CN102807566B - 1,7-diaryl-1,6-trans diene-3,5-diketone, its preparation method and application - Google Patents
1,7-diaryl-1,6-trans diene-3,5-diketone, its preparation method and application Download PDFInfo
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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
Technical field
The present invention relates to compound of a kind of synthetic and its preparation method and application, particularly relate to trans diene-3, the 5-dione compounds of class 1, a 7-diaryl-1,6-, the invention still further relates to its preparation method and the application in preparation tumor.
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 the second of all mortalities, is only second to cardiovascular and cerebrovascular diseases.The methods for the treatment of of tumour has operative treatment, radiotherapy and pharmacological agent (chemotherapy).At present, chemotherapy remains the Main Means of clinical treatment tumour, and seeking antitumor medicine is one of focus of new drug research.Curcumine is the natural product with anti-tumor activity.Contriver recognizes by the transformation to natural product, can find the better natural product derivative of new anti-tumor activity.Viewed from the association of structure, 1,7-diaryl-1,6-trans diene-3,5-diketone is the analog of curcumine, may expand the anti-tumor activity of curcumine.According to this conception, contriver proposes the present invention.
Summary of the invention
First technical problem that the present invention will solve is, provides the compound (6a-i) of general formula I:
In formula, R
1for 3-indyl, R
2be 2,3,4,9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl, R
1for 3-indyl, R
2for 9H-pyridine-3-[3,4-b] indyl, R
1for 3-indyl, R
2for 3-indyl, R
1for 4-hydroxy 3-methoxybenzene base, R
2be 2,3,4,9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl, R
1for 4-hydroxy 3-methoxybenzene base, R
2for 9H-pyridine-3-[3,4-b] indyl, R
1for 4-hydroxy 3-methoxybenzene base, R
2for 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
2for 9H-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.
The compound (6a-i) of the general formula I representative of synthesis is numbered: R in 6a
1for 3-indyl, R
2be R in 2,3,4,9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl, 6b
1for 3-indyl, R
2for R in 9H-pyridine-3-[3,4-b] indyl, 6c
1for 3-indyl, R
2for R in 3-indyl, 6d
1for 4-hydroxy 3-methoxybenzene base, R
2be R in 2,3,4,9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl, 6e
1for 4-hydroxy 3-methoxybenzene base, R
2for R in 9H-pyridine-3-[3,4-b] indyl, 6f
1for 4-hydroxy 3-methoxybenzene base, R
2for R in 3-indyl, 6g
1be 3,5-dimethoxy-4 '-hydroxy phenyl, R
2be R in 2,3,4,9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl, 6h
1be 3,5-dimethoxy-4 '-hydroxy phenyl, R
2for R in 9H-pyridine-3-[3,4-b] indyl, 6i
1for 3-pyridyl, R
2it is 2,3,4,9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl.
More than numbering just for convenience of description, there is no any limited significance to invention.
Second technical problem that the present invention will solve is to provide the preparation method of general formula compound 6a-i, and the method comprises:
(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) under 12-I-53-acetoxyl periodate (DMP) and sodium bicarbonate exist, solvent is made by 9H-pyridine [3 with tetrahydrofuran (THF) (THF), 4-b] indole-3-carbinol is oxidized to 9H-pyridine [3,4-b] indole-3-formaldehyde;
(3) by (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 3-methoxy-4-hydroxybenzaldehyde, 1H-indole-3-formaldehyde, syringaldehyde, pyridine-3-formaldehyde by diacetylmethane coupling, preparation 1,7-diaryl-1,6-trans diene-3,5-diketone, to obtain final product.
This preparation method can summarize with the route of Fig. 1, Fig. 2.
The 3rd technical problem that the present invention will solve there is provided the application of described compound in preparation tumor.
The 4th technical problem that the present invention will solve is at mouse S
180model is evaluated the anti-tumor activity of the compounds of this invention.
