3-pyridyl)-5,6-hexene-2,4-diketone (5d)
In the 150mL three-necked bottle, add the ETHYLE ACETATE of 10.58ml (102.9mmol) methyl ethyl diketone, 5.0g (72.1mmol) boron oxide and 50.0mL, load onto reflux condensate device, oil bath constant temperature stirs 1h down for 70 ℃.Add 3.7g (34.3mmol) pyridine 3-formaldehyde and 4.8ml (34.3mmol) tributyl borate then, oil bath constant temperature stirs 30min for 85 ℃; 1.8mL (41.1mmol) n-Butyl Amine 99 that continuation will be diluted in the 10mL ETHYLE ACETATE slowly is added drop-wise in 30min in the three-necked bottle, and 100 ℃ of oil bath isothermal reaction 1h are cooled to room temperature then; In reaction flask, drip the hydrochloric acid of 36mL (1mol/L), 50 ℃ of refluxing and stirring 30min of constant temperature leave standstill, fully layering, and water layer is with ethyl acetate extraction 3 times.Merge the vinyl acetic monomer layer, washing is extremely neutral, anhydrous sodium sulfate drying, and filtration, filtrate decompression are concentrated into dried, silica gel column chromatography separating purification (sherwood oil: acetone=6: 1), obtain 0.59g (9.2%) yellow solid target compound.
Embodiment 12 preparation 1-(3-indyl)-7-(2,3,4,9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl)-1,6-heptadiene-3,5-diketone (6a)
In the 150mL three-necked bottle, add 1.191g (5.25mmol) 4-(3-indyl)-5,6-hexene-2, the ETHYLE ACETATE of 4-diketone (5a), 254mg (3.68mmol) boron oxide and 30.0mL is loaded onto reflux condensate device, 70 ℃ of following stirring reaction 1h of oil bath constant temperature.Add 500mg (2.5mmol) then (S)-2,3,4,9-tetrahydrochysene-1H-pyridine [3,4-b] indole-3-formaldehydes (4a) and 575mg (2.5mmol) tributyl borate, oil bath constant temperature stirs 30min for 85 ℃; 0.1ml (2.5mmol) n-Butyl Amine 99 that is diluted in the 10mL ETHYLE ACETATE slowly is added drop-wise in 30min in the three-necked bottle, and 100 ℃ of oil bath constant temperature continue reaction 1h, are cooled to room temperature then; Reaction mixture is with the hydrochloric acid of 5mL (1mol/L), and 50 ℃ of refluxing and stirring reactions of constant temperature 30min leaves standstill, fully layering, and water layer is with ethyl acetate extraction 3 times.Merge the vinyl acetic monomer layer, washing is extremely neutral, anhydrous sodium sulfate drying, and filtration, filtrate decompression are concentrated into dried, column chromatographic isolation and purification (methylene dichloride: methyl alcohol=25: 1), obtain 94mg (9%) yellow solid target compound.
Mp?116℃；
(c＝0.14，CH
3OH)；ESI/MS(m/e)409[M-H]
-；IR(KBr)：3218，1618，1567，1449，1328，1264，1217，1057，963；
1HNMR(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).
Embodiment 13 preparation 1-(3-indyl)-7-(9H-pyridine-3-[3,4-b] indyl)-1,6-heptadiene-3,5-diketone (6b)
In the 150mL three-necked bottle, add 1.191g (5.25mmol) 4-(3-indyl)-5,6-hexene-2, the ETHYLE ACETATE of 4-diketone (5a), 254mg (3.68mmol) boron oxide and 30.0mL is loaded onto reflux condensate device, 70 ℃ of following stirring reaction 1h of oil bath constant temperature.Add 490mg (2.5mmol) 9H-pyridine [3,4-b] indole-3-formaldehydes (4b) and 575mg (2.5mmol) tributyl borate then, oil bath constant temperature stirs 30min for 85 ℃; 0.1ml (2.5mmol) n-Butyl Amine 99 that is diluted in the 10mL ETHYLE ACETATE slowly is added drop-wise in 30min in the three-necked bottle, and 100 ℃ of oil bath constant temperature continue reaction 1h, are cooled to room temperature then; Reaction mixture is with the hydrochloric acid of 5mL (1mol/L), and 50 ℃ of refluxing and stirring reactions of constant temperature 30min leaves standstill, fully layering, and water layer is with ethyl acetate extraction 3 times.Merge the vinyl acetic monomer layer, washing is extremely neutral, anhydrous sodium sulfate drying, and filtration, filtrate decompression are concentrated into dried, column chromatographic isolation and purification (sherwood oil: acetone=3: 1), obtain 124mg (12%) red solid target compound.
