CN100502846C - 3,4,5,-substituted benzyl ethylene derivatives and their preparation and use - Google Patents
3,4,5,-substituted benzyl ethylene derivatives and their preparation and use Download PDFInfo
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- CN100502846C CN100502846C CNB2004100306687A CN200410030668A CN100502846C CN 100502846 C CN100502846 C CN 100502846C CN B2004100306687 A CNB2004100306687 A CN B2004100306687A CN 200410030668 A CN200410030668 A CN 200410030668A CN 100502846 C CN100502846 C CN 100502846C
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Abstract
A 3,4,5-trisubstituted allyl benzene derivate with cell toxicant activity, its production and use are disclosed. It achieves high inhibiting activity for prostatic cancer cell(PC-3), nasopharyngeal carcinoma cell(CNE), oral epithelial cancer cell(KB), lung cancer cell(A549), hepatocarcinoma cell(BEL-7404) and uterine neck cancer cell(Hela).
Description
Invention field
The present invention relates to organic chemistry, pharmaceutical chemistry and area of pharmacology, particularly, the present invention relates to 3,4, the preparation method of trisubstituted allyl benzene derivatives of 5-and key intermediate thereof reaches at this series compound six kinds of tumor cell lines such as Human Prostate Cancer Cells (PC-3), nasopharyngeal carcinoma cell (CNE), oral squamous carcinoma cell strain (KB), human lung carcinoma cell (A549), human liver cancer cell (BEL-7404), the growth of tumour cell that human cervical carcinoma cell (Hela) is carried out suppresses screening active ingredients.This compounds is found has certain inhibition tumor cell growth activity, can expect as the antitumor drug purposes.
Background of invention
At present, because the problems of bringing in the industrial development such as environmental pollution, the existent environment of people quality constantly descends, and the sickness rate of tumor disease and fatality rate are also constantly risen.Yet the specific drug of treatment tumor disease can not be satisfactory, and at present the selectivity of the clinical used cytotoxic drug of antitumor not high cause to Normocellular pernicious killing and wounding, limited the general applicability of such medicine.Therefore, seek and find that the high cytotoxicity antitumor drug of new selectivity is worldwide research focus.We also are devoted to the research of antitumor drug.Zhao Yu in 2002 etc. separate from Compositae Folium Nelumbinis Farfugium kaemferi and obtain 4-geranyl-3,5-dimethoxy cinnamyl alcohol and 4-geranyl-3, and 5-dimethoxy cinnamaldehyde has also been made cell toxicity test to it, discovery has certain cytotoxicity (Zhao to the KB cell, Y., Hao, X.J., Lu, W., Cai, J.C., Yu, H., Sev é net, T.and Gu é ritte, F. (2002) J.Nat.Prod.65,902-908.), therefore the objective of the invention is to this compounds is synthesized and structure of modification, growth produces stronger by inhibiting 3 to tumor cell line in the hope of seeking, 4, the trisubstituted allyl benzene derivatives of 5-.According to the whole world especially sensitivity of often swell the tumor spectrum of disease and the tumor cell of China, we have selected Human Prostate Cancer Cells (PC-3), nasopharyngeal carcinoma cell (CNE), oral squamous carcinoma cell (KB), human lung carcinoma cell (A549), human liver cancer cell (BEL-7404), the index that human cervical carcinoma cell (Hela) six strain tumor cells are estimated as cell in vitro cytotoxic activity pharmacology.
Goal of the invention
The object of the present invention is to provide a kind of chemical compound, particularly, the invention provides a kind of 3,4 shown in formula (1) that have, the trisubstituted allyl benzene derivatives of 5-and officinal salt or solvate with cytotoxic activity:
Wherein:
R
1, R
2, or R
3Can be identical or different, can be respectively hydrogen, contain the saturated or unsaturated alkyl of 1～16 carbon, replace or unsubstituted aryl, replace or unsubstituted aryl alkyl, replace or unsubstituted aryl alkenyl, the acyl group that contains 1～8 carbon replaces or unsubstituted pi-allyl aryl;
R can be-COOH-CH
2OH ,-CHO ,-COOR
4,-CONH
2,-CONHR
4,-CON (R
4)
2, R wherein
4Be the alkyl that contains 1～8 carbon, replace or unsubstituted phenyl, replace or unsubstituted benzene alkyl;
Wherein " replace or not replace " be meant that group can not be substituted or be substituted, substituent group can be a halogen, amino, nitro, sulfydryl, cyano group, hydroxyl contains the alkyl of 1～8 carbon, contains the alkoxyl of 1～8 carbon, the acyl group that contains 1～8 carbon, aryl, aryl alkyl, amido, amide groups, alkylthio group, arylthio;
Another object of the present invention has provided the key intermediate 3,4 with cytotoxic activity formula (1) chemical compound as the formula (7), the trisubstituted benzaldehyde series compound of 5-and officinal salt or solvate:
Formula (7)
Radicals R wherein
1, R
2, or R
3Definition and formula (1) identical;
Another object of the present invention has provided the preparation method of formula (1) and formula (7) chemical compound;
Another purpose of the present invention has provided the purposes that is used to prepare control tumor disease medicine of formula (1) and formula (7) chemical compound;
Another object of the present invention has provided a kind of pharmaceutical composition that is used for anti-tumor disease that contains formula (1) and formula (7) chemical compound.
Summary of the invention
The invention provides a kind of 3,4 shown in formula (1) that have, the trisubstituted allyl benzene derivatives of 5-and officinal salt or solvate:
Wherein:
R
1, R
2, or R
3Can be identical or different, can be respectively hydrogen, contain the saturated or unsaturated alkyl of 1～16 carbon, replace or unsubstituted aryl, replace or unsubstituted aryl alkyl, replace or unsubstituted aryl alkenyl, the acyl group that contains 1～8 carbon replaces or unsubstituted pi-allyl aryl;
R can be-COOH-CH
2OH ,-CHO ,-COOR
4,-CONH
2,-CONHR
4,-CON (R
4)
2, R wherein
4Be the alkyl that contains 1～8 carbon, replace or unsubstituted aryl, replace or unsubstituted aryl alkyl;
Wherein " replace or not replace " be meant that group can not be substituted or be substituted, substituent group is to be selected from halogen, amino; nitro, sulfydryl, cyano group; hydroxyl contains the alkyl of 1～8 carbon, contains the alkoxyl of 1～8 carbon; the acyl group that contains 1～8 carbon, aryl, aryl alkyl; amido; amide groups, alkylthio group, arylthio.
The preferred R of the present invention has following formula (2), formula (3), and implication shown in formula (4), formula (5) or the formula (6):
R=COOCH
3Formula (2)
R=COOCH
2CH
3Formula (3)
R=COOH formula (4)
R=CH
2OH formula (5)
R=CHO formula (6);
The preferred formula of the present invention (1) chemical compound and officinal salt thereof or solvate are:
Wherein:
R
1And R
3Can be identical or different, can be respectively hydrogen, contain the alkyl of 1～8 carbon;
R
2Can be the alkyl or alkenyl that contains 1～16 carbon, replace or unsubstituted aryl alkyl, replace or unsubstituted aryl alkenyl.
Further preferred formula (1) chemical compound of the present invention and officinal salt thereof or solvate are:
Wherein:
R
1And R
3Can be identical or different, can be respectively hydrogen, methyl or ethyl;
R
2Can be the alkyl or alkenyl that contains 1～16 carbon, replace or unsubstituted benzyl, replace or unsubstituted phenyl pi-allyl.
Except as otherwise noted:
Term of the present invention " alkyl " comprises alkyl, thiazolinyl and alkynyl; " alkyl " is meant straight or branched alkyl that contains 1～8 carbon or the cycloalkyl that contains 3-8 carbon, can be methyl, ethyl, propyl group, isopropyl, cyclopropyl, butyl, isobutyl group, the tert-butyl group, cyclobutyl, amyl group, isopentyl, neopentyl, cyclopenta, hexyl, cyclohexyl, heptyl, suberyl, octyl group etc.; Term " thiazolinyl " contains the straight chain of 2～8 carbon or the cycloalkenyl group of branched-chain alkenyl or 3～8 carbon, can be vinyl, acrylic, pi-allyl, cyclobutenyl, isobutenyl, pentenyl, isopentene group, cyclopentenyl, hexenyl, cyclohexenyl group etc.; Term " aryl " comprises isocyclic aryl and contains 1-3 heterocyclic aryl that is selected from nitrogen, oxygen or sulfur heteroatom that wherein aryl can some or all ofly be hydrogenated, and can be phenyl, naphthyl, pyridine radicals, pyrrole radicals, furyl, thienyl, (hydrogenation) quinolyl, (hydrogenation) isoquinolyl, indyl, triazol radical oxazolyl, tetrahydrofuran base, piperidyl, morpholinyl etc.; " amido " comprises methylamino, ethylamino-, Propylamino, dimethylamino, diethylin etc.; " amide groups " comprises formamido, acetamido, propionamido-, amide-based small etc.;
The present invention's " replacement or not replacement " is meant that group can not be substituted or be substituted, and substituent group can be a halogen, amino; nitro, sulfydryl, cyano group; hydroxyl contains the alkyl of 1～8 carbon, contains the alkoxyl of 1～8 carbon; the acyl group that contains 1～8 carbon, aryl, aryl alkyl; amido; amide groups, alkylthio group, arylthio.