Accompanying drawing explanation
Fig. 1 is (S)-2,3,4,9-synthetic route chart of tetrahydrochysene-1H-pyridine [3,4-b] indole-3-formaldehyde (4a) and 9H-pyridine [3,4-b] indole-3-formaldehyde (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 the synthetic route chart of 1,7-diaryl-1,6-trans diene-3,5-diketone (6a-i).
4c is indole-3-formaldehyde, and 4d is Vanillin, and 4e is 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, to above-mentioned being described in more detail with other technical characteristic and advantage of the present invention.
Embodiment 1 prepares (S)-2,3,4,9-tetrahydrochysene-1H-pyridine [3,4-b] Indole-3-Carboxylic Acid (1)
800ml water, the 0.4ml vitriol oil and 10g (49mmol) L-Trp is added in 1000ml eggplant bottle, be stirred to after L-Trp all dissolves and add formaldehyde solution 15ml, after reaction 6-7, adularescent solid is separated out, adjust PH=7 with strong aqua, filter after leaving standstill.Obtain 10.440g (98%) colorless solid target compound.
Embodiment 2 prepares (S)-2,3,4,9-tetrahydrochysene-1H-pyridine [3,4-b] indole-3-carboxylic acid methyl ester (2a)
Dropwise drip 13ml thionyl chloride add the bath of 100ml methyl alcohol cryosel in 250ml eggplant bottle under, after stirring 30min, slowly add 10g (45.8mmol) (S)-2,3,4,9-tetrahydrochysene-1H-pyridine [3,4-b] Indole-3-Carboxylic Acid (1), (S)-2,3,4 after reaction 9-10h, 9-tetrahydrochysene-1H-pyridine [3,4-b] Indole-3-Carboxylic Acid (1) all dissolves, drained by reaction solution, and add ether and filter.Filter cake ethyl acetate adds the aqueous solution modulation PH=8 of saturated sodium bicarbonate after suspending, extraction.Ester layer is washed to neutrality, anhydrous sodium sulfate drying, and filtration, filtrate reduced in volume are extremely dry, column chromatographic isolation and purification (sherwood oil: acetone=2: 1) obtain 3.982g (36%) colorless solid target compound.
Embodiment 3 prepares 9H-pyridine [3,4-b] indole-3-carboxylic acid methyl ester (2b)
4g (17.2mmol) (S)-2 is added in 250ml eggplant bottle, 3,4,9-tetrahydrochysene-1H-pyridine [3,4-b] indole-3-carboxylic acid methyl ester (2a), add DMF (NN-dimethyl formamide) under cryosel bath and dissolved, repeatedly add 3.804g (24.1mmol) potassium permanganate on a small quantity, add ethanol 50ml after reaction 30min and stir 30min, reaction solution is poured in watch-glass and dries up.Wear away with THF (tetrahydrofuran (THF)), collect washing lotion, washing lotion is evaporated to dry, uses ether foam washing, filters and obtains 1.477g (38%) faint yellow solid target compound.
Embodiment 4 prepares (S)-2,3,4,9-tetrahydrochysene-1H-pyridine [3,4-b] indole-3-carbinol (3a)
4g (17.2mmol) (S)-2 is added in 250ml eggplant bottle, 3,4,9-tetrahydrochysene-1H-pyridine [3,4-b] indole-3-carboxylic acid methyl ester (2a) is with THF, after dissolve with methanol, 3.268g (86mmol) sodium borohydride is repeatedly added on a small quantity, reaction 9-10h, TLC monitoring under ice bath.After reaction terminates, add saturated aqueous potassium hydrogen sulfate and adjust PH=5, reaction solution is evaporated to removing THF, and reaction solution is adjusted to PH=8 with saturated sodium bicarbonate again, extraction into ethyl acetate.Ester layer is washed to neutrality, anhydrous sodium sulfate drying, and filtration, filtrate reduced in volume are to dry.Obtain 868mg (25%) colorless solid target compound.
