CN104230869A - Substitutive flavonoid compound as well as preparation method and application thereof - Google Patents
Substitutive flavonoid compound as well as preparation method and application thereof Download PDFInfo
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- CN104230869A CN104230869A CN201410376529.3A CN201410376529A CN104230869A CN 104230869 A CN104230869 A CN 104230869A CN 201410376529 A CN201410376529 A CN 201410376529A CN 104230869 A CN104230869 A CN 104230869A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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Abstract
The invention relates to the technical field of biological medicines, and firstly provides a flavonoid compound shown as a general formula (I) and an application of the flavonoid compound in preparation of an anti-tumor medicine. In addition, the invention further provides a medicine composition containing the flavonoid compound. The flavonoid compound can be competitively combined with Bcl-2, Bcl-xL and Mcl-1 protein so as to specifically cause the apoptosis of tumor cells, so that the flavonoid compound can be possibly developed into a safe and efficient anti-cancer medicine of targeted Bcl-2 family protein. In addition, the compound provided by the invention also has good antifungal activity. Thus, based on data, the compound provided by the invention has good development prospects.
Description
Technical field
The present invention relates to medical art, more specifically, the present invention relates to flavonoid compound, the invention still further relates to the composition of this compounds, preparation method and for the preparation of the purposes in the treatment disease relevant to Bcl-2 protein family anti-apoptotic members high expression level or the medicine of symptom, antitumour drug and synergistic agent.
Background technology
Apoptosis is the programmed cell death carried out after cell is subject to certain token stimulus, is the basic biological phenomena of one of cell.And Bcl-2 protein family plays important regulating effect at apoptosis path.It can be divided into anti-apoptotic member (as Bcl-2, Bcl-x
l, Mcl-1 etc.) and short apoptosis member two class.Research shows that the overexpression of Bcl-2 protein family anti-apoptotic members can cause normal apoptosis path to be obstructed, relevant to the generation of numerous disease (as tumour, autoimmune disorder etc.), particularly one of tumour generation and the major reason that resistance occurs.（
Nature?2000,?407,?796-801;?Nat?Rev?Cancer?2004,?4,?592-603.）
Research shows that Bcl-2 protein family anti-apoptotic members is found in overexpression in many tumours, expression level difference in different tumour and different tumors subtypes (
oncogene 2003,22,8590-607; Oncogene 2008,27,6398-406).By the Anti-G value of the anti-apoptotic members of overexpression in inhibition tumor cell, can recover its normal apoptosis pathway, increase its susceptibility to chemotherapy radiotherapy, be the New Policy for the treatment of tumour.Bcl-2 protein family anti-cell anti-apoptotic member is combined with the Bcl-2 protein family conservative region (BH) 3 of short apoptosis member by the hydrophobic groove on its surface and interacts, and regulates the normal Apoptosis of cell.Micromolecular inhibitor, by being incorporated into anti-apoptotic member surface hydrophobicity groove, can disturbing short apoptosis member BH3 region to combine with it and play the apoptotic effect of promotion.(
nat Rev Cancer 2005,5,876-85; Kelly, P. N.; Cell Death Differ 2011,18,1414-24.) in recent years this type small molecular inhibitor cause the broad interest of investigator, find a series of micromolecular inhibitor by different approaches, wherein have four (ABT-199, ABT-263, AT-101, GX15-07) enter clinical study as oral antitumor drug.Result of study shows that Bcl-2 protein family anti-apoptotic members micromolecular inhibitor shows good antitumor action and to other antitumor drugs or radiocurable synergy synergy, has good development prospect.(Nat Rev Drug Discov 2008,7,989-100;
chinese Journal of New Drugs 2008,17,2008-2013.; Pharmacy progress 2004,28,97-103; Clin Cancer Res 2012,18,1-7; J Thorac Oncol 2011,6,1757-1760; Lung Cancer 2011,74,481-485)
Summary of the invention
The present invention seeks to provide the novel flavonoid compound of a class or its pharmacy acceptable salt.The present invention discloses the preparation method of this compounds, medical use and composition.
The present invention has the flavonoid compounds such as the luteolin of Bcl-2 protein family anti-apoptotic members inhibit activities for lead compound with this laboratory discovery in early stage, adopt Computer-Aided Drug Design technology, design, synthesized the flavonoid Bcl-2 protein family anti-apoptotic members micromolecular inhibitor of a class brand new, the active testing of kinds of tumor cells is shown, this compounds shows good anti-tumor activity, is expected to develop the anti-cancer agent becoming a class brand new.