The further embodiment of the present invention is: when the radicals R in the formula (1) is structure shown in the formula (3), be called 3,4 shown in the formula (I), the trisubstituted cinnamic acid ethyl ester compound of 5-:
Radicals R wherein
1, R
2, or R
3Definition identical with the definition of formula (1) chemical compound.
The preferred formula of the present invention (I) chemical compound comprises:
When the radicals R in the formula (1) is structure shown in the formula (4), be called 3,4 shown in the formula (II), the trisubstituted compounds derived from phenyl acrylic acid of 5-:
Radicals R wherein
1, R
2, or R
3Definition identical with the definition of formula (1) chemical compound.
The preferred formula of the present invention (II) chemical compound comprises:
When the radicals R in the formula (1) is structure shown in the formula (5), be called 3,4 shown in the formula (III), the trisubstituted cinnamyl alcohol compounds of 5-:
Radicals R wherein
1, R
2, or R
3Definition identical with the definition of formula (1) chemical compound.
The preferred formula of the present invention (III) chemical compound comprises:
When the radicals R in the formula (1) is structure shown in the formula (6), be called 3,4 shown in the formula (IV), the trisubstituted cinnamaldehyde compounds of 5-:
Radicals R wherein
1, R
2, or R
3Definition identical with the definition of formula (1) chemical compound.
The preferred formula of the present invention (IV) chemical compound comprises:
Have the chemical compound of formula (7) structure, be called 3,4 shown in the formula V, the trisubstituted benzaldehyde compounds of 5-:
Radicals R wherein
1, R
2, or R
3Definition identical with the definition of formula (1) chemical compound.
The preferred formula V chemical compound of the present invention comprises:
Another object of the present invention provides a kind of method by intermediate formula (7) compound formula (1) chemical compound.This synthesis route feature is: with the formula V chemical compound by obtaining formula (I) chemical compound with triphenyl carbethoxyl group methine phosphine alkane experience stannum (wittig) prepared in reaction of loving and respect one's elder brother Wei; Obtain formula (II) chemical compound by formula (I) chemical compound through basic hydrolysis; Formula (I) chemical compound obtains formula (III) chemical compound by the lithium aluminium hydride reduction; Formula (IV) chemical compound can be by formula (III) chemical compound through Pyridinium chlorochromate on silica gel alumina mixture (PCCAl
2O
3) oxidation obtain, perhaps obtain by aldol reaction by formula V chemical compound and acetaldehyde solution.The concrete preparation process of Compound I, II, III, IV is as follows:
Radicals R wherein
1, R
2, or R
3Definition identical with the definition in the formula (1).
A further object of the present invention provides the preparation method of key intermediate formula (7) chemical compound, is described below respectively according to the definition of formula (7) chemical compound:
As 3,5 R of formula (7) chemical compound
1And R
3When replacing, be the example explanation with the methyl for alkyl.(VI-a) methylates by dimethyl sulfate by the raw material gallicin, obtains the product (VI-b) of 3,4,5 trimethylizations; Obtain chemical compound (VI-c) by the reduction of chemical compound (VI-b) by lithium aluminium hydride; Chemical compound (VI-c) obtains product (VI-d) by the Pyridinium chlorochromate on silica gel oxidation; Chemical compound (VI-d) obtains R by the demethylation of phenylmercaptan. and HMPA
1And R
3Chemical compound (VI) for methyl; This chemical compound (VI) and halides (R
2X) substitution reaction taking place obtains formula R
1And R
3Chemical compound (V-M) for methyl.The concrete preparation process of chemical compound (V-M) is as follows:
As 3,5 R of formula (7) chemical compound
1And R
3During for acyl group or hydrogen replacement, be that example is illustrated with acetyl group and hydrogen respectively, obtain product and be respectively chemical compound (VI-A) and chemical compound (VI-H).(VI-d) is raw material with chemical compound, sloughs three methyl with aluminum chloride under the room temperature and gets tri hydroxybenzaldehyde (VI-e); Chemical compound (VI-e) obtains triacetyl product (VI-f) by the acetylation of acetic anhydride pyridine; Chemical compound (VI-f) is at N, and N-two
Under the existence of methylformamide by with potassium carbonate and halides (R
2X) reaction obtains chemical compound (V-A); Chemical compound (V-A) further produces chemical compound (V-H) again under the hydrolysis of potassium carbonate.The concrete preparation process of chemical compound (V-A) and chemical compound (V-H) is as follows:
Formula (1) chemical compound and intermediate formula (7) chemical compound thereof have important biological, external six strain tumor cells are comprised Human Prostate Cancer Cells (PC-3), nasopharyngeal carcinoma cell (CNE), (oral squamous carcinoma cell strain (KB), human lung carcinoma cell (A549), human liver cancer cell (BEL-7404), the test of the cytotoxic activity of human cervical carcinoma cell (Hela) show this type of have the noval chemical compound of propenyl benzene structure (inhibited as compound IV-a) and intermediate series compound (as V-e) thereof to growth of tumour cell, might develop into new control tumour medicine.
But formula of the present invention (1) chemical compound and formula (7) compound or pharmaceutically acceptable salt thereof and solvate thereof can combine with spoke material or carrier pharmaceutically commonly used, have growth of tumour cell the active pharmaceutical composition that can be used for anti-curing oncoma thereby prepare.Above-mentioned various kinds of drug compositions can adopt drug forms such as injection, tablet, capsule, aerosol, suppository, membrane, drop pill, externally-applied liniment, ointment.
Formula of the present invention (1) chemical compound and formula (7) compound or pharmaceutically acceptable salt thereof and solvate thereof can with antitumor drug that has now gone on the market such as platinum medicine cisplatin (DDP), camptothecine irinotecan (Irinatecan, CPT-11), the vinca alkaloids medicine loses carbon vincaleucoblastine (Vinorebine, the NVB nvelbine), deoxidation born of the same parents former times class medicine gemcitabine (Gemcitabine, Gemzar, strong selecting), etoposide (Etoposide), paclitaxel (Paclitaxel) etc. is united use, prepare and have tumor growth and suppress active cytotoxicity compositions, can be used for treating tumor disease.Such pharmaceutical composition can adopt drug forms such as injection, tablet, capsule, aerosol, suppository, membrane, drop pill, externally-applied liniment, ointment.
Further specify the present invention below by embodiment.Embodiment has provided synthetic and the dependency structure appraising datum and the part activity data of representative compounds.Mandatory declaration, following embodiment is used to illustrate the present invention rather than limitation of the present invention.The simple modifications subordinate that essence according to the present invention is carried out the present invention is in the scope of protection of present invention.
Embodiment 1: 3,4, the preparation of 5-tri-methoxybenzoate (VI-b)
Get sodium hydroxide (10g, 0.25mol) soluble in water, the cooling back adds chemical compound gallicin (VI-a, 10.8g, 0.058mol), stirring and dissolving, be brownish red, drip 27ml dimethyl sulfate (during dropping control temperature be lower than 40 ℃) while stirring, the liquid feeding post-heating that finishes refluxed 2 hours, and solution is pale brown color.Add the alkali faintly acid that neutralizes after the cooling,, wash with water after the filtration to nearly neutrality stirring insulation 1 hour below 10 ℃, get pale solid, (yield is 70% to column chromatography purification for petrol ether/ethyl acetate=6:1, crude product/silica gel=1:50) get chemical compound (VI-b) 9.28g.
Embodiment 2: 3,4, the preparation of 5-trimethoxy benzylalcohol (VI-c)
(55mg 1.49mmol) adds in the 5ml oxolane, then will be dissolved in 3 of 5ml oxolane with lithium aluminium hydride, 4,5-tri-methoxybenzoate (VI-b, 0.226g, 1mmol) splash in the mixed liquor, the liquid feeding post-heating that finishes refluxed 5 hours, at room temperature stirred and spent the night.Add low amounts of water then and decompose excessive lithium aluminium hydride, regulate PH to acid with 1M hydrochloric acid then, use saturated aqueous common salt respectively with organic facies after the extracted with diethyl ether, distilled water wash is used anhydrous sodium sulfate drying at last.Filter, filtrate concentrate crude product, column chromatography purification (petrol ether/ethyl acetate=3:1, crude product/silica gel=1:50) (VI-c) 0.148g, yield is 72%.