Embodiment 5 prepares 9H-pyridine [3,4-b] indole-3-carbinol (3b)
4g (17.7mmol) 9H-pyridine [3 is added in 250ml eggplant bottle, 4-b] indole-3-carboxylic acid methyl ester (2b) is with THF, after dissolve with methanol, 3.36g (88.5mmol) sodium borohydride is repeatedly added on a small quantity, reaction 9-10h, TLC monitoring under ice bath.After reaction terminates, add saturated aqueous potassium hydrogen sulfate and adjust PH=5, reaction solution is evaporated to removing THF, and reaction solution is adjusted to PH=8 with saturated sodium bicarbonate again, extraction into ethyl acetate.Ester layer is washed to neutrality, anhydrous sodium sulfate drying, and filtration, filtrate reduced in volume are to dry.Obtain 708mg (20%) colorless solid target compound.
Embodiment 6 prepares (S)-2,3,4,9-tetrahydrochysene-1H-pyridine [3,4-b] indole-3-formaldehyde (4a)
2g (9.9mmol) (S)-2 is added in 250ml eggplant bottle, 3,4,9-tetrahydrochysene-1H-pyridine [3,4-b] indole-3-carbinol (3a), 998mg (11.8mmol) sodium bicarbonate THF dissolve, 5.876g (13.7mmol) DMP (dess-martin oxygenant) is slowly added, reaction 9-10h, TLC monitoring under ice bath.After reaction terminates, filter.Filtrate reduced in volume, to dry, is separated with preparative TLC plate.Obtain 594mg (30%) dark yellow solid target compound.
Embodiment 7 prepares 9H-pyridine [3,4-b] indole-3-formaldehyde (4b)
2g (10mmol) 9H-pyridine [3 is added in 250ml eggplant bottle, 4-b] indole-3-carbinol (3b), 1.008g (12mmol) sodium bicarbonate THF dissolve, 5.936g (14mmol) DMP (dess-martin oxygenant) is slowly added under ice bath, reaction 9-10h, TLC monitoring.After reaction terminates, filter.Filtrate reduced in volume is to dry, and (sherwood oil: acetone=6: 1) obtains 803mg (41%) faint yellow solid target compound to silica gel column chromatography separating purification.
Embodiment 8 prepares 4-(3-indyl)-5,6-hexene-2,4-diketone (5a)
In 150mL three-necked bottle, add the ethyl acetate of 10.58ml (102.9mmol) methyl ethyl diketone, 5.0g (72.1mmol) boron oxide and 50.0mL, load onto reflux condensate device, at oil bath constant temperature 70 DEG C, stir 1h.Then add 4.973g (34.3mmol) indoles 3-formaldehyde and 4.8ml (34.3mmol) tributyl borate, oil bath constant temperature 85 DEG C stirs 30min; Continue the 1.8mL be diluted in 10mL ethyl acetate (41.1mmol) n-Butyl Amine 99 to be slowly added drop-wise in three-necked bottle in 30min, 100 DEG C of oil bath isothermal reaction 1h, are then cooled to room temperature; In reaction flask, drip the hydrochloric acid of 36mL (1mol/L), constant temperature 50 DEG C of return stirring 30min, leave standstill, abundant layering, aqueous layer with ethyl acetate extracts 3 times.Merge vinyl acetic monomer layer, be washed to neutrality, anhydrous sodium sulfate drying, filtration, filtrate reduced in volume are to dry, and (sherwood oil: acetone=5: 1) obtains 1.713g (22%) yellow solid target compound to silica gel column chromatography separating purification.