In a first aspect of the present invention, provide the flavonoid compound shown in a kind of logical formula I or its pharmacy acceptable salt, solvate, prodrug or polymorphic form:
In formula, R
1a, R
1b, R
1c, R
1d, R
1e, R
1fbe the arbitrary class in following groups independently: a) hydrogen; B) hydroxyl; C) amino; The straight or branched alkoxyl group of the C1-8 d) replaced; E) – O (CH
2)
nr
2; F)-(CH
2)
nr
2; The straight or branched alkyl of the C1-8 g) replaced; The straight or branched thiazolinyl of the C2-6 h) replaced; The alkynyl of the straight or branched of the C2-6 i) replaced; The straight or branched alkanoyloxy of the C1-8 j) replaced;
N is 1-8, R
2for phenyl or the 3-8 unit heterocyclic aryl of replacement;
Described replacement to refer to replace by following one or more substituting group: hydrogen, C1-8 alkyl, C2-6 thiazolinyl, C2-6 alkynyl, halo C1-8 alkyl, C1-8 alkoxyl group, halogen, trifluoromethyl, nitro, cyano group, sulfonic group, carboxyl, hydroxyl, amino.
In another preference, in described compound, n is 1-3.
In another preference, in described compound, R
1a, R
1bcan be hydrogen or-(CH independently
2)
nr
2, but be hydrogen or-(CH when the two is different
2)
nr
2; R
1c, R
1e, R
1fcan be the straight or branched alkoxyl group, – O (CH of hydroxyl, amino, C1-8 independently
2)
nr
2, R
1dcan be the straight or branched alkoxyl group of hydroxyl, amino, C1-8 independently;
N is 1-8, R
2for phenyl or the 3-8 unit heterocyclic aryl of replacement;
Described replacement to refer to replace by following one or more substituting group: hydrogen, C1-8 alkyl, halo C1-8 alkyl, C1-8 alkoxyl group, halogen, trifluoromethyl, nitro, cyano group, sulfonic group, carboxyl.
In another preference, in described compound, R
1a, R
1bcan be hydrogen or substituted benzyl independently, but be hydrogen or substituted benzyl when the two is different; ; R
1c, R
1e, R
1fcan be hydroxyl, amino, the straight or branched alkoxyl group of C1-8, substituted benzyloxy independently, R
1dcan be the straight or branched alkoxyl group of hydroxyl, amino, C1-8 independently; Described replacement refers to that the one or more positions in 2,3 or 4 on phenyl ring are that following arbitrary group replaces: hydrogen, C1-8 alkyl, halo C1-8 alkyl, C1-8 alkoxyl group, halogen, trifluoromethyl, nitro, cyano group, sulfonic group, carboxyl.
In another preference, described compound is any one in following compounds:
In a second aspect of the present invention, provide a kind of composition, it contains compound described in first aspect present invention or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
In another preference, described composition is pharmaceutical composition.
In a third aspect of the present invention, provide the compound described in first aspect or the application of its pharmacy acceptable salt in the medicine preparing the disease relevant to Bcl-2 protein family anti-apoptotic members high expression level.
In another preference, described disease is tumour.More specifically, described tumour is leukemia or lung cancer.
In a third aspect of the present invention, additionally provide compound described in first aspect or its pharmacy acceptable salt is preparing the application in antifungal drug.
In a fourth aspect of the present invention, provide the preparation method of two class particular compound described in first aspect.
First, provide the preparation method of flavonoid compound IV, V that a kind of substituted benzyl replaces, it is characterized in that, comprise the following steps:
(1) chromocor compound II in the basic conditions, in inert solvent, reacts with the benzyl chloride that phenyl ring replaces for R, generates compound III;
(2) compound III, in acid condition, refluxes in inert solvent, reacting generating compound IV;
(3) as the R in compound IV
1d, R
1e, R
1fin one or more when being alkoxyl group, in inert solvent, add BBr3, the alkyl sloughing one or more alkoxyl group generates hydroxyl, and other group is constant, and compound IV is further converted to compound V;
In compound IV and compound V, the replacement position at substituted benzyl place is R
1aor R
1b; R
1d, R
1e, R
1fas claimed in claim 1; R
1d, R
1e, R
1fin be not the group of alkoxyl group, constant after reaction; The position of substitution of R refers to the one or more positions in 2,3 or 4 on phenyl ring, and R is that following arbitrary group replaces: hydrogen, C1-8 alkyl, halo C1-8 alkyl, halogen.
In another preference, the alkali used in the synthesis of described compound (III) is mineral alkali.Preferably, described mineral alkali is K
2cO
3.