Mp?87.1～87.9℃；
(c＝0.13，CH
3OH)；ESI/MS(m/e)404.4[M-H]
-；IR(KBr)：3210，1614，1567，1499，1430，1341，1245，1126，953，740；
1HNMR(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).
Embodiment 14 preparations 1, two (the 3-indyls)-1 of 7-, 6-heptadiene-3,5-diketone (6c)
In the 500mL three-necked bottle, add the ETHYLE ACETATE of 5g (50mmol) methyl ethyl diketone, 2.415g (35mmol) boron oxide and 250.0mL, load onto reflux condensate device, oil bath constant temperature stirs 1h down for 70 ℃.Add 15.95g (110mmol) indoles 3-formaldehyde and 25.3g (110mmol) tributyl borate then, oil bath constant temperature stirs 30min for 85 ℃; 4.4ml (110mmol) n-Butyl Amine 99 that continuation will be diluted in the 10mL ETHYLE ACETATE slowly is added drop-wise in 30min in the three-necked bottle, and 100 ℃ of oil bath isothermal reaction 1h are cooled to room temperature then; In reaction flask, drip the hydrochloric acid of 220mL (1mol/L), 50 ℃ of refluxing and stirring 30min of constant temperature leave standstill, fully layering, and water layer is with ethyl acetate extraction 3 times.Merge the vinyl acetic monomer layer, washing is extremely neutral, anhydrous sodium sulfate drying, and filtration, filtrate decompression are concentrated into dried, silica gel column chromatography separating purification (sherwood oil: acetone=3: 1), obtain 503mg (3%) red solid target compound.
Mp?74～75℃；
(c＝0.30，CH
3OH)；ESI/MS(m/e)353.4[M-H]
-；IR(KBr)：3735，3391，2360，11610，1572，1509，1419，1293，1245，1131，1104，959，740；
1HNMR(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).
Embodiment 15 preparation (S)-1-(4-hydroxy 3-methoxybenzene base)-7-(2,3,4,9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl)-1,6-heptadiene-3,5-diketone (6d)
In the 150mL three-necked bottle, add 1.228g (5.25mmol) 6-(4-hydroxyl-3-methoxyphenyl)-5; 6-hexene-2; The ETHYLE ACETATE of 4-diketone (5b), 254mg (3.68mmol) boron oxide and 30.0mL is loaded onto reflux condensate device, 70 ℃ of following stirring reaction 1h of oil bath constant temperature.Add 500mg (2.5mmol) then (S)-2,3,4,9-tetrahydrochysene-1H-pyridine [3,4-b] indole-3-formaldehydes (4a) and 575mg (2.5mmol) tributyl borate, oil bath constant temperature stirs 30min for 85 ℃; 0.1ml (2.5mmol) n-Butyl Amine 99 that is diluted in the 10mL ETHYLE ACETATE slowly is added drop-wise in 30min in the three-necked bottle, and 100 ℃ of oil bath constant temperature continue reaction 1h, are cooled to room temperature then; Reaction mixture is with the hydrochloric acid of 5mL (1mol/L), and 50 ℃ of refluxing and stirring reactions of constant temperature 30min leaves standstill, fully layering, and water layer is with ethyl acetate extraction 3 times.Merge the vinyl acetic monomer layer, washing is extremely neutral, anhydrous sodium sulfate drying, and filtration, filtrate decompression are concentrated into dried, column chromatographic isolation and purification (methylene dichloride: methyl alcohol=25: 1), obtain 208mg (20%) yellow solid target compound.