Embodiment 9 prepares 6-(4-hydroxyl-3-methoxyphenyl)-5,6-hexene-2,4-diketone (5b)
In 150mL three-necked bottle, add the ethyl acetate of 10.58ml (102.9mmol) methyl ethyl diketone, 5.0g (72.1mmol) boron oxide and 50.0mL, load onto reflux condensate device, at oil bath constant temperature 70 DEG C, stir 1h.Then add 5.2g (34.3mmol) Vanillin and 4.8ml (34.3mmol) tributyl borate, oil bath constant temperature 85 DEG C stirs 30min; Continue the 1.8mL be diluted in 10mL ethyl acetate (41.1mmol) n-Butyl Amine 99 to be slowly added drop-wise in three-necked bottle in 30min, 100 DEG C of oil bath isothermal reaction 1h, are then cooled to room temperature; In reaction flask, drip the hydrochloric acid of 36mL (1mol/L), constant temperature 50 DEG C of return stirring 30min, leave standstill, abundant layering, aqueous layer with ethyl acetate extracts 3 times.Merge vinyl acetic monomer layer, be washed to neutrality, anhydrous sodium sulfate drying, filtration, filtrate reduced in volume are to dry, and (sherwood oil: acetone=5: 1) obtains 3.66g (48%) yellow solid target compound to silica gel column chromatography separating purification.
Embodiment 10 prepares 6-(4-hydroxyl-3,5-dimethoxy phenyl)-5,6-hexene-2,4-diketone (5c)
In 150mL three-necked bottle, add the ethyl acetate of 10.58ml (102.9mmol) methyl ethyl diketone, 5.0g (72.1mmol) boron oxide and 50.0mL, load onto reflux condensate device, at oil bath constant temperature 70 DEG C, stir 1h.Then add 6.2g (34.3mmol) syringic aldehyde and 4.8ml (34.3mmol) tributyl borate, oil bath constant temperature 85 DEG C stirs 30min; Continue (1.8mL, the 41.1mmol) n-Butyl Amine 99 be diluted in 10mL ethyl acetate to be slowly added drop-wise in three-necked bottle in 30min, 100 DEG C of oil bath isothermal reaction 1h, are then cooled to room temperature; In reaction flask, drip the hydrochloric acid of 36mL (1mol/L), constant temperature 50 DEG C of return stirring 30min, leave standstill, abundant layering, aqueous layer with ethyl acetate extracts 3 times.Merge vinyl acetic monomer layer, be washed to neutrality, anhydrous sodium sulfate drying, filtration, filtrate reduced in volume are to dry, and (sherwood oil: acetone=4: 1) obtains 2.77g (31%) yellow solid target compound to silica gel column chromatography separating purification.
Embodiment 11 prepares 6-(3-pyridyl)-5,6-hexene-2,4-diketone (5d)
In 150mL three-necked bottle, add the ethyl acetate of 10.58ml (102.9mmol) methyl ethyl diketone, 5.0g (72.1mmol) boron oxide and 50.0mL, load onto reflux condensate device, at oil bath constant temperature 70 DEG C, stir 1h.Then add 3.7g (34.3mmol) pyridine 3-formaldehyde and 4.8ml (34.3mmol) tributyl borate, oil bath constant temperature 85 DEG C stirs 30min; Continue the 1.8mL be diluted in 10mL ethyl acetate (41.1mmol) n-Butyl Amine 99 to be slowly added drop-wise in three-necked bottle in 30min, 100 DEG C of oil bath isothermal reaction 1h, are then cooled to room temperature; In reaction flask, drip the hydrochloric acid of 36mL (1mol/L), constant temperature 50 DEG C of return stirring 30min, leave standstill, abundant layering, aqueous layer with ethyl acetate extracts 3 times.Merge vinyl acetic monomer layer, be washed to neutrality, anhydrous sodium sulfate drying, filtration, filtrate reduced in volume are to dry, and (sherwood oil: acetone=6: 1) obtains 0.59g (9.2%) yellow solid target compound to silica gel column chromatography separating purification.