In another preference, the reaction conditions used in the synthesis of described compound (III) is common heating or microwave.
In another preference, the inert solvent used in the synthesis of described compound (III) is DMF, DMSO or its combination.
In another preference, the acid used in the synthesis of described compound (IV) is organic acid.Preferably, the acid used is methylsulfonic acid or trifluoroacetic acid.
In another preference, the inert solvent used in the synthesis of described compound (IV) is chloroform.
In another preference, the inert solvent used in the synthesis of described compound (V) is methylene dichloride.
Secondly, additionally provide the preparation method of flavonoid compound VIII, IX that a kind of substituted benzyl replaces, it is characterized in that, comprise the following steps:
(1) chromocor compound VI in the basic conditions, in inert solvent, reacts with the benzyl chloride that phenyl ring replaces for R, generates compound VI I;
(2) compound VI I, under acidic conditions, refluxes in inert solvent, reacting generating compound VIII;
(3) as the R in compound VI II
1c, R
1d, R
1fin one or more when being alkoxyl group, in inert solvent, add BBr3, the alkyl sloughing one or more alkoxyl group generates hydroxyl, and other group is constant, and compound VI II is further converted to Compound I X;
R
1c, R
1d, R
1fas claimed in claim 1; R
1c, R
1d, R
1fin be not the group of alkoxyl group, constant after reaction; The position of substitution of R refers to the one or more positions in 2,3 or 4 on phenyl ring, and R is that following arbitrary group replaces: hydrogen, C1-8 alkyl, halo C1-8 alkyl, halogen.
In another preference, the alkali used in the synthesis of described compound (VII) is mineral alkali.Preferably, the mineral alkali used is K
2cO
3.
In another preference, the reaction conditions used in the synthesis of described compound (VII) is common heating or microwave.
In another preference, the inert solvent used in the synthesis of described compound (VII) is DMF, DMSO or its combination.
In another preference, the acid used in the synthesis of described compound (VIII) is organic acid.Preferably, the acid used is methylsulfonic acid or trifluoroacetic acid.
In another preference, the inert solvent used in the synthesis of described compound (VIII) is chloroform.
In another preference, the inert solvent used in the synthesis of described compound (IX) is methylene dichloride.
The medicinal compositions that the present invention relates to can be solid form or liquid form, and described pharmaceutical dosage form can be tablet, capsule, powder agent, granule, suspensoid or injection.When the compounds of this invention is used for such use, can with one or more pharmaceutically acceptable carrier or mixed with excipients, as solvent, thinner etc., and can with following form oral administration: tablet, pill, capsule, dispersible powder, particle or suspension (containing 0.05-5% suspension agent according to appointment), syrup (containing 10-50% is sugared according to appointment), with elixir (containing 20-50% ethanol of having an appointment), or with the administration of external application mode: ointment, gel, pastille adhesive plaster etc., or carry out parenteral routes with sterile injectable solution or form of suspension (containing 0.05-5% suspension agent of having an appointment in isotonic medium).Such as, these pharmaceutical preparations containing the about 0.01-99% mixed with carrier, can more preferably be about the activeconstituents of 0.1%-90% (weight).
" safe and effective amount " refers to: the amount of compound is enough to improve the state of an illness, and is unlikely to produce severe side effect.Safe and effective amount was determined according to the age, the state of an illness, the course for the treatment of etc. for the treatment of target.
" pharmaceutically acceptable carrier " refers to: one or more biocompatible solid or liquid filler or gelatinous mass, and their are applicable to people and use, and must have enough purity and enough low toxicity." consistency " herein means generation be in composition each component energy and compound of the present invention and they between mutually admix, and the curative effect of not obvious reduction compound.Pharmaceutically acceptable carrier part example has sugar (as glucose, sucrose, lactose etc.), starch is (as W-Gum, yam starch etc.), cellulose and its derivates is (as Xylo-Mucine, ethyl cellulose sodium, cellulose ethanoate etc.), gelatin, talcum powder, solid lubricant is (as sodium stearate, Magnesium Stearate), calcium sulfate, vegetables oil is (as soya-bean oil, sesame oil, peanut oil, olive wet goods), polyvalent alcohol is (as propylene glycol, glycerine, N.F,USP MANNITOL, sorbyl alcohol etc.), emulsifying agent (as Tweens), wetting agent (as sodium laurylsulfonate), tinting material, seasonings, stablizer, antioxidant, sanitas, apirogen water etc.