Embodiment 3: 3,4, the preparation of 5-TMB (VI-d)
In flask, add Pyridinium chlorochromate on silica gel (0.775g, 0.3mol), with dichloromethane dissolving, stirring at room, it is dissolved 3,4 with dichloromethane to reinject, (0.51mmol), stirring at room 20 minutes generates brown thing to 5-trimethoxy benzylalcohol for VI-c, 0.1g.Sucking filtration, insoluble matter washs with ether, merging filtrate, respectively with 5% sodium hydroxide, 5% hydrochloric acid, saturated sodium bicarbonate solution, saturated nacl aqueous solution washing, organic facies anhydrous magnesium sulfate drying.Filter, precipitation is led crude product, and (yield is 85% to column chromatography purification for petrol ether/ethyl acetate=7:1, crude product/silica gel=1:50) must drip body chemical compound (VI-d) 85mg.
Embodiment 4: the preparation of syringic aldehyde (VI)
In flask, add sodium hydride (48mg, 2mmol) and the 5ml dry toluene, phenylmercaptan. (0.2ml reinjects, 2mmol) stir half an hour, add HMPA (0.35ml, calcium hydride is handled) thereupon, injection is dissolved with 3,4,5-TMB (VI, 0.31g, 1.5mmol) toluene solution, it is yellow muddy that material is, and reflux was reduced to room temperature after two hours, added the 10ml dichloromethane, tell organic layer, water layer dichloromethane extraction three times, reuse 1M hydrochloric acid transfer PH to acid, separate out white solid, extremely colourless with dichloromethane extraction, organic facies merges the back and uses the saturated common salt water washing, and anhydrous sodium sulfate drying spends the night, and filters, column chromatography purification (petrol ether/ethyl acetate=5:1, crude product/silica gel=1:50) get the faint yellow solid crude product, column chromatography gets chemical compound (VI) 0.252g, and yield is 92%.
Embodiment 5: the preparation of compound VI-e (3,4, the 5-tri hydroxybenzaldehyde)
Be equipped with aluminum chloride (8.14g at one, 61.2mmol) reaction bulb in add the 25ml dichloromethane, slowly add 5ml dichloromethane dissolved 3 again, 4,5-TMB (3g, 15.3mmol) solution, stirring at room 24 hours, and then add aluminum chloride (8.14g, 61.2mmol), again in stirring at room 48 hours.Remove excessive aluminum chloride with 1M hydrochloric acid then and remove, concentrate and remove dichloromethane and part water, extract with ethyl acetate (60ml * 5), combining extraction liquid spends the night with anhydrous sodium sulfate drying.(5-tri hydroxybenzaldehyde 500mg, yield are 21.2% to the rapid column chromatography purification for chloroform: methanol=20:1, crude product/silica gel=1:20) get 3,4.
Embodiment 6: the preparation of compound VI-f (2,3-diacetoxy-5-carboxaldehyde radicals-phenyl acetate)
With 3,4, (420mg 2.72mmol) is dissolved in the 8ml pyridine 5-tri hydroxybenzaldehyde, and the cooling of solution ice bath adds the 16ml acetic anhydride down.This solution at room temperature stirred following 4 hours, then this solution was added in ethyl acetate (25ml) mixed liquor of the saturated ammonium chloride of icing (15ml), got the upper strata acetic acid ethyl fluid after the separatory funnel layering then.Organic layer is washed till nearly neutrality with pure water, and the reuse anhydrous sodium sulfate drying spends the night, and filters, concentrate column chromatography purification (petrol ether/ethyl acetate=6:1, crude product/silica gel=1:50) get 2,3-diacetoxy-5-carboxaldehyde radicals-phenyl acetate 280mg, yield is 36.7%).
VI-f chemical compound: (n-hexane/ethyl acetate: 5/2): 0.48
1H-NMR(400MHZ，CDCl3)：δ 9.85(1H，s)，7.70(2H，s)，2.29(9H，s)；
Embodiment 7: the preparation of chemical compound V-1 (3-acetoxyl group-2-benzyloxy-5-carboxaldehyde radicals-phenyl acetate)
This example relate to a class as the formula (6) have 3,4 of cytotoxic activity, the trisubstituted allyl benzene derivatives key intermediate 3,4 of 5-, a general synthetic method of the trisubstituted benzaldehyde series compound of 5-.Be specifically related to the synthetic of chemical compound V-1 (3-acetoxyl group-2-benzyloxy-5-carboxaldehyde radicals-phenyl acetate).With 2, (56mg, 0.2mmol) adding fills 3ml N to 3-diacetoxy-5-carboxaldehyde radicals-phenyl acetate, in the flask of dinethylformamide.Add then bromobenzyl (68mg, 0.4mmol), potassium carbonate (82mg, 0.6mmol) heat and stir 24 hours after, filter, filtrate concentrate crude product, crude product through column chromatography purification (petrol ether/ethyl acetate=7:1, crude product/silica gel=1:50) chemical compound V-l (63mg, 96%).
V-l chemical compound: (n-hexane/ethyl acetate: 5/2): 0.44
1H-NMR(400MHZ，CDCl3)：δ 9.81(1H，s)，7.65(2H，s)，7.39(5H，m)，2.29(6H，s)，5.18(2H，s)。
Embodiment 8: the preparation of chemical compound V-k (4-benzyloxy-3,5-dihydroxy-benzaldehyde)
This example relate to a class as the formula (6) have 3,4 of cytotoxic activity, the trisubstituted allyl benzene derivatives key intermediate 3,4 of 5-, a general synthetic method of the trisubstituted benzaldehyde series compound of 5-.Be specifically related to the synthetic of chemical compound V-k (4-benzyloxy-3,5-4-dihydroxy benzaldehyde).With potassium carbonate (175mg, 1.28mmol, 0.9ml water) solution joins 3-acetoxyl group-2-benzyloxy-5-carboxaldehyde radicals-phenyl acetate (141mg, 0.43mmol) methanol (5ml) solution in, at room temperature stirred 10 minutes, filter, after dark brown solution reuse ethyl acetate (15ml * 4) extraction that filtrate concentrating obtains, anhydrous sodium sulfate drying spends the night, rapid column chromatography purification (petrol ether/ethyl acetate=2:1, crude product/silica gel=1:50) get 4-benzyloxy-3,5-dihydroxy-benzaldehyde 100mg, yield are 94.9%.
V-k chemical compound: Rf (ethyl acetate): 0.57
1H-NMR(400MHZ，CDCl3)：δ 9.78(1H，s)，7.05(2H，s)，7.39(5H，m)，5.99(2H，brs)，5.18(2H，s)。
Embodiment 9: the preparation of chemical compound V-f (4-(4-bromo-benzyloxy)-3,5-dimethoxy benzaldehyde)
This example relate to a class as the formula (6) have 3,4 of cytotoxic activity, the trisubstituted allyl benzene derivatives key intermediate 3,4 of 5-, a general synthetic method of the trisubstituted benzaldehyde series compound of 5-.Be specifically related to the synthetic of chemical compound V-f (4-(4-bromo-benzyloxy)-3,5-dimethoxy benzaldehyde).In the three-necked bottle of a 1000ml, add successively sodium hydride (64mg, 1.2mmol) and methanol (7ml), syringic aldehyde (VI, 0.2g, (3ml) solution of methanol 1.08mmol) and 4-bromo-benzyl bromine (333mg, 1.4mmol), reflux 3 hours.Be chilled to room temperature, filter, filtrate concentrates, and adds low amounts of water, transfers PH to acid with 1MHCl, with extracted with diethyl ether (30ml * 3), saturated common salt water washing after drying spends the night, and filters, and filtrate concentrates the back and gets white solid 4-benzyloxy-3 with the ether recrystallization, 5-dimethoxy benzaldehyde 219mg, yield are 62.5%.
The V-f chemical compound:
Rf (n-hexane/ethyl acetate: 5/2): 0.51
1H-NMR(400MHZ，CDCl
3)：δ 9.87(1H，s)，7.12(2H，s)，3.90(6H，s)，5.08(2H，s)，7.35(2H，d，J＝8.4Hz)，7.47(2H，d，J＝8.4Hz)。
Embodiment 10: the preparation of chemical compound V-j (4-(4-ethyoxyl-benzyloxy)-3,5-dimethoxy benzaldehyde)
This example relate to a class as the formula (6) have 3,4 of cytotoxic activity, the trisubstituted allyl benzene derivatives key intermediate 3,4 of 5-, a general synthetic method of the trisubstituted benzaldehyde series compound of 5-.Be specifically related to the synthetic of chemical compound V-j (4-(4-ethyoxyl-benzyloxy)-3,5-dimethoxy benzaldehyde).With oxolane with syringic aldehyde (VI, 20mg, 0.11mmol), 4-ethyoxyl benzylalcohol (25mg, 0.165mmol), (43mg, 0.165mmol) dissolving splashes into 40% diethyl azodiformate toluene solution to triphenylphosphine then.Reactant liquor stirred 72 hours, and warp concentrates then, (yield is 75% to column chromatography purification for petrol ether/ethyl acetate=6:1, crude product/silica gel=1:50) obtain white solid chemical compound V-j26mg.