Mp?103～104℃；
(c＝0.75，CH
3OH)；ESI/MS(m/e)415.5[M-H]
-；IR(KBr)：3238，2363，1703，1590，1512，1451，1331，1277，1215，1160，1124，1061，969，814，742；
1HNMR(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).
Embodiment 16 preparation 1-(4-hydroxy 3-methoxybenzene base)-7-(9H-pyridine-3-[3,4-b] indyl)-1,6-heptadiene-3,5-diketone (6e)
In the 150mL three-necked bottle, add 1.228g (5.25mmol) 6-(4-hydroxyl-3-methoxyphenyl)-5; 6-hexene-2; The ETHYLE ACETATE of 4-diketone (5b), 254mg (3.68mmol) boron oxide and 30.0mL is loaded onto reflux condensate device, 70 ℃ of following stirring reaction 1h of oil bath constant temperature.Add 490mg (2.5mmol) 9H-pyridine [3,4-b] indole-3-formaldehydes (4b) and 575mg (2.5mmol) tributyl borate then, oil bath constant temperature stirs 30min for 85 ℃; 0.1ml (2.5mmol) n-Butyl Amine 99 that is diluted in the 10mL ETHYLE ACETATE slowly is added drop-wise in 30min in the three-necked bottle, and 100 ℃ of oil bath constant temperature continue reaction 1h, are cooled to room temperature then; Reaction mixture is with the hydrochloric acid of 5mL (1mol/L), and 50 ℃ of refluxing and stirring reactions of constant temperature 30min leaves standstill, fully layering, and water layer is with ethyl acetate extraction 3 times.Merge the vinyl acetic monomer layer, washing is extremely neutral, anhydrous sodium sulfate drying, and filtration, filtrate decompression are concentrated into dried, column chromatographic isolation and purification (sherwood oil: acetone=3: 1), obtain 210mg (20.4%) red solid target compound.
Mp?91℃；
(c＝0.14，CH
3OH)；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；
1HNMR(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).
Embodiment 17 preparation 1-(4-hydroxy 3-methoxybenzene base)-7-(3-indyl)-1,6-heptadiene-3,5-diketone (6f)
In the 150mL three-necked bottle, add 1.228g (5.25mmol) 6-(4-hydroxyl-3-methoxyphenyl)-5; 6-hexene-2; The ETHYLE ACETATE of 4-diketone (5b), 254mg (3.68mmol) boron oxide and 30.0mL is loaded onto reflux condensate device, 70 ℃ of following stirring reaction 1h of oil bath constant temperature.Add 362.5mg (2.5mmol) indole-3-formaldehyde and 575mg (2.5mmol) tributyl borate then, oil bath constant temperature stirs 30min for 85 ℃; 0.1ml (2.5mmol) n-Butyl Amine 99 that is diluted in the 10mL ETHYLE ACETATE slowly is added drop-wise in 30min in the three-necked bottle, and 100C oil bath constant temperature continues reaction 1h, is cooled to room temperature then; Reaction mixture is with the hydrochloric acid of 5mL (1mol/L), and 50 ℃ of refluxing and stirring reactions of constant temperature 30min leaves standstill, fully layering, and water layer is with ethyl acetate extraction 3 times.Merge the vinyl acetic monomer layer, washing is extremely neutral, anhydrous sodium sulfate drying, and filtration, filtrate decompression are concentrated into dried, column chromatographic isolation and purification (sherwood oil: acetone=3: 1), obtain 212.7mg (25%) red solid target compound.