Flavonoid compound of the present invention shows and Bcl-2, Bcl-x
lbinding ability good with Mcl-1 albumen, particularly part of compounds Mcl-1 albumen shows better binding ability.Therefore these compounds have the medicine of the preparation disease relevant to Bcl-2 protein family anti-apoptotic members high expression level, and prepare the potential use that synergistic agent and other antitumor drug or radiotherapy share to treat tumour.
Flavonoid compound of the present invention shows good broad-spectrum anti-tumor activity, particularly part of compounds to human solid tumor's (lung cancer) and neoplastic hematologic disorder (leukemia) and shows better cytotoxic activity to human leukemia cell line.Therefore, compound of the present invention is expected good DEVELOPMENT PROSPECT.
In addition, flavonoid compound of the present invention has certain broad-spectrum antifungal activity in vitro, particularly part of compounds shows better inhibit activities to Candida glabrata, illustrates that the compounds of this invention has the present purposes of the medicine preparing anti-fungal infection.
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and can combining mutually between specifically described each technical characteristic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, tiredly no longer one by one to state at this.
Embodiment
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or according to the condition that manufacturer advises.Unless otherwise indicated, otherwise per-cent and number are weight percent and parts by weight.
embodiment 1-6:2-((3-benzyl-4-hydroxy-5-methyl oxygen base) phenyl)-5,7-dimethoxy-4 's
h-benzopyran-4-one (compound in table 1
1), 2-((2-benzyl-4-hydroxy-5-methyl oxygen base) phenyl)-5,7-dimethoxy-4 's
h-benzopyran-4-one (compound in table 1
5), 2-((3-benzyl-4,5-dihydroxyl) phenyl)-5,7-dihydroxyl-4
h-chromene-4 ketone (compound in table 1
3), 2-((3-benzyl-4,5-dihydroxyl) phenyl)-5-hydroxyl-7-methoxyl groups-4
h-chromene-4 ketone (compound in table 1
4), 2-((2-benzyl-4,5-dihydroxyl) phenyl)-5,7-dihydroxyl-4
h-chromene-4 ketone (compound in table 1
7) and 2-((2-benzyl-4,5-dihydroxyl) phenyl)-5-hydroxyl-7-methoxyl groups-4
h-chromene-4 ketone (compound in table 1
8) preparation:
1, the preparation of 2-hydroxyl-4,6-dimethoxys-methyl phenyl ketone
2,4,6-trihydroxy-acetophenone monohydrate (3.72g, 20mmol) is joined in acetone (60ml), add salt of wormwood (6.06g, 40mmol) under stirring, do not dissolve, slowly drip methyl-sulfate (4ml, 42mmol), drip and finish, stirring at room temperature 4 hours, level of response is monitored by TLC.Question response terminates, filtering solid insoluble, slowly adds water (100ml), repeatedly vibrates, and leaves standstill half an hour, and adularescent solid is separated out.Filter, dry white solid (3.0g), yield 75%.
2, the preparation of 4-benzyloxy-m-methoxybenzaldehyde
3-methoxy-4-hydroxybenzaldehyde (4.56g, 30mmol) is dissolved in DMF(45ml) in, add salt of wormwood (4.56g, 33mmol) and benzyl chloride (4.18g, 33mmol), reflux 6 hours, level of response is monitored by TLC.Question response terminates, and is cooled to room temperature, filtering solid insoluble, slowly adds water (150ml) under rapid stirring, leaves standstill a moment, and adularescent solid is separated out, and filters, dry white solid (5.8g), yield 80%.
3, (
e) preparation of-3-(4-(benzyloxy)-3-methoxyphenyl)-1-(2-hydroxyl-4,6-Dimethoxyphenyl) third-2-alkene-1-ketone
By intermediate 2-hydroxyl-4,6-dimethoxy-methyl phenyl ketone (2g, 10.2mmol) with intermediate 4-benzyloxy-m-methoxybenzaldehyde (2.5g, 10.2mmol) be dissolved in methyl alcohol (50ml), stir the potassium hydroxide aqueous solution (6ml) of lower slowly dropping 50%, solution colour turns yellow gradually, drips and finishes, stirring at room temperature 36 hours, level of response is monitored by TLC.After question response terminates, stir the lower hydrochloric acid soln dripping 1mol/L, be adjusted to PH=5, leave standstill a moment, filter and obtain yellow oily solid, with methyl alcohol (30ml) washing, filter, dry yellow solid (3.0g), yield about 70%.