The V-j chemical compound:
Rf (n-hexane/ethyl acetate: 5/2): 0.50
1H-NMR(400MHZ，CDCl
3)：δ 9.85(1H，s)，7.10(2H，s)，3.89(6H，s)，5.06(2H，s)，7.35(2H，d，J＝6.8Hz)，6.85(2H，d，J＝6.8Hz)。
Prepare following table one illustrated embodiment 11-20 chemical compound according to method with one of embodiment 1-10:
Table one
List the physicochemical data of each chemical compound in the table one below:
V-a: white solid, Rf (n-hexane/ethyl acetate: 5/2) 0.57;
1H-NMR (400MHZ, CDCl
3): δ 9.86 (1H, s), 7.11 (2H, s), 3.90 (6H, s), 5.13 (2H, s, H-1 '), 7.42 (2H, dd, J=7.6,1.2Hz), 7.33 (3H, m);
V-b: white solid, Rf (n-hexane/ethyl acetate: 5/2) 0.57;
1H-NMR (400MHZ, CDCl
3): δ 9.86 (1H, s), 7.12 (2H, s), 3.91 (6H, s), 4.07 (2H, t, H-1 '), 1.57 (2H, m), 1.30 (2H, m); 1.26 (24H, m), 0.88 (3H, t);
V-c: white solid, Rf (n-hexane/ethyl acetate: 5/2) 0.61;
1H-NMR (400MHZ, CDCl
3): δ 9.88 (1H, s), 7.14 (2H, s), 3.89 (6H, s), 5.20 (2H, s, H-1 '), 7.67 (1H, dd, J=8.4,2.4Hz), 7.12 (1H, dd, J=8.4,2.4Hz), 7.03 (1H, d, J=2.4Hz);
V-d: weak yellow liquid, Rf (n-hexane/ethyl acetate: 5/2) 0.65;
1H-NMR (400MHZ, CDCl
3): δ 9.87 (1H, s), 7.12 (2H, s), 3.93 (6H, s), 4.67 (2H, brd, J=7.2Hz), 5.54 (1H, brt, J=7.2Hz), 2.03 (4H, m); 5.05 (1H, m), 1.67 (1H, s), 1.65 (1H, s); 1.58 (1H, s);
V-e: white solid, Rf (n-hexane/ethyl acetate: 5/2) 0.57;
1H-NMR (400MHZ, CDCl
3): δ 9.86 (1H, s), 7.11 (2H, s), 3.90 (6H, s), 5.00 (2H, s, H-1 '), 7.15 (1H, brd, J=7.2Hz), 7.52 (1H, dd, J=7.2,7.6Hz), 7.32 (1H, dd, J=7.2,7.6Hz), 7.75 (1H, brd, J=7.6Hz);
V-g: white solid, Rf (n-hexane/ethyl acetate: 5/2) 0.57;
1H-NMR (400MHZ, CDCl
3): δ 9.87 (1H, s), 7.12 (2H, s), 3.93 (6H, s), 5.09 (2H, s, H-1 '), 7.70 (1H, s), 7.43 (1H, d, J=7.6Hz); 7.22 (1H, dd, J=7.6,7.6Hz);
V-h: white solid, Rf (n-hexane/ethyl acetate: 5/2) 0.54;
1H-NMR (400MHZ, CDCl
3): δ 9.87 (1H, s), 7.12 (2H, s), 3.92 (6H, s), 5.07 (2H, s, H-1 '), 7.64 (1H, s), 7.41 (1H, d, J=8.4,7.28 (1H, d, J=8.4Hz);
V-i: faint yellow solid, Rf (n-hexane/ethyl acetate: 5/2) 0.63;
1H-NMR (400MHZ, CDCl
3): δ 9.87 (1H, s), 7.11 (2H, s), 3.89 (6H, s), 5.15 (2H, s, H-1 '), 7.47 (1H, d, J=8.0Hz), 7.29 (1H, dd, J=8.0,2.0Hz); 7.23 (1H, d, J=2.0Hz);
V-m: white solid, Rf (n-hexane/ethyl acetate: 5/2) 0.57; 1H-NMR (400MHZ, CDCl3): δ 9.86 (1H, s), 7.12 (2H, s), 3.90 (6H, s), 5.17 (2H, brd, J=6.4Hz), 6.24 (1H, dt, J=12.0,6.4Hz), 7.34 (1H, d, J=12.0Hz), 7.39 (5H, m);
V-n: weak yellow liquid, Rf (n-hexane/ethyl acetate: 5/2) 0.60; 1H-NMR (400MHZ, CDCl3): δ 9.87 (1H, s), 7.12 (2H, s), 3.93 (6H, s), 4.65 (2H, brd, J=7.2Hz), 5.55 (1H, brt, J=6.8Hz), 2.03 (8H, m), 5.10 (1H, brt), 5.08 (1H, brt), 1.66 (3H, brs), 1.58 (3H, br), 1.60 (3H, brs), 1.68 (3H, brs).
Embodiment 21: the preparation of Compound I-f (3-[4-(4-bromo-benzyloxy)-3, the 5-dimethoxy is severe] ethyl acrylate)
This example relate to a class have cytotoxic activity suc as formula 3,4 shown in (I), the general synthetic method of the trisubstituted cinnamic acid ethyl ester of 5-.Be specifically related to the preparation of Compound I-f (3-[4-(4-bromo-benzyloxy)-3,5-dimethoxy benzene] ethyl acrylate).In flask, add chemical compound V-f (1.19g, 3.39mmol) and 25ml benzene, stirring and dissolving, add then triphenyl carbethoxyl group methine phosphine alkane (1.9g, 5.42mmol), reflux 2 hours, be chilled to room temperature, concentrate crude product, column chromatography purification (petrol ether/ethyl acetate=7:1, crude product/silica gel=1:50) get white solid Compound I-f992mg, yield is 69.5%.The I-f chemical compound:
Rf (n-hexane/ethyl acetate: 5/2): 0.66
1H-NMR(400MHZ，CDCl
3)：δ1.34(3H，t)，4.27(2H，q)，6.35(1H，d，J＝16.0Hz)，7.59(1H，d，J＝16.0Hz)，6.74(2H，s)，3.85(6H，s)，5.00(2H，s)，7.35(2H，d，J＝8.4Hz)，7.46(2H，d，J＝8.4Hz)。
Embodiment 22: the preparation of Compound I-b (3-[4-benzyloxy-3,5-dihydroxy-benzene] ethyl acrylate)
This example relate to a class have cytotoxic activity suc as formula 3,4 shown in (I), the general synthetic method of the trisubstituted cinnamic acid ethyl ester of 5-.Be specifically related to the preparation of Compound I-b (3-[4-benzyloxy-3,5-dihydroxy-benzene] ethyl acrylate).Make the intermediate of I-b chemical compound by the chemical compound V-A that makes according to embodiment 7 methods and triphenyl carbethoxyl group methine phosphine alkane by the method for embodiment 20, the method hydrolysis according to embodiment 8 obtains white solid Compound I-b again, and two step yields are 60%.