Embodiment 12 prepares 1-(3-indyl)-7-(2,3,4,9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl)-1,6-heptadiene-3,5-diketone (6a)
1.191g (5.25mmol) 4-(3-indyl)-5 is added in 150mL three-necked bottle, 6-hexene-2, the ethyl acetate of 4-diketone (5a), 254mg (3.68mmol) boron oxide and 30.0mL, load onto reflux condensate device, stirring reaction 1h at oil bath constant temperature 70 DEG C.Then add 500mg (2.5mmol) (S)-2,3,4,9-tetrahydrochysene-1H-pyridine [3,4-b] indole-3-formaldehyde (4a) and 575mg (2.5mmol) tributyl borate, oil bath constant temperature 85 DEG C stirs 30min; Slowly be added drop-wise in three-necked bottle in 30min by the 0.1ml be diluted in 10mL ethyl acetate (2.5mmol) n-Butyl Amine 99,100 DEG C of oil bath constant temperature continue reaction 1h, are then cooled to room temperature; The reaction mixture hydrochloric acid of 5mL (1mol/L), constant temperature 50 DEG C of return stirring reaction 30min, leave standstill, abundant layering, aqueous layer with ethyl acetate extracts 3 times.Merge vinyl acetic monomer layer, be washed to neutrality, anhydrous sodium sulfate drying, filtration, filtrate reduced in volume are to dry, and (methylene dichloride: methyl alcohol=25: 1) obtains 94mg (9%) yellow solid target compound to column chromatographic isolation and purification.
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 prepares 1-(3-indyl)-7-(9H-pyridine-3-[3,4-b] indyl)-1,6-heptadiene-3,5-diketone (6b)
1.191g (5.25mmol) 4-(3-indyl)-5 is added in 150mL three-necked bottle, 6-hexene-2, the ethyl acetate of 4-diketone (5a), 254mg (3.68mmol) boron oxide and 30.0mL, load onto reflux condensate device, stirring reaction 1h at oil bath constant temperature 70 DEG C.Then add 490mg (2.5mmol) 9H-pyridine [3,4-b] indole-3-formaldehyde (4b) and 575mg (2.5mmol) tributyl borate, oil bath constant temperature 85 DEG C stirs 30min; Slowly be added drop-wise in three-necked bottle in 30min by the 0.1ml be diluted in 10mL ethyl acetate (2.5mmol) n-Butyl Amine 99,100 DEG C of oil bath constant temperature continue reaction 1h, are then cooled to room temperature; The reaction mixture hydrochloric acid of 5mL (1mol/L), constant temperature 50 DEG C of return stirring reaction 30min, leave standstill, abundant layering, aqueous layer with ethyl acetate extracts 3 times.Merge vinyl acetic monomer layer, be washed to neutrality, anhydrous sodium sulfate drying, filtration, filtrate reduced in volume are to dry, and (sherwood oil: acetone=3: 1) obtains 124mg (12%) red solid target compound to column chromatographic isolation and purification.
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 prepares 1,7-two (3-indyl)-1,6-heptadiene-3,5-diketone (6c)
In 500mL three-necked bottle, add the ethyl acetate of 5g (50mmol) methyl ethyl diketone, 2.415g (35mmol) boron oxide and 250.0mL, load onto reflux condensate device, at oil bath constant temperature 70 DEG C, stir 1h.Then add 15.95g (110mmol) indoles 3-formaldehyde and 25.3g (110mmol) tributyl borate, oil bath constant temperature 85 DEG C stirs 30min; Continue the 4.4ml be diluted in 10mL ethyl acetate (110mmol) n-Butyl Amine 99 to be slowly added drop-wise in three-necked bottle in 30min, 100 DEG C of oil bath isothermal reaction 1h, are then cooled to room temperature; In reaction flask, drip the hydrochloric acid of 220mL (1mol/L), constant temperature 50 DEG C of return stirring 30min, leave standstill, abundant layering, aqueous layer with ethyl acetate extracts 3 times.Merge vinyl acetic monomer layer, be washed to neutrality, anhydrous sodium sulfate drying, filtration, filtrate reduced in volume are to dry, and (sherwood oil: acetone=3: 1) obtains 503mg (3%) red solid target compound to silica gel column chromatography separating purification.