4,2-((4-benzyloxy-3-methoxyl group) phenyl)-5,7-dimethoxy-4 's
hthe preparation of-benzopyran-4-one
By intermediate (
e)-3-(4-(benzyloxy)-3-methoxyphenyl)-1-(2-hydroxyl-4,6-Dimethoxyphenyl) the third-2-alkene-1-ketone (0.42g, 1mmol) be dissolved in pyridine (15ml), iodine (0.3g is added after dissolving, 1.2mmol), reflux, level of response is monitored by TLC.After reaction terminates, add enough saturated sodium thiosulfate solution, have solid to separate out under stirring, filter, re-crystallizing in ethyl acetate, obtains white solid 0.3g, yield 71%.
5,2-((3-benzyl-4-hydroxy-5-methyl oxygen base) phenyl)-5,7-dimethoxy-4 's
h-benzopyran-4-one (1) and 2-((2-benzyl-4-hydroxy-5-methyl oxygen base) phenyl)-5,7-dimethoxy-4 's
hthe preparation of-benzopyran-4-one (5)
By intermediate 2-((4-benzyloxy-3-methoxyl group) phenyl)-5,7-dimethoxy-4 's
h-benzopyran-4-one (1.25g, 3mmol) is dissolved in chloroform (16ml), adds methylsulfonic acid (4ml), is positioned in microwave reactor, under 300W condition, and reflux 13 minutes.After reaction terminates, washing (50ml), stratification, aqueous phase uses a small amount of washed with dichloromethane again, merges organic phase, dry concentrated, anti-phase (C18) column chromatography purification (MeOH:H
2o), separation and purification obtains compound
1with
5sterling, and 2-(4-hydroxyl-3-methoxyphenyl)-5,7-dimethoxy-4 's
h-benzopyran-4-one sterling.
6,2-((3-benzyl-4,5-dihydroxyl) phenyl)-5,7-dihydroxyl-4
h-chromene-4 ketone (3) and 2-((3-benzyl-4,5-dihydroxyl) phenyl)-5-hydroxyl-7-methoxyl group-4
hthe preparation of-chromene-4 ketone (4)
By 2-((3-benzyl-4-hydroxy-5-methyl oxygen base) phenyl)-5,7-dimethoxy-4 's
h-benzopyran-4-one (
1) (0.5g, 1.19mmol) be dissolved in anhydrous methylene chloride (10ml) ,-30
ounder C stirs, slowly drip the boron tribromide dichloromethane solution (10ml) of 1M, solution slowly turns yellow, and drip and finish, be naturally warming up to room temperature, TLC monitors reaction process.After reaction terminates, in reaction solution, slowly add water (30ml), be extracted with ethyl acetate, collect organic phase, concentrated, anti-phase (C18) column chromatography purification (MeOH:H
2o), separation and purification obtains compound
3with
4sterling.
7,2-((2-benzyl-4,5-dihydroxyl) phenyl)-5,7-dihydroxyl-4
h-chromene-4 ketone (7) and 2-((2-benzyl-4,5-dihydroxyl) phenyl)-5-hydroxyl-7-methoxyl group-4
hthe preparation of-chromene-4 ketone (8)
By intermediate 2-((2-benzyl-4,5-dihydroxyl) phenyl)-5-hydroxyl-7-methoxyl group-4
h-chromene-4 ketone (
5) (0.5g, 1.19mmol) be dissolved in anhydrous methylene chloride (10ml) ,-30
ounder C stirs, slowly drip the boron tribromide dichloromethane solution (10ml) of 1M, solution slowly turns yellow, and drip and finish, be naturally warming up to room temperature, TLC monitors reaction process.After reaction terminates, in reaction solution, slowly add water (30ml), be extracted with ethyl acetate, collect organic phase, concentrated, anti-phase (C18) column chromatography purification (MeOH:H
2o), separation and purification obtains compound
7with
8sterling.
embodiment 7-8:2-((3-benzyl-4-hydroxy-5-methyl oxygen base) phenyl)-5-hydroxyl-7-methoxyl groups-4
h-benzopyran-4-one (compound in table 1
2) and 2-((2-benzyl-4-hydroxy-5-methyl oxygen base) phenyl)-5-hydroxyl-7-methoxyl groups-4
h-benzopyran-4-one (compound in table 1
6) preparation:
1,2-((4-benzyloxy-3-methoxyl group) phenyl)-5-hydroxyl-7-methoxyl groups-4
hthe preparation of-benzopyran-4-one
By intermediate (
e)-3-(4-(benzyloxy)-3-methoxyphenyl)-1-(2-hydroxyl-4,6-Dimethoxyphenyl) the third-2-alkene-1-ketone (0.42g, 1mmol) be dissolved in pyridine (15ml), iodine (0.5g is added after dissolving, 2mmol), reflux, level of response is monitored by TLC.After reaction terminates, add enough saturated sodium thiosulfate solution, have solid to separate out under stirring, filter, re-crystallizing in ethyl acetate, obtains white solid (0.25g), yield 59%.