The I-b chemical compound:
Rf (n-hexane/ethyl acetate: 5/2): 0.28
1H-NMR(400MHZ，CDCl
3)：δ 1.34(3H，t)，4.27(2H，q)，6.30(1H，d，J＝16.0Hz)，7.53(1H，d，J＝16.0Hz)，6.70(2H，s)，5.09(2H，s)，7.40(5H，m)。
Method according to one of embodiment 21 and embodiment 22 prepares following table two illustrated embodiment 23-32 chemical compounds:
Table two
Face is listed the physicochemical data of each chemical compound in the table two:
I-a: white solid, Rf (n-hexane/ethyl acetate: 5/2) 0.63;
1H-NMR (400MHZ, CDCl
3): δ 1.34 (3H, t), 4.27 (2H, q), 6.30 (1H, d, J=16.0Hz), 7.53 (1H, d, J=16.0Hz) 6.70 (2H, s), 3.85 (6H, s), 5.09 (2H, s), 7.40 (5H, m);
I-c: white solid, Rf (n-hexane/ethyl acetate: 5/2) 0.68;
1H-NMR (400MHZ, CDCl
3): δ 1.35 (3H, t), 4.28 (2H, q), 6.36 (1H, d, J=16.0Hz), 7.61 (1H, d, J=16.0Hz, H-5), 6.76 (2H, s), 3.85 (6H, s), 5.13 (2H, s), 7.01 (1H, d, J=8.4Hz), 7.12 (1H, dd, J=8.4,2.4Hz), 7.69 (1H, d, J=2.4Hz);
I-d: white solid, Rf (n-hexane/ethyl acetate: 5/2) 0.78;
1H-NMR (400MHZ, CDCl
3): δ 1.35 (3H, t), 4.28 (2H, q), 6.35 (1H, d, J=16.0Hz), 7.61 (1H, d, J=16.0Hz), 6.76 (2H, s), 3.88 (6H, s), 4.01 (2H, t), 1.76 (2H, m), 1.44 (2H, m), 1.34 (2H, m), 1.27 (22H, m), 0.89 (3H, t);
I-e: white solid, Rf (n-hexane/ethyl acetate: 5/2) 0.65;
1H-NMR (400MHZ, CDCl
3): δ 1.34 (3H, t), 4.27 (2H, q), 6.35 (1H, d, J=16.0Hz), 7.59 (1H, d, J=16.0Hz), 6.74 (2H, s), 3.89 (6H, s), 5.00 (2H, s), 7.15 (1H, brd, J=7.2Hz), 7.52 (1H, dd, J=7.2,7.6Hz), 7.32 (1H, dd, J=7.2,7.6Hz), 7.75 (1H, brd, J=7.6Hz);
I-g: little yellow liquid, Rf (n-hexane/ethyl acetate: 5/2) 0.71;
1H-NMR (400MHZ, CDCl
3): δ 1.34 (3H, t), 4.26 (2H, q), 6.35 (1H, d, J=16.0Hz), 7.60 (1H, d, J=16.0Hz), 6.74 (2H, s), 3.88 (6H, s), 4.59 (2H, brd, J=7.2Hz), 5.55 (1H, brt, J=7.2Hz), 1.99 (4H, m), 5.07 (1H, brt), 1.67 (3H, s), 1.65 (3H, s), 1.59 (3H, s);
I-h: white solid, Rf (n-hexane/ethyl acetate: 5/2) 0.67;
1H-HMR (400MHZ, CDCl
3): δ 1.35 (3H, t), 4.27 (2H, q), 6.35 (1H, d, J=16.0Hz), 7.60 (1H, d, J=16.0Hz), 6.74 (2H, s), 3.86 (6H, s), 5.01 (2H, s), 7.37 (1H, brd, J=7.6Hz), 7.20 (1H, dd, J=7.6,8.0Hz), 7.43 (1H, brd, J=7.6Hz), 7.70 (1H, s);
I-i: white solid, Rf (n-hexane/ethyl acetate: 5/2) 0.63;
1H-NMR (400MHZ, CDCl
3): δ 1.34 (3H, t), 4.27 (2H, q), 6.35 (1H, d, J=16.0Hz), 7.60 (1H, d, J=16.0Hz), 6.74 (2H, s), 3.86 (6H, s), 5.00 (2H, s, H-1 '), 7.64 (1H, d, J=1.6Hz), 7.40 (1H, d, J=8.4Hz), 7.29 (1H, dd, J=8.4,1.6Hz);
I-j: white solid, Rf (n-hexane/ethyl acetate: 5/2) 0.59;
1H-NMR (400MHZ, CDCl
3): δ 1.34 (3H, t), 4.27 (2H, q), 6.35 (1H, d, J=16.0Hz), 7.59 (1H, d, J=16.0Hz), 6.73 (2H, s), 3.83 (6H, s), 5.08 (2H, s), 7.22 (1H, d, J=7.6Hz), 7.48 (1H, brd, J=7.6Hz), 7.29 (1H, brs);
I-k: white solid, Rf (n-hexane/ethyl acetate: 5/2) 0.61;
1H-NMR (400MHZ, CDCl
3): δ 1.34 (3H, t), 4.27 (2H, q), 6.34 (1H, d, J=16.0Hz), 7.59 (1H, d, J=16.0Hz), 6.73 (2H, s), 3.84 (6H, s), 4.98 (2H, s), 7.36 (2H, brd, J=8.4Hz), 6.85 (2H, brd, J=8.4), 4.03 (2H, q), 1.40 (3H, t);
I-1: colourless liquid, Rf (n-hexane/ethyl acetate: 5/2) 0.72;
1H-NMR (400MHZ, CDCl
3): δ 1.34 (3H, t), 4.26 (2H, q), 6.35 (1H, d, J=16.0Hz), 7.60 (1H, d, J=16.0Hz), 6.74 (2H, s), 3.87 (6H, s), 4.55 (2H, d, J=7.2Hz, H-1 '), 5.57 (1H, brt, J=6.8Hz), 2.02 (8H, m), 5.10 (1H, brt), 5.08 (1H, brt), 1.66 (3H, brs), 1.59 (3H, brs), 1.61 (3H, brs), 1.68 (3H, brs).
Embodiment 33: the preparation of Compound I I-f (3-[4-(4-bromo-benzyloxy)-3,5-dimethoxy benzene] acrylic acid)
This example relate to a class have cytotoxic activity suc as formula 3,4 shown in (II), the general synthetic method of the trisubstituted cinnamic acid of 5-.Be specifically related to the preparation of Compound I I-f (3-[4-(4-bromo-benzyloxy)-3,5-dimethoxy benzene] acrylic acid).With Compound I-f (122mg, 0.29mm0l) be added in the flask of 25ml, use the 5ml dissolve with ethanol, add potassium hydroxide aqueous solution (48mg, 0.87mmol, 3m1 water), reflux 3 hours is chilled to room temperature, and being concentrated into does not have the alcohol flavor, add 2ml water then, it is acid transferring to PH with 1M hydrochloric acid, as seen has the solid of a large amount of whites to separate out, with ether (10ml * 3) extraction, organic facies saturated common salt water washing, anhydrous sodium sulfate drying is dry to spend the night, and filters, concentrate 3-[4-(4-bromo-benzyloxy)-3, the 5-dimethoxy benzene] acrylic acid 110mg, yield 97%.
The II-f chemical compound:
Rf (n-hexane/ethyl acetate/formic acid: 3/1/0.05): 0.21
1H-NMR(400MHZ，CDCl
3)：δ 6.36(1H，d，J＝16.0Hz)，7.70(1H，d，J＝16.0Hz)，6.76(2H，s)，3.86(6H，s)，5.01(2H，s)，7.35(2H，d，J＝8.4Hz)，7.47(2H，d，J＝8.4Hz)。
Prepare following table three illustrated embodiment 34-44 chemical compounds according to the method identical with embodiment 33:
Table three
List the physicochemical data of each chemical compound in the table three below:
II-a: little yellow solid, Rf (n-hexane/ethyl acetate/formic acid: 3/1/0.05) 0.23;
1H-NMR (400MHZ, CDCl
3): δ 6.36 (1H, d, J=16.0Hz), 7.70 (1H, d, J=16.0Hz), 6.77 (2H, s), 3.86 (6H, s), 5.06 (2H, s), 7.47 (2H, brd, J=7.2Hz), 7.30-7.35 (3H, m);
II-b: little yellow liquid, Rf (n-hexane/ethyl acetate/formic acid: 3/1/0.05) 0.27;
1H-NMR (400MHZ, CDCl
3): δ 6.36 (1H, d, J=16.0Hz), 7.71 (1H, d, J=16.0Hz), 6.77 (2H, s), 3.89 (6H, s), 4.59 (2H, brd, J=7.2Hz), 5.55 (1H, brt, J=7.2Hz), 2.02 (4H, m), 5.07 (1H, brt), 1.67 (3H, s), 1.66 (3H, s), 1.59 (3H, s);
II-c: little yellow solid, Rf (n-hexane/ethyl acetate/formic acid: 3/1/0.05) 0.24;
1H-NMR (400MHZ, CDCl
3): δ 6.36 (1H, d, J=16.0Hz), 7.69 (1H, d, J=16.0Hz), 6.76 (2H, s), 3.85 (6H, s), 5.08 (2H, s, H-1 '), 7.68 (1H, d, J=8.4Hz), 7.10 (1H, dd, J=8.4,2.4Hz), 6.98 (1H, d, J=2.4Hz);
II-d: white solid, Rf (n-hexane/ethyl acetate/formic acid: 3/1/0.05) 0.28;
1H-NMR (400MHZ, CDCl
3): δ 6.35 (1H, d, J=16.0Hz), 7.70 (1H, d, J=16.0Hz), 6.77 (2H, s), 3.88 (6H, s), 4.01 (2H, t), 1.75 (1H, m), 1.44 (2H, m), 1.26 (24H, m), 0.88 (3H, t);
II-e: white solid, Rf (n-hexane/ethyl acetate/formic acid: 3/1/0.05) 0.24;
1H-NMR (400MHZ, CDCl
3): δ 6.37 (1H, d, J=16.0Hz), 7.72 (1H, d, J=16.0Hz), 6.78 (2H, s), 3.86 (6H, s), 5.15 (2H, s), 7.54 (1H, d, J=8.4Hz), 7.33 (1H, dd, J=8.4,1.6Hz, H-4 '), 7.16 (1H, dd, J=8.4,1.6Hz), 7.72 (1H, d, J=8.4Hz);
II-g: white solid, Rf (n-hexane/ethyl acetate/formic acid: 3/1/0.05) 0.21;
1H-NMR (400MHZ, CDCl