Mp?66～67℃；
(c＝0.45，CH
3OH)；ESI/MS(m/e)360[M-H]
-；IR(KBr)：3313，2362，1573，1511，1459，1424，1266，1244，1129，1029，961，741，533；
1HNMR(300MHz，DMSO-d6)：δ＝11.85(s，1H)，9.59(s，1H)，8.01(t，J＝2.4Hz，1H)，7.91(d，J＝15.9Hz，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＝6.6Hz，1H)，6.85～6.69(m，3H)，6.11(s，1H)，3.85(s，3H).
Embodiment 18 preparation (S)-1-(3,5-dimethoxy-4 '-hydroxy phenyl)-7-(2,3,4,9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl)-1,6-heptadiene-3,5-diketone (6g)
In the 150mL three-necked bottle, add 1.386g (5.25mmol) 6-(4-hydroxyl-3; The 5-dimethoxy phenyl)-5,6-hexene-2, the ETHYLE ACETATE of 4-diketone (5c), 254mg (3.68mmol) boron oxide and 30.0mL; Load onto reflux condensate device, 70 ℃ of following stirring reaction 1h of oil bath constant temperature.Add 500mg (2.5mmol) then (S)-2,3,4,9-tetrahydrochysene-1H-pyridine [3,4-b] indole-3-formaldehydes (4a) and 575mg (2.5mmol) tributyl borate, oil bath constant temperature stirs 30min for 85 ℃; 183mg (2.5mmol) n-Butyl Amine 99 that is diluted in the 10mL ETHYLE ACETATE slowly is added drop-wise in 30min in the three-necked bottle, and 100 ℃ of oil bath constant temperature continue reaction 1h, are cooled to room temperature then; Reaction mixture is with the hydrochloric acid of 5mL (1mol/L), and 50 ℃ of refluxing and stirring reactions of constant temperature 30min leaves standstill, fully layering, and water layer is with ethyl acetate extraction 3 times.Merge the vinyl acetic monomer layer, washing is extremely neutral, anhydrous sodium sulfate drying, and filtration, filtrate decompression are concentrated into dried, column chromatographic isolation and purification (methylene dichloride: methyl alcohol=25: 1), obtain 267mg (25.4%) yellow solid target compound.
Mp?114℃；
(c＝0.59，CH
3OH)；ESI/MS(m/e)445.5[M-H]
-；IR(KBr)：3389，1600，1510，1453，1331，1264，1217，1111，743；
1HNMR(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).
Embodiment 19 preparation 1-(3,5-dimethoxy-4 '-hydroxy phenyl)-7-(9H-pyridine-3-[3,4-b] indyl)-1,6-heptadiene-3,5-diketone (6h)
In the 150mL three-necked bottle, add 1.386g (5.25mmol) 6-(4-hydroxyl-3; The 5-dimethoxy phenyl)-5,6-hexene-2, the ETHYLE ACETATE of 4-diketone (5c), 254mg (3.68mmol) boron oxide and 30.0mL; Load onto reflux condensate device, 70 ℃ of following stirring reaction 1h of oil bath constant temperature.Add 490mg (2.5mmol) 9H-pyridine [3,4-b] indole-3-formaldehydes (4b) and 575mg (2.5mmol) tributyl borate then, oil bath constant temperature stirs 30min for 85 ℃; 0.1ml (2.5mmol) n-Butyl Amine 99 that is diluted in the 10mL ETHYLE ACETATE slowly is added drop-wise in 30min in the three-necked bottle, and 100 ℃ of oil bath constant temperature continue reaction 1h, are cooled to room temperature then; Reaction mixture is with the hydrochloric acid of 5mL (1mol/L), and 50 ℃ of refluxing and stirring reactions of constant temperature 30min leaves standstill, fully layering, and water layer is with ethyl acetate extraction 3 times.Merge the vinyl acetic monomer layer, washing is extremely neutral, anhydrous sodium sulfate drying, and filtration, filtrate decompression are concentrated into dried, column chromatographic isolation and purification (sherwood oil: acetone=3: 1), obtain 145mg (13%) red solid target compound.
Mp?110℃；
(c＝0.65，CH
3OH)；ESI/MS(m/e)441.4[M-H]
-；IR(KBr)：3351，1598，1509，1457，1333，1214，1112，962，824；
1HNMR(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).