2,2-((3-benzyl-4-hydroxy-5-methyl oxygen base) phenyl)-5-hydroxyl-7-methoxyl groups-4
h-benzopyran-4-one (2) and 2-((2-benzyl-4-hydroxy-5-methyl oxygen base) phenyl)-5-hydroxyl-7-methoxyl group-4
hthe preparation of-benzopyran-4-one (6)
By intermediate 2-((4-benzyloxy-3-methoxyl group) phenyl)-5-hydroxyl-7-methoxyl group-4
h-benzopyran-4-one (1.25g, 3mmol) is dissolved in chloroform (16ml), adds methylsulfonic acid (4ml), is positioned in microwave reactor, under 300W condition, and reflux 13 minutes.After reaction terminates, washing (50ml), stratification, aqueous phase uses a small amount of washed with dichloromethane again, merges organic phase, dry concentrated, anti-phase (C18) column chromatography purification (MeOH:H
2o), separation and purification obtains compound
2with
6sterling, and 2-(4-hydroxyl-3-methoxyphenyl)-5-hydroxyl-7-methoxyl group-4
h-benzopyran-4-one sterling.
embodiment 9-12:2-(3,4-Dimethoxyphenyl)-5-benzyloxy-7-methoxyl group-4
h-benzopyran-4-one (compound in table 1
9), 2-((2-benzyl-4,5-dimethoxy) phenyl)-5-hydroxyl-7-methoxyl groups-4
h-chromene-4 ketone (compound in table 1
10), 2-((2-benzyl-4,5-dihydroxyl) phenyl)-5,7-dihydroxyl-4
h-chromene-4 ketone (compound in table 1
7) and 2-((2-benzyl-4,5-dihydroxyl) phenyl)-5-hydroxyl-7-methoxyl groups-4
h-chromene-4 ketone (compound in table 1
8) preparation:
1, (
e) preparation of-3-(3,4-dimethoxy phenyl)-1-(2-hydroxyl-4,6-Dimethoxyphenyl) third-2-alkene-1-ketone
2-hydroxyl-4,6-dimethoxys-methyl phenyl ketone (0.5 g, 2.5mmol) is dissolved in 9ml methyl alcohol, adds 3,4-dimethoxy benzaldehyde (0.42g, 2.5mmol), 3,4-dimethoxy benzaldehyde adds the potassium hydroxide aqueous solution (4.5ml) of 50%, stirring at room temperature 36 hours after dissolving.After question response terminates, regulate PH<7 with the hydrochloric acid soln of 1mol/L.Reaction solution filtered on buchner funnel, collects yellow solid.Filtrate extracts by ethyl acetate (30ml × 2).Merge organic phase, anhydrous MgSO4 is dry, underpressure distillation.Merge yellow solid, add methyl alcohol (50ml) wherein, stir 5 minutes, filter, collect filter cake, obtain yellow solid 0.64g, yield 72.7%.
2,2-(3,4-dimethoxy) phenyl)-5-hydroxyl-7-methoxyl group-4
hthe preparation of-benzopyran-4-one
By intermediate (
e)-3-(3,4-dimethoxy phenyl)-1-(2-hydroxyl-4,6-Dimethoxyphenyl) third-2-alkene-1-ketone (0.6 g, 1.7mmol) be dissolved in 8ml pyridine, then add iodine (0.86g, 3.4mmol), reflux stirs 13 hours.After completion of the reaction, add hypo solution 30ml, filter, crude product ethyl acetate (20ml) recrystallization obtains yellow solid 0.41g, yield 72%.
3,2-(3,4-Dimethoxyphenyl)-5-benzyloxy-7-methoxyl group-4
hthe preparation of-benzopyran-4-one (9)
By 2-(3,4-dimethoxy) phenyl)-5-hydroxyl-7-methoxyl group-4
h-benzopyran-4-one (1.72 g, 5.2mmol) is dissolved in 30mlDMF, then adds salt of wormwood (0.8 g, 5.72mmol), adds benzyl chloride (1.33g, 10.4mmol) reflux and stir 6 hours.After reaction terminates, add 100ml water in reaction solution, filter, filtrate extracts by ethyl acetate (20ml × 3).Merge organic phase, anhydrous MgSO4 is dry, underpressure distillation.Merge crude product silica gel column chromatography (ethyl acetate/normal hexane=1:4) to obtain
9sterling.