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 prepares (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)
1.228g (5.25mmol) 6-(4-hydroxyl-3-methoxyphenyl)-5 is added in 150mL three-necked bottle, 6-hexene-2, the ethyl acetate of 4-diketone (5b), 254mg (3.68mmol) boron oxide and 30.0mL, load onto reflux condensate device, stirring reaction 1h at oil bath constant temperature 70 DEG C.Then add 500mg (2.5mmol) (S)-2,3,4,9-tetrahydrochysene-1H-pyridine [3,4-b] indole-3-formaldehyde (4a) and 575mg (2.5mmol) tributyl borate, oil bath constant temperature 85 DEG C stirs 30min; Slowly be added drop-wise in three-necked bottle in 30min by the 0.1ml be diluted in 10mL ethyl acetate (2.5mmol) n-Butyl Amine 99,100 DEG C of oil bath constant temperature continue reaction 1h, are then cooled to room temperature; The reaction mixture hydrochloric acid of 5mL (1mol/L), constant temperature 50 DEG C of return stirring reaction 30min, leave standstill, abundant layering, aqueous layer with ethyl acetate extracts 3 times.Merge vinyl acetic monomer layer, be washed to neutrality, anhydrous sodium sulfate drying, filtration, filtrate reduced in volume are to dry, and (methylene dichloride: methyl alcohol=25: 1) obtains 208mg (20%) yellow solid target compound to column chromatographic isolation and purification.
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 prepares 1-(4-hydroxy 3-methoxybenzene base)-7-(9H-pyridine-3-[3,4-b] indyl)-1,6-heptadiene-3,5-diketone (6e)
1.228g (5.25mmol) 6-(4-hydroxyl-3-methoxyphenyl)-5 is added in 150mL three-necked bottle, 6-hexene-2, the ethyl acetate of 4-diketone (5b), 254mg (3.68mmol) boron oxide and 30.0mL, load onto reflux condensate device, stirring reaction 1h at oil bath constant temperature 70 DEG C.Then add 490mg (2.5mmol) 9H-pyridine [3,4-b] indole-3-formaldehyde (4b) and 575mg (2.5mmol) tributyl borate, oil bath constant temperature 85 DEG C stirs 30min; Slowly be added drop-wise in three-necked bottle in 30min by the 0.1ml be diluted in 10mL ethyl acetate (2.5mmol) n-Butyl Amine 99,100 DEG C of oil bath constant temperature continue reaction 1h, are then cooled to room temperature; The reaction mixture hydrochloric acid of 5mL (1mol/L), constant temperature 50 DEG C of return stirring reaction 30min, leave standstill, abundant layering, aqueous layer with ethyl acetate extracts 3 times.Merge vinyl acetic monomer layer, be washed to neutrality, anhydrous sodium sulfate drying, filtration, filtrate reduced in volume are to dry, and (sherwood oil: acetone=3: 1) obtains 210mg (20.4%) red solid target compound to column chromatographic isolation and purification.
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 prepares 1-(4-hydroxy 3-methoxybenzene base)-7-(3-indyl)-1,6-heptadiene-3,5-diketone (6f)
1.228g (5.25mmol) 6-(4-hydroxyl-3-methoxyphenyl)-5 is added in 150mL three-necked bottle, 6-hexene-2, the ethyl acetate of 4-diketone (5b), 254mg (3.68mmol) boron oxide and 30.0mL, load onto reflux condensate device, stirring reaction 1h at oil bath constant temperature 70 DEG C.Then add 362.5mg (2.5mmol) indole-3-formaldehyde and 575mg (2.5mmol) tributyl borate, oil bath constant temperature 85 DEG C stirs 30min; Slowly be added drop-wise in three-necked bottle in 30min by the 0.1ml be diluted in 10mL ethyl acetate (2.5mmol) n-Butyl Amine 99,100C oil bath constant temperature continues reaction 1h, is then cooled to room temperature; The reaction mixture hydrochloric acid of 5mL (1mol/L), constant temperature 50 DEG C of return stirring reaction 30min, leave standstill, abundant layering, aqueous layer with ethyl acetate extracts 3 times.Merge vinyl acetic monomer layer, be washed to neutrality, anhydrous sodium sulfate drying, filtration, filtrate reduced in volume are to dry, and (sherwood oil: acetone=3: 1) obtains 212.7mg (25%) red solid target compound to column chromatographic isolation and purification.