Embodiment 20 preparation 1-(3-pyridyl)-7-(2,3,4,9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl)-1,6-heptadiene-3,5-diketone (6i)
In the 150mL three-necked bottle, add 496mg (2.63mmol) 6-(3-pyridyl)-5,6-hexene-2, the ETHYLE ACETATE of 4-diketone (5d), 127mg (1.84mmol) boron oxide and 30.0mL is loaded onto reflux condensate device, 70 ℃ of following stirring reaction 1h of oil bath constant temperature.Add 250mg (1.25mmol) then (S)-2,3,4,9-tetrahydrochysene-1H-pyridine [3,4-b] indole-3-formaldehydes (4a) and 288mg (1.25mmol) tributyl borate, oil bath constant temperature stirs 30min for 85 ℃; 0.1ml (2.5mmol) n-Butyl Amine 99 that is diluted in the 10mL ETHYLE ACETATE slowly is added drop-wise in 30min in the three-necked bottle, and 100 ℃ of oil bath constant temperature continue reaction 1h, are cooled to room temperature then; Reaction mixture is with the hydrochloric acid of 2.5mL (1mol/L), and 50 ℃ of refluxing and stirring reactions of constant temperature 30min leaves standstill, fully layering, and water layer is with ethyl acetate extraction 3 times.Merge the vinyl acetic monomer layer, washing is extremely neutral, anhydrous sodium sulfate drying, and filtration, filtrate decompression are concentrated into dried, column chromatographic isolation and purification (methylene dichloride: methyl alcohol=25: 1), obtain 44mg (9.5%) yellow solid target compound.
Mp?141～142℃；
(c＝0.71，CH
3OH)；ESI/MS(m/e)372.4[M+H]
+；IR(KBr)：3054，2875，2360，1591，1512，1452，1326，1298，1265，1164，1059，742；
1HNMR(300MHz，DMSO-d6)：δ＝10.97(s，1H)，8.85(s，1H)，8.55(d，J＝2.8Hz，1H)，8.12(d，J＝4.7Hz，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).
Embodiment 21 suppresses the tumor cell proliferation experiment
Compound of the present invention is all with the PBS preparation that contains 1%DMSO.K562 (people's chronic leukemia cell), HL60 (human promyelocytic leukemia cell), MCF-7 (human breast cancer cell), HepG2 (hepatocellular carcinoma cells), S180 (mouse ascites oncocyte), Mes-SA (people's sarcoma of uterus cell) six strain tumour cells have been used altogether.
Respectively that growth conditions is good, as to be in logarithmic phase HepG2, K562, MCF-7, HL60, S180, Mes-SA cell are according to 2 * 10
4The density of individual/mL is inoculated in 96 orifice plates, every hole 100 μ l.At 37 ℃, 5%CO
2Cultivate 4h in the incubator, add the compound of the present invention through sterilising treatment by preset concentration gradient, control group adds the solvent of equal-volume sample dissolution.After continuing to cultivate 48h, it is the MTT solution of 5mg/mL that every hole adds 25 μ l concentration, places 37 ℃ to hatch 4h, carefully removes every hole, supernatant (suspension cell is removed supernatant after centrifugal) back and adds 100 μ l DMSO (DMSO 99.8MIN.), and about 15min dissolution precipitation vibrates.The 570nm wavelength is measured O.D. (absorbancy) value down on ELIASA immediately.Calculate tumour inhibiting rate and IC
50The result lists table 1 in.The result shows that compound of the present invention has the effect of clear and definite inhibition tumor cell proliferation, except that compound 6i to MCF-7 restraining effect remarkable (IC
50Greater than 100 μ mol/L) outside, all above tumor cell line is had cytotoxic activity.
Anti-tumour cell proliferative activity (the IC of table 16a-i
50± SD μ M)
a
Zorubicin is represented with A, Cur=curcumine, n=6.