4,2-((2-benzyl-4,5-dimethoxy) phenyl)-5-hydroxyl-7-methoxyl groups-4
hthe preparation of-chromene-4 ketone (10)
By intermediate 2-(3,4-Dimethoxyphenyl)-5-benzyloxy-7-methoxyl group-4
h-benzopyran-4-one (1g, 2.4mmol) is dissolved in 8ml chloroform, pours in the microwave reaction bottle of 30ml, adds methylsulfonic acid 2ml, reacts 1 hour under 65 DEG C of conditions.In reaction flask, add 20ml methylene dichloride, 20ml water washing, organic phase is dry with anhydrous MgSO4, and underpressure distillation, obtains crude product, anti-phase (C18) column chromatography purification (MeOH:H
2o), separation and purification obtains compound
10sterling and 2-(3,4-dimethoxy) phenyl)-5-hydroxyl-7-methoxyl group-4
h-benzopyran-4-one sterling.
5,2-((2-benzyl-4,5-dihydroxyl) phenyl)-5,7-dihydroxyl-4
h-chromene-4 ketone (7) and 2-((2-benzyl-4,5-dihydroxyl) phenyl)-5-hydroxyl-7-methoxyl group-4
hthe preparation of-chromene-4 ketone (8)
By intermediate 2-((2-benzyl-4,5-dimethoxy) phenyl)-5-hydroxyl-7-methoxyl group-4
h-chromene-4 ketone (0.4g, 0.96mmol) is dissolved in 10ml DCM, and solution cools to-30 DEG C, gets 1mlBBr3 and is dissolved in 9mlDCM, and be added drop-wise in above-mentioned solution by the BBr3 solution prepared, reaction solution at room temperature stirs 3 hours.Add 30ml water subsequently, add 20ml ethyl acetate, merge organic phase, anhydrous MgSO4 is dry, underpressure distillation, crude product anti-phase (C18) column chromatography purification (MeOH:H
2o), separation and purification obtains compound
7with
8sterling.
embodiment 13-19:2-((3 – methoxyl group-4-(2-chlorobenzyl)) phenyl)-5,7-dimethoxy-4 's
h-benzopyran-4-one (compound in table 1
11), 2-((3-(2-chlorobenzyl)-4-hydroxy-5-methyl oxygen base) phenyl)-5,7-dimethoxy-4 's
h-benzopyran-4-one (compound in table 1
20), 2 – ((2-(2-chlorobenzyl)-4-hydroxy-5-methyl oxygen base) phenyl)-5,7-dimethoxy-4 's
h-benzopyran-4-one (compound in table 1
47), 2 – ((3 – (2-chlorobenzyl)-4,5-dihydroxyl) phenyl)-5,7-dihydroxyl-4
h-benzopyran-4-one (compound in table 1
29), 2 – ((3-(2-chlorobenzyl)-4,5-dihydroxyl) phenyl)-5-hydroxyl-7-methoxyl group-4
h-benzopyran-4-one (compound in table 1
38), 2 – ((2 – (2-chlorobenzyl)-4,5-dihydroxyl) phenyl)-5,7-dihydroxyl-4
h-benzopyran-4-one (compound in table 1
56) and 2 – ((2-(2-chlorobenzyl)-4,5-dihydroxyl) phenyl)-5-hydroxyl-7-methoxyl group-4
h-benzopyran-4-one (compound in table 1
65) preparation:
1,2-((3 – methoxyl group-4-(2-chlorobenzyl)) phenyl)-5,7-dimethoxy-4 's
hthe preparation of-benzopyran-4-one (11)
By intermediate 2-(4-hydroxyl-3-methoxyphenyl)-5,7-dimethoxy-4 's
h-benzopyran-4-one (0.98g, 3mmol) is dissolved in DMF(15ml) in, under stirring, add salt of wormwood (0.46g, 3.3mmol), solid is not molten.Add 2-benzyl chloride chlorine (0.53g, 3.3mmol) reflux 2 hours, TLC point plate monitoring reaction process.Reaction terminates, and filtering solid insoluble, slowly adds 75ml water under rapid stirring, leaves standstill a moment, and adularescent solid is separated out, and filters, dry white solid 2-(4-(2-chlorine benzyloxy)-3-methoxyphenyl)-5,7-dimethoxy-4 's
h-benzopyran-4-one (1.09g), yield 80%.
1H?NMR?(600?MHz,?DMSO)?δ?7.64?–?7.59?(m,?2H,?-Ar-H),?7.56?(d,?