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 prepares (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)
1.386g (5.25mmol) 6-(4-hydroxyl-3 is added in 150mL three-necked bottle, 5-dimethoxy phenyl)-5,6-hexene-2, the ethyl acetate of 4-diketone (5c), 254mg (3.68mmol) boron oxide and 30.0mL, load onto reflux condensate device, stirring reaction 1h at oil bath constant temperature 70 DEG C.Then add 500mg (2.5mmol) (S)-2,3,4,9-tetrahydrochysene-1H-pyridine [3,4-b] indole-3-formaldehyde (4a) and 575mg (2.5mmol) tributyl borate, oil bath constant temperature 85 DEG C stirs 30min; Slowly be added drop-wise in three-necked bottle in 30min by the 183mg be diluted in 10mL ethyl acetate (2.5mmol) n-Butyl Amine 99,100 DEG C of oil bath constant temperature continue reaction 1h, are then cooled to room temperature; The reaction mixture hydrochloric acid of 5mL (1mol/L), constant temperature 50 DEG C of return stirring reaction 30min, leave standstill, abundant layering, aqueous layer with ethyl acetate extracts 3 times.Merge vinyl acetic monomer layer, be washed to neutrality, anhydrous sodium sulfate drying, filtration, filtrate reduced in volume are to dry, and (methylene dichloride: methyl alcohol=25: 1) obtains 267mg (25.4%) yellow solid target compound to column chromatographic isolation and purification.
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 prepares 1-(3,5-dimethoxy-4 '-hydroxy phenyl)-7-(9H-pyridine-3-[3,4-b] indyl)-1,6-heptadiene-3,5-diketone (6h)
1.386g (5.25mmol) 6-(4-hydroxyl-3 is added in 150mL three-necked bottle, 5-dimethoxy phenyl)-5,6-hexene-2, the ethyl acetate of 4-diketone (5c), 254mg (3.68mmol) boron oxide and 30.0mL, load onto reflux condensate device, stirring reaction 1h at oil bath constant temperature 70 DEG C.Then add 490mg (2.5mmol) 9H-pyridine [3,4-b] indole-3-formaldehyde (4b) and 575mg (2.5mmol) tributyl borate, oil bath constant temperature 85 DEG C stirs 30min; Slowly be added drop-wise in three-necked bottle in 30min by the 0.1ml be diluted in 10mL ethyl acetate (2.5mmol) n-Butyl Amine 99,100 DEG C of oil bath constant temperature continue reaction 1h, are then cooled to room temperature; The reaction mixture hydrochloric acid of 5mL (1mol/L), constant temperature 50 DEG C of return stirring reaction 30min, leave standstill, abundant layering, aqueous layer with ethyl acetate extracts 3 times.Merge vinyl acetic monomer layer, be washed to neutrality, anhydrous sodium sulfate drying, filtration, filtrate reduced in volume are to dry, and (sherwood oil: acetone=3: 1) obtains 145mg (13%) red solid target compound to column chromatographic isolation and purification.
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 prepares 1-(3-pyridyl)-7-(2,3,4,9-tetrahydrochysene-1H-pyridine-3-[3,4-b] indyl)-1,6-heptadiene-3,5-diketone (6i)
496mg (2.63mmol) 6-(3-pyridyl)-5 is added in 150mL three-necked bottle, 6-hexene-2, the ethyl acetate of 4-diketone (5d), 127mg (1.84mmol) boron oxide and 30.0mL, load onto reflux condensate device, stirring reaction 1h at oil bath constant temperature 70 DEG C.Then 250mg (1.25mmol) (S)-2 is added, 3,4,9-tetrahydrochysene-1H-pyridine [3,4-b] indole-3-formaldehyde (4a) and 288mg (1.25mmol) tributyl borate, oil bath constant temperature 85 DEG C stirs 30min; Slowly be added drop-wise in three-necked bottle in 30min by the 0.1ml be diluted in 10mL ethyl acetate (2.5mmol) n-Butyl Amine 99,100 DEG C of oil bath constant temperature continue reaction 1h, are then cooled to room temperature; The reaction mixture hydrochloric acid of 2.5mL (1mol/L), constant temperature 50 DEG C of return stirring reaction 30min, leave standstill, abundant layering, aqueous layer with ethyl acetate extracts 3 times.Merge vinyl acetic monomer layer, be washed to neutrality, anhydrous sodium sulfate drying, filtration, filtrate reduced in volume are to dry, and (methylene dichloride: methyl alcohol=25: 1) obtains 44mg (9.5%) yellow solid target compound to column chromatographic isolation and purification.