3): δ 6.36 (1H, d, J=15.6Hz), 7.70 (1H, d, J=15.6Hz), 6.76 (2H, s), 3.87 (6H, s), 5.02 (2H, s), 7.70 (1H, brs), 7.43 (1H, brd, J=7.6Hz), 7.1 (1H, dd, J=7.6,6.8Hz), 7.37 (1H, brd, J=6.8Hz);
II-h: white solid, Rf (n-hexane/ethyl acetate/formic acid: 3/1/0.05) 0.21;
1H-NMR (400MHZ, CDCl
3): δ 6.36 (1H, d, J=16.0Hz), 7.70 (1H, d, J=16.0Hz), 6.77 (2H, s), 3.88 (6H, s), 5.01 (2H, s), 7.64 (1H, s), 7.41 (1H, d, J=8.0Hz), 7.30 (1H, d, J=8.0Hz);
II-i: white solid Rf (n-hexane/ethyl acetate/formic acid: 3/1/0.05) 0.18;
1H-NMR (400MHZ, CDCl
3): δ 6.36 (1H, d, J=16.0Hz), 7.69 (1H, d, J=16.0Hz), 6.76 (2H, s), 3.85 (6H, s), 5.09 (2H, s), 7.23 (1H, d, J=8.0Hz), 7.48 (1H, brd, J=8.0Hz), 7.29 (1H, brs);
II-j: white solid, Rf (n-hexane/ethyl acetate/formic acid: 3/1/0.05) 0.21;
1H-NMR (400MHZ, CDCl
3): δ 6.35 (1H, d, J=15.6Hz), 7.70 (1H, d, J=15.6Hz), 6.76 (2H, s), 3.86 (6H, s), 5.00 (2H, s), 7.38 (2H, brd, J=8.4,6.8Hz), 6.85 (2H, brd, J=8.4,6.8Hz);
II-k: white solid, Rf (n-hexane/ethyl acetate/formic acid: 3/1/0.05) 0.23;
1H-NMR (400MHZ, CDCl
3): δ 6.50 (1H, d, J=16.0Hz), 7.61 (1H, d, J=16.0Hz), 7.06 (2H, s), 3.91 (6H, s), 5.05 (2H, s), 7.08 (1H, brs), 7.28-7.42 (3H, m);
II-m: little yellow liquid, Rf (n-hexane/ethyl acetate/formic acid: 3/1/0.05) 0.21;
1H-NMR (400MHZ, CDCl
3): δ 6.36 (1H, d, J=16.0Hz), 7.71 (1H, d, J=16.0Hz), 6.77 (2H, s), 3.89 (6H, s), 4.56 (2H, d, J=7.2Hz), 5.56 (1H, brt, J=7.2Hz), 2.03 (8H, m), 5.10 (1H, brt), 5.08 (1H, brt), 1.66 (3H, brs), 1.59 (3H, brs), 1.61 (3H, brs), 1.68 (3H, brs).
Embodiment 45: the preparation of compound III-e (3-[4-(4-bromo-benzyloxy)-3,5-dimethoxy benzene] propenyl)
This example relate to a class have cytotoxic activity suc as formula 3,4 shown in (III), the general synthetic method of the trisubstituted cinnamyl alcohol of 5-.Be specifically related to the preparation of compound III-e (3-[4-(4-bromo-benzyloxy)-3,5-dimethoxy benzene] propenyl).In a there-necked flask, add successively lithium aluminium hydride (28mg, 0.725mmol) and the 8ml ether, cryosel is bathed and is chilled to 0 ℃, (122mg 0.29mmol), stirs 30min to add the Compound I-f that is dissolved in the 2ml ether.Add the unnecessary lithium aluminium hydride of water decomposition, it is acid then transferring to PH with 1M hydrochloric acid, ether (10ml * 3) extracts, organic facies saturated common salt water washing, and anhydrous sodium sulfate drying spends the night, filter, filtrate dense crude product, column chromatography purification (petrol ether/ethyl acetate=3:1, crude product/silica gel=1:50) 3-[4-(4-bromo-benzyloxy)-3, the 5-dimethoxy benzene] propenyl 86mg, yield is 78.1%.Compound III-e:
White solid, Rf (n-hexane/ethyl acetate: 5/2): 0.17
1H-NMR(400MHZ，CDCl
3)：δ 4.45(2H，brd，J＝6.4Hz)，5.85(1H，dt，J＝12.0，6.4Hz)，6.52(1H，d，J＝12.0Hz)，6.46(2H，s)，3.83(6H，s)，4.95(2H，s)，7.37(2H，d，J＝8.0Hz)，7.47(2H，d，J＝8.0Hz)。
Prepare following table four illustrated embodiment 46-56 chemical compounds according to the method identical with embodiment 45:
Table four
List the physicochemical data of each chemical compound in the table four below:
III-a: white solid, Rf (n-hexane/ethyl acetate: 5/2) 0.17;
1H-NMR (400MHZ, CDCl
3): δ 4.32 (2H, brd, J=6.0Hz), 6.31 (1H, dt, J=12.0,6.0Hz), 6.52 (1H, d, J=12.0Hz), 6.61 (2H, s), 3.83 (6H, s), 5.01 (2H, s), 7.48 (2H, brd, J=7.6Hz), 7.28-7.36 (3H, m);
III-b: white solid, Rf (n-hexane/ethyl acetate: 5/2) 0.34;
1H-NMR (400MHZ, CDCl
3): δ 4.32 (2H, brd, J=4.8Hz), 6.30 (1H, dt, J=4.8,15.6Hz), 6.54 (1H, d, J=15.6Hz), 6.61 (2H, s), 3.85 (6H, s), 3.95 (2H, s), 1.74 (2H, m), 1.43 (2H, m), 1.26 (24H, m), 0.87 (3H, t);
III-c: white solid, Rf (n-hexane/ethyl acetate: 5/2) 0.19;
1H-NMR (400MHZ, CDCl
3): δ 4.32 (2H, brd, J=5.2Hz), 6.31 (1H, dt, J=15.6,5.2Hz), 6.54 (1H, d, J=15.6Hz), 6.31 (2H, s), 3.82 (6H, s), 5.07 (2H, s), 7.68 (1H, d, J=8.4Hz), 7.10 (1H, dd, J=8.4,2.4Hz), 6.98 (1H, d, J=2.4Hz);
III-d: white solid, Rf (n-hexane/ethyl acetate: 5/2) 0.19;
1H-NMR (400MHZ, CDCl
3): δ 4.33 (2H, brd, J=5.6Hz), 6.30 (1H, dt, J=5.6,15.6Hz), 6.55 (1H, d, J=15.6Hz), 6.62 (2H, s), 3.83 (6H, s), 5.09 (2H, s), 7.15 (1H, brd, J=7.2Hz), 7.52 (1H, dd, J=7.2,7.6Hz), 7.32 (1H, dd, J=7.2,7.6Hz), 7.75 (1H, brd, J=7.6Hz);
III-f: white solid, Rf (n-hexane/ethyl acetate: 5/2) 0.18;
1H-NMR (400MHZ, CDCl
3): δ 4.33 (2H, brd, J=5.6Hz), 6.30 (1H, dt, J=5.6,16.0Hz), 6.55 (1H, d, J=16.0Hz), 6.61 (2H, s), 3.85 (6H, s), 5.00 (2H, t), 7.22 (1H, brd, J=8.0Hz), 7.31 (1H, dd, J=8.0,8.0Hz), 6.98 (1H, dd, J=8.0,2.0Hz), 7.28 (1H, d, J=2.0Hz);
III-g: white solid, Rf (n-hexane/ethyl acetate: 5/2) 0.19;
1H-NMR (400MHZ, CDCl
3): δ 4.32 (2H, brd, J=5.6Hz), 6.30 (1H, dt, J=5.6,16.0Hz), 6.55 (1H, d, J=16.0Hz), 6.61 (2H, s), 3.86 (6H, s), 4.47 (2H, brd, J=7.2Hz), 5.57 (1H, brt, J=7.2Hz), 1.75 (3H, s), 1.67 (1H, s);
III-h: white solid, Rf (n-hexane/ethyl acetate: 5/2) 0.16;
1H-NMR (400MHZ, CDCl
3): δ 4.23 (2H, brd, J=6.8Hz), 6.35 (1H, dt, J=6.8,16.0Hz), 7.61 (1H, d, J=16.0Hz) 6.74 (2H, s), 3.86 (6H, s), 5.00 (2H, s), 7.64 (1H, d, J=1.6Hz), 7.40 (1H, d, J=8.4Hz), 7.29 (1H, d, J=8.4,1.6Hz);
III-i: white solid, Rf (n-hexane/ethyl acetate: 5/2) 0.17;
1H-NMR (400MHZ, CDCl
3): δ 4.27 (2H, brd, J=7.2Hz), 6.35 (1H, dt, J=7.2,16.0Hz), 7.59 (1H, d, J=16.0Hz), 6.73 (2H, s), 3.83 (6H, s), 5.08 (2H, s), 7.21 (1H, d, J=8.0Hz), 7.48 (1H, dd, J=8.0,1.6Hz), 7.29 (1H, d, J=1.6Hz);
III-j: white solid, Rf (n-hexane/ethyl acetate: 5/2) 0.12;
1H-NMR (400MHZ, CDCl
3): δ 4.32 (2H, brd, J=4.8Hz), 6.28 (1H, dt, J=4.8,16.0Hz), 6.55 (1H, d, J=16.0,4.8Hz), 6.59 (2H, s), 3.83 (6H, s), 4.94 (2H, s), 7.38 (2H, dd, J=6.8,2.0Hz), 6.84 (2H, dd, J=6.8,2.0Hz), 4.01 (2H, q), 1.41 (1H, t, J=2.0Hz);
III-k: the dense Rf of little yellow liquid (n-hexane/ethyl acetate: 5/2) 0.23;
1H-NMR (400MHZ, CDCl
3): δ 4.32 (2H, brd, J=5.6Hz), 6.29 (1H, dt, J=5.6,16.0Hz), 6.54 (1H, d, J=16.0Hz), 6.60 (2H, s), 3.86 (6H, s), 4.51 (2H, brd, J=7.2Hz), 5.57 (1H, brt, J=7.2Hz), 2.04 (4H, m), 5.08 (1H, brt), 1.68 (3H, s), 1.66 (3H, s), 1.59 (3H, s);
III-m: little yellow liquid, Rf (n-hexane/ethyl acetate: 5/2) 0.24;
1H-NMR (400 MHZ, CDCl
3): δ 6.60 (2H, s), 3.86 (6H, s), 6.54 (1H, d, J=15.6Hz), 6.35 (1H, dt, J=15.6,6.0Hz), 4.53 (2H, d, J=7.2Hz), 5.57 (1H, brt, J=7.2Hz), 2.02 (8H, m), 5.10 (1H, brt), 5.09 (1H, brt), 1.65 (3H, brs), 1.59 (3H, brs), 1.60 (3H, brs), 1.68 (3H, brs).