Embodiment 22 compound 6a-i are at S
180Anti-tumor activity on the mouse model
Get under the aseptic condition and be inoculated in 7-10 days S180 sarcoma of ICR mouse, add an amount of saline water and be mixed with tumor cell suspension, cell count is 2 * 10
7/ ml, it is subcutaneous to be inoculated in healthy male ICR mouse forelimb armpit, every injected in mice 0.2ml.Behind the tumor inoculation 24h, the aqueous solution of treatment group mouse abdominal injection every day 0.2ml The compounds of this invention, dosage is 2 μ mol/kg.Blank control group mouse abdominal injection every day 0.2ml saline water.Experiment proceeds to the 8th day, claims the mouse body weight, and cuts open and get the tumour of respectively organizing mouse and weigh, and adds up the tumour inhibiting rate of each treated animal at last.The curative effect of solid tumor heavily suppresses percentage with knurl and representes, calculates as follows: the heavy inhibiting rate %=of knurl (1-administration group knurl weight/blank control group knurl is heavy) * 100%.The result lists table 2 in.The result shows that compound 6a, 6b, 6c, 6d, 6h, 6i have obvious anti-tumor in vivo effect, and its tumour inhibiting rate is respectively 34.38%, 25.09%, 24.92%, 42.87%, 19.61%, 23.89%.
The anti-tumor in vivo proliferation activity of table 26a-i
Knurl is reused
representes n=10; A) compare p＜0.001 with saline water; B) with physiology salt
Water is than p＜0.01; C) compare p＜0.001 with saline water, compare p＜0.05. with curcumine
Above-described embodiment describes preferred implementation of the present invention; Be not that scope of the present invention is limited; Design under the prerequisite of spirit not breaking away from the present invention; Various distortion and improvement that those of ordinary skills make technical scheme of the present invention all should fall in the definite protection domain of claims of the present invention.
Claims (3)
1. compound that general formula is I:
In the formula, R
1Be 3-indyl, R
2Be 2,3,4,9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl, R
1Be 3-indyl, R
2Be 9H-pyridine-3-[3,4-b] indyl, R
1Be 3-indyl, R
2Be 3-indyl, R
1Be 4-hydroxy 3-methoxybenzene base, R
2Be 2,3,4,9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl, R
1Be 4-hydroxy 3-methoxybenzene base, R
2Be 9H-pyridine-3-[3,4-b] indyl, R
1Be 4-hydroxy 3-methoxybenzene base, R
2Be 3-indyl, R
1Be 3,5-dimethoxy-4 '-hydroxy phenyl, R
2Be 2,3,4,9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl, R
1Be 3,5-dimethoxy-4 '-hydroxy phenyl, R
2Be 9H-pyridine-3-[3,4-b] indyl, R
1Be 3-pyridyl, R
2Be 2,3,4,9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl.
2. method for preparing the described compound of claim 1 is characterized in that may further comprise the steps:
(1) in the presence of 12-I-53-acetoxyl periodate (DMP) and sodium hydrogencarbonate, makes solvent with (S)-2,3,4 with THF (THF); 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) in the presence of 12-I-53-acetoxyl periodate (DMP) and sodium hydrogencarbonate, make solvent 9H-pyridine [3,4-b] indole-3-carbinol is oxidized to 9H-pyridine [3,4-b] indole-3-formaldehyde with THF (THF);
(3) with (S)-2,3,4; 9-tetrahydrochysene-1H-pyridine [3,4-b] indole-3-formaldehyde, 9H-pyridine [3,4-b] indole-3-formaldehyde and 1H-indole-3-formaldehyde and 4-hydroxy 3-methoxybenzene formaldehyde, 1H-indole-3-formaldehyde, 3; 5-dimethoxy-4 '-hydroxy benzaldehyde, pyridine-3-formaldehyde prepare 1,7-diaryl-1 through the diacetylmethane coupling; 6-trans diene-3, the 5-diketone promptly gets.
3. the purposes of the described compound of claim 1 in preparation medicine for treating tumor thing.
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