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 inhibition tumor cell proliferation experiment
Compound of the present invention is all prepared with the PBS containing 1%DMSO.Employ K562 (people's chronic leukemia cell), HL60 (human promyelocytic leukemia), 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 altogether.
Respectively by good for growth conditions, be in HepG2, K562, MCF-7, HL60, S180, Mes-SA cell of logarithmic phase according to 2 × 10
4the density of individual/mL is inoculated in 96 orifice plates, every hole 100 μ l.At 37 DEG C, 5%CO
2cultivate 4h in incubator, add the compound of the present invention through sterilising treatment by the concentration gradient preset, control group adds the solvent of equal-volume sample dissolution.After continuing to cultivate 48h, every hole adds the MTT solution that 25 μ l concentration are 5mg/mL, be placed in 37 DEG C and hatch 4h, carefully remove supernatant liquor (suspension cell removes supernatant liquor after centrifugal) and add 100 μ l DMSO (dimethyl sulfoxide (DMSO)) in every hole afterwards, vibrate about 15min dissolution precipitation.O.D. (absorbancy) value is measured under 570nm wavelength immediately in microplate reader.Calculate tumour inhibiting rate and IC
50.Result lists table 1 in.Result shows that compound of the present invention has the effect of clear and definite inhibition tumor cell propagation, to the not remarkable (IC of MCF-7 restraining effect except compound 6i
50be greater than 100 μm of ol/L), all to above tumor cell line, there is cytotoxic activity outward.
Anti-tumour cell proliferative activity (the IC of table 16a-i
50± SD μM)
a
Zorubicin A represents, Cur=curcumine, n=6.
Embodiment 22 compound 6a-i is at S
180anti-tumor activity on mouse model
Get under aseptic condition and be inoculated in the ICR mouse S180 sarcoma of 7-10 days, add appropriate normal saline tumor cells suspension, cell count is 2 × 10
7/ ml, is inoculated in healthy male ICR mouse forelimb armpit subcutaneous, every injected in mice 0.2ml.After tumor inoculation 24h, the aqueous solution for the treatment of group mouse abdominal injection every day 0.2ml the compounds of this invention, dosage is 2 μm of ol/kg.Naive mice abdominal injection every day 0.2ml physiological saline.Experiment proceeds to the 8th day, claim Mouse Weight, and the tumour taking each group of mouse is weighed, and finally adds up the tumour inhibiting rate of each treated animal.The curative effect of solid tumor represents with the heavy inhibition percentage of knurl, is calculated as follows: tumor-like hyperplasia %=(1-administration group knurl heavy/blank group knurl weight) × 100%.Result lists table 2 in.Result shows that compound 6a, 6b, 6c, 6d, 6h, 6i have obvious Anticancer effect in vivo, 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
represent, n=10; A) p < 0.001 compared with physiological saline; B) with physiology salt
Water compares p < 0.01; C) p < 0.001 compared with physiological saline, p < 0.05. compared with curcumine
Above-described embodiment is only be described the preferred embodiment of the present invention; not scope of the present invention is limited; under not departing from the present invention and designing the prerequisite of spirit; the various distortion that those of ordinary skill in the art make technical scheme of the present invention and improvement, all should fall in protection domain that claims of the present invention determines.
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.
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