Embodiment 57: the preparation of compound IV-b (3-[4-(4-ethyoxyl-benzyloxy)-3,5-dimethoxy benzene] acrylic aldehyde)
This example relate to a class have cytotoxic activity suc as formula 3,4 shown in (IV), the general synthetic method of the trisubstituted cinnamaldehyde of 5-.Be specifically related to the preparation of compound IV-b (3-[4-(4-ethyoxyl-benzyloxy)-3,5-dimethoxy benzene] acrylic aldehyde).One of raw material that this is routine is chemical compound V-j (4-(4-ethyoxyl-benzyloxy)-3, a 5-dimethoxy benzaldehyde), and it is to be obtained by syringic aldehyde (VI) and the method for 4-ethyoxyl benzylalcohol by embodiment 10.((28 μ l 0.26mmol), and at room temperature stirred 24 hours to add 40% acetaldehyde solution then for 60mg, 0.19mmol) dissolving with chemical compound V-j with 1.5ml ethanol in reaction bulb.Reaction finishes the back makes solution reach saturated with sodium chloride and with extracted with diethyl ether (8ml * 3), organic layer spends the night with anhydrous sodium sulfate drying, filter, filtrate concentrate crude product, column chromatography purification (petrol ether/ethyl acetate=6:1, crude product/silica gel=1:50) 3-[4-(4-ethyoxyl-benzyloxy)-3, the 5-dimethoxy benzene] acrylic aldehyde 45mg, yield is 65%.
Rf (n-hexane/ethyl acetate: 5/2): 0.41
1H-NMR(400MHZ，CDCl3)：δ 9.68(1H，d，J＝7.6Hz)，6.63(1H，dd，J＝15.6，7.6Hz)，7.38(1H，d，J＝15.6Hz)，6.77(2H，s)，3.86(6H，s)，5.01(2H，s)，7.36(2H，d，J＝8.4Hz)，6.85(2H，d，J＝8.4Hz)，4.04(2H，q)，1.40(3H，t)。
Embodiment 58: the preparation of compound IV-d (3-[4-farnesyl-3,5-dimethoxy benzene] acrylic aldehyde)
This example relate to a class have cytotoxic activity suc as formula 3,4 shown in (IV), the general synthetic method of the trisubstituted cinnamaldehyde of 5-.Be specifically related to the preparation of compound IV-d (3-[-farnesyl-3,5-dimethoxy benzene] acrylic aldehyde).One of raw material that this is routine is compound III-m (3-[4-farnesyl-3, a 5-dimethoxy benzene] propenyl), and it is to make chemical compound V-l by initiation material farnesyl bromine and syringic aldehyde according to embodiment 9, and the method according to embodiment 20,47 makes then.(100mg 0.24mmol) is dissolved in 10mlCH with compound III-m
2Cl
2, in this solution, add Pyridinium chlorochromate on silica gel three oxygen aluminum mixture (PCC-Al then
2O
3, 750mg, 0.38mmol), stirring at room 3 hours is filtered at last, filtrate concentrate crude product, (yield is 70% to column chromatography purification for petrol ether/ethyl acetate=6:1, crude product/silica gel=1:50) obtain compound IV-d69mg.
Compound IV-d:
Rf (n-hexane/ethyl acetate: 5/2): 0.55
1H-NMR(400MHz，CDCl
3)：δ 9.68(1H，d，J＝7.6Hz)，6.64(1H，dd，J＝16.0，7.6Hz)，7.40(1H，d，J＝16.0Hz)，6.79(2H，s)，3.90(6H，s)，4.58(2H，d，J＝7.2Hz)，5.56(1H，brt，J＝6.8Hz)，2.02(8H，m)，5.10(1H，brt)，5.08(1H，brt)，1.67(3H，brs)，1.59(3H，brs)，1.60(3H，brs)，1.69(3H，brs)。
Method according to one of embodiment 57 and embodiment 58 prepares following table four illustrated embodiments 59 and embodiment 60 chemical compounds:
Table five
List the physicochemical data of each chemical compound in the table five below:
IV-a: little yellow solid, Rf (n-hexane/ethyl acetate: 5/2): 0.57;
1H-NMR (400MHZ, CDCl
3): δ 9.68 (1H, d, J=7.6Hz), 6.64 (1H, dd, J=16.0,7.6Hz), 7.40 (1H, d, J=16.0Hz), 6.78 (2H, s), 3.89 (6H, s), 4.61 (2H, brd, J=7.2Hz), 5.55 (1H, brt, J=7.2Hz), 2.04 (4H, m), 5.05 (1H, brt), 1.67 (3H, s), 1.65 (3H, s), 1.59 (3H, s);
IV-c: little yellow solid, Rf (n-hexane/ethyl acetate: 5/2): 0.38;
1H-NMR (400MHZ, CDCl
3): δ 9.69 (1H, d, J=7.6Hz), 6.64 (1H, dd, J=15.6,7.6Hz), 7.40 (1H, d, J=15.6Hz), 6.80 (2H, s), 3.91 (9H, s);
In order to understand essence of the present invention better, respectively with the inhibiting The pharmacological results of chemical compound, its new purposes in pharmaceutical field is described below to six kinds of tumor cell line growths.
Embodiment 61: compound IV-a is to the cytotoxic activity of KB cell
KB (oral epithelium cancer) cell contains 10% hyclone, the streptomycin of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturings in the culture medium.Cell is with every hole 5 * 10
3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of humid air.
The mensuration of cell survival rate is with improveing mtt assay.Cell is through after 24 hours hatch, and the dimethyl sulfoxide solution of the compound IV-a that will newly join joins in each hole with Concentraton gradient respectively, makes that the chemical compound ultimate density is respectively 100ug/mL in the hole, 33.3ug/mL, 11.1ug/mL and 3.7ug/mL.After 72 hours, the phosphate buffer that adds 10 μ L MTT (5mg/mL), continue 37 ℃ of cultivations after 4 hours again, removed unconverted MTT in centrifugal 5 minutes, add 200 μ L dimethyl sulfoxines in every hole, with the MTT crystal Jia Za (formazan) of dissolving and reducing, formed formazan microplate reader colorimetric under the 570nm wavelength, cell survival rate is by the ratio calculation of sample with respect to reference substance.Wherein compound IV-a is to KB cell 503nhibiting concentration IC
50Obtain by dose effect curve.
The IC of compound IV-a
50For: 2.40 * 10
-6M
Experiment conclusion: (the KB cell is Cytotoxic effective tool and the evaluation index of test compounds to tumor cell.KB cell half-inhibition concentration is reached 10
-6Other chemical compound of M level is hopeful to develop into antitumor drug) this experiment shows that this type of has the chemical compound of cinnamaldehyde structure, and the KB cell is had stronger cytotoxicity, might develop into the new medicine with antitumor action.
According to the method for embodiment 61, we have tested the pharmacologically active of all chemical compounds to the KB cell, and concrete data are example (seeing Table six) with several embodiment.
Table six
| Embodiment number | 62 | 63 | 64 | 65 |
| The chemical compound code name | II-a | II-e | III-k | V-j |
| IC 50(10 -5M) | 4.58 | 3.79 | 7.09 | 3.86 |
Embodiment 66: Compound I-b is to the cytotoxic activity of PC-3 cell
PC-3 (carcinoma of prostate) cell F-12 culture medium culturing contains 10% hyclone, the streptomycin of 100U/mL penicillin and 100U/mL in the culture medium.Cell is with every hole 5 * 10
3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of humid air.
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as embodiment 60.
The IC of Compound I-b
50For: 3.86 * 10
-5M
Experiment conclusion: this experiment shows that this type of has the chemical compound of benzaldehyde structure, and the PC-3 cell is had stronger cytotoxicity, might develop into the new medicine with antitumor action.
According to the method for embodiment 66, we have tested the pharmacologically active of all chemical compounds to the PC-3 cell, and concrete data are example (seeing Table seven) with several embodiment
Table seven
| Embodiment number | 67 | 68 | 69 | 70 |
| The chemical compound code name | III-d | III-h | III-k | V-g |
| IC 50(10 -5M) | 9.74 | 7.08 | 7.09 | 6.28 |
Embodiment 71: chemical compound V-k is to the cytotoxic activity of CNE cell
CNE (nasopharyngeal carcinoma) cell contains 10% hyclone, the streptomycin of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturings in the culture medium.With every hole 5 * 10
3The concentration of cell joins in 96 orifice plates, contains 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of humid air.
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as embodiment 61.
The IC of chemical compound V-k
50For: 3.90 * 10
-5M
Experiment conclusion: this experiment shows that this type of has the chemical compound of benzaldehyde structure, and the CNE cell is had stronger cytotoxicity, might develop into the new medicine with antitumor action.
According to the method for embodiment 71, we have tested the pharmacologically active of all chemical compounds to the CNE cell, and concrete data are example (seeing Table eight) with several embodiment.
Table eight
| Embodiment number | 72 | 73 | 74 | 75 |
| The chemical compound code name | II-m | III-d | III-f | III-g |
| IC 50(10 -5M) | 8.35 | 5.82 | 7.06 | 14.63 |
Embodiment 76: Compound I I-b is to the cytotoxic activity of A549 cell
A549 (people's pulmonary carcinoma) cell contains 10% hyclone, the streptomycin of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturings in the culture medium.Cell is with every hole 5 * 10
3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of humid air.
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as embodiment 61.
The IC of Compound I I-b
50For: 5.43 * 10
-5M
Experiment conclusion: this experiment shows that this type of has the chemical compound of cinnamic acid structure, and the A549 cell is had stronger cytotoxicity, might develop into the new medicine with antitumor action.
According to the method for embodiment 76, we have tested the pharmacologically active of all chemical compounds to the A549 cell, and concrete data are example (seeing Table nine) with several embodiment.
Table nine
| Embodiment number | 77 | 78 | 79 | 80 |
| The chemical compound code name | II-g | II-i | III-i | V-n |
| IC 50(10 -5M) | 6.73 | 5.93 | 10.89 | 6.88 |
Embodiment 81: the cytotoxic activity of compound III-1 pair BEL-7404 cell
BEL-7404 (people's hepatocarcinoma) cell contains 10% hyclone, the streptomycin of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturings in the culture medium.Cell is with every hole 5 * 10
3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of humid air.
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as embodiment 61.
The IC of compound III-l
50For: 3.13 * 10
-5M
Experiment conclusion: this experiment shows that this type of has the chemical compound of cinnamyl alcohol structure, and the BEL-7404 cell is had stronger cytotoxicity, might develop into the new medicine with antitumor action.
According to the method for embodiment 81, we have tested the pharmacologically active of all chemical compounds to the BEL-7404 cell, and concrete data are example (seeing Table ten) with several embodiment.
Table ten
| Embodiment number | 82 | 83 | 84 | 85 |
| The chemical compound code name | II-d | II-g | III-h | V-n |
| IC 50(10 -5M) | 5.58 | 3.18 | 4.16 | 10.47 |
Embodiment 86: compound IV-c is to the cytotoxic activity of Hela cell
Hela (human cervical carcinoma) cell contains 10% hyclone, the streptomycin of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturings in the culture medium.Cell is with every hole 5 * 10
3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of humid air.
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as embodiment 61.
The IC of compound IV-c
50For: 2.94 * 10
-5M
Experiment conclusion: this experiment shows that this type of has the chemical compound of cinnamaldehyde structure, and the Hela cell is had stronger cytotoxicity, might develop into the new medicine with antitumor action.
According to the method for embodiment 86, we have tested the pharmacologically active of all chemical compounds to the Hela cell, and concrete data are example (seeing Table 11) with several embodiment.
Table ten one
| Embodiment number | 87 | 88 | 89 | 90 |
| The chemical compound code name | III-c | III-d | III-h | V-f |
| IC 50(10 -5M) | 9.75 | 6.53 | 7.55 | 8.65 |
In order to understand essence of the present invention better, the various pharmaceutical dosage forms of using this compounds below respectively are the preparation method of tablet, capsule, injection, aerosol, suppository, membrane, drop pill, externally-applied liniment and ointment for example, and its new application in pharmaceutical field is described.
Embodiment 91:Tablet
With the chemical compound that contains chemical compound in claim 1 and the claim 2 (is example with compound IV-a) 2000mg, according to adding spoke material 8000mg behind the general pressed disc method mixing of pharmaceutics, be pressed into 100, every heavy 100mg.
Embodiment 92:Capsule
With the chemical compound that contains chemical compound in claim 1 and the claim 2 (is example with compound III-h) 2000mg, according to the requirement of pharmaceutics capsule with 8000mg spoke material mixing after, the Capsules of packing into, the heavy 100mg of each capsule.
Embodiment 93:Injection
With the chemical compound that contains chemical compound in claim 1 and the claim 2 (is example with chemical compound V-k) 2000mg, according to the conventional dose method, carry out activated carbon adsorption, behind 0.65 μ filtering with microporous membrane, insert nitrogen pot and make hydro-acupuncture preparation.Every canned 2ml of injection, canned 1000 bottles altogether.
Embodiment 94:Aerosol
With the chemical compound that contains chemical compound in claim 1 and the claim 2 (is example with compound III-i) 2000mg, after the dissolving of an amount of propylene glycol, add distilled water and other spoke material after, the settled solution of making 200ml is promptly.
Embodiment 95:Suppository
With the chemical compound that contains chemical compound in claim 1 and the claim 2 (is example with chemical compound V-n) 2000mg, it porphyrize adding glycerol is an amount of, grind well the back and add the glycerin gelatine that has melted, grind evenly, impouring has been coated with in the model of lubricant, makes 20 on chemical compound V-n bolt.
Embodiment 96:Membrane
With the chemical compound that contains chemical compound in claim 1 and the claim 2 (is example with chemical compound V-f) 2000mg, polyvinyl alcohol, medicinal glycerin, water etc. are stirred the dissolving of expansion post-heating, 80 eye mesh screens filter, and again chemical compound V-f are joined stirring and dissolving in the filtrate, 200 of the machine-processed films of filming.
Embodiment 97:Drop pill
With the chemical compound that contains chemical compound in claim 1 and the claim 2 (is example with Compound I I-g) 2000mg, behind substrate 700mg heat fused mixings such as gelatin, splash in the cryogenic liquid paraffin, make drop pill 100 balls altogether.
Embodiment 98:Externally-applied liniment
With the chemical compound that contains chemical compound in claim 1 and the claim 2 (is example with Compound I I-d) 2g, according to the conventional dose method, with spoke material 0.5g mixed grindings such as emulsifying agents, adding distil water is made to 50ml again.
Embodiment 99:Ointment
With the chemical compound that contains chemical compound in claim 1 and the claim 2 (is example with compound III-d) 2000mg, grind well promptly with oleaginous base 198g such as vaseline behind the porphyrize.
Claims (4)
1. formula V chemical compound is used for preparing the purposes of the medicine of preventing and treating tumor disease:
Wherein: substituent R
1And R
3Can be identical or different, be respectively hydrogen, contain the alkyl of 1～8 carbon;
Substituent R
2Be the alkyl or alkenyl that contains 1～16 carbon, replace or unsubstituted arylmethyl;
Wherein " replace or not replace " be meant that group can not be substituted or be substituted, substituent group is selected from halogen, amino, nitro, sulfydryl, cyano group, hydroxyl contains the alkyl of 1～8 carbon, containing 1～8 carbon has alkoxyl.
2. according to the purposes of claim 1, its Chinese style V chemical compound is:
3. pharmaceutical composition that is used to prevent and treat tumor disease, it contains the chemical compound or their officinal salt and the pharmaceutically acceptable auxiliaries that define in each according to claim 1-2 as active component of treatment effective dose.
4. according to the pharmaceutical composition of claim 3, its pharmaceutical dosage form is injection, tablet, capsule, aerosol, suppository, membrane, drop pill, externally-applied liniment, ointment.
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