J?=?2.2?Hz,?1H),?7.53?–?7.51?(m,?1H,?-Ar-H),?7.41?–?7.39?(m,?2H,?-Ar-H),?7.20?(d,?
J?=?8.6?Hz,?1H),?6.85?(d,?
J?=?2.3?Hz,?1H,?H-8),?6.77?(s,?1H,?H-3),?6.49?(d,?
J?=?2.3?Hz,?1H,?H-6),?5.23?(s,?2H,?-CH
2-),?3.89?(s,?3H,?-OCH
3),?3.89?(s,?3H,?-OCH
3)?,?3.82?(s,?3H,?-OCH
3).?MS?(ESI):?m/z?453.43?(M?+H)
+。
2,2 – ((3-(2-chlorobenzyl)-4-hydroxy-5-methyl oxygen base) phenyl)-5,7-dimethoxy-4 's
h-benzopyran-4-one (9) and 2-((2-(2-chlorobenzyl)-4-hydroxy-5-methyl oxygen base) phenyl)-5,7-dimethoxy-4 's
hthe preparation of-benzopyran-4-one (12)
By intermediate 2-(4-(2-chlorine benzyloxy)-3-methoxyphenyl)-5,7-dimethoxy-4 's
h-benzopyran-4-one (1.36g, 3mmol) is dissolved in 16ml anhydrous chloroform, adds 4ml methylsulfonic acid, is positioned in microwave reactor, under 300W condition, and reflux 13 minutes.After reaction terminates, washing (50ml), stratification, aqueous phase uses a small amount of washed with dichloromethane again, merges organic phase, dry concentrated, anti-phase (C18) column chromatography purification (MeOH:H
2o), separation and purification obtains compound
9with
12sterling, and 2-(4-hydroxyl-3-methoxyphenyl)-5,7-dimethoxy-4 's
h-benzopyran-4-one sterling.
3,2 – ((3 – (2-chlorobenzyl)-4,5-dihydroxyl) phenyl)-5,7-dihydroxyl-4
h-benzopyran-4-one (10) and 2 – ((3-(2-chlorobenzyl)-4,5-dihydroxyl) phenyl)-5-hydroxyl-7-methoxyl group-4
hthe preparation of-benzopyran-4-one (11)
By intermediate 2-(3-(2-chlorobenzyl)-4-hydroxy-5-methyl oxygen base phenyl)-5,7-dimethoxy-4 's
h-benzopyran-4-one (0.6g, 1.32mmol) is dissolved in 10ml anhydrous methylene chloride, and-30
ounder C stirs, slowly drip the boron tribromide dichloromethane solution (10ml) of 1M, solution slowly turns yellow, and drip and finish, be naturally warming up to room temperature, TLC monitors reaction process.After reaction terminates ,-30
oslowly add water (30ml) in C downhill reaction liquid, drip and finish, be extracted with ethyl acetate, collect organic phase, concentrated, anti-phase (C18) column chromatography purification (MeOH:H
2o), separation and purification obtains compound
10with
11sterling.
4,2 – ((2 – (2-chlorobenzyl)-4,5-dihydroxyl) phenyl)-5,7-dihydroxyl-4
h-benzopyran-4-one (13) and 2 – ((2-(2-chlorobenzyl)-4,5-dihydroxyl) phenyl)-5-hydroxyl-7-methoxyl group-4
hthe preparation of-benzopyran-4-one (14)
By intermediate 2-(2-(2-chlorobenzyl)-4-hydroxy-5-methyl oxygen base phenyl)-5,7-dimethoxy-4 's
h-benzopyran-4-one (0.6g, 1.32mmol) is dissolved in 10ml anhydrous methylene chloride, and-30
ounder C stirs, slowly drip the boron tribromide dichloromethane solution (10ml) of 1M, solution slowly turns yellow, and drip and finish, be naturally warming up to room temperature, TLC monitors reaction process.After reaction terminates ,-30
oslowly add water (30ml) in C downhill reaction liquid, drip and finish, be extracted with ethyl acetate, collect organic phase, concentrated, anti-phase (C18) column chromatography purification (MeOH:H
2o), separation and purification obtains compound
13with
14sterling.
embodiment 20-73
Repeat embodiment 13-19, difference is: use different raw materials, thus compound in obtained table 1
12-19,21-28,48-55,30-37,39-46,57-64,66-73.Specific as follows:
(1) by intermediate 2-(4-hydroxyl-3-methoxyphenyl)-5,7-dimethoxy-4 's
h-benzopyran-4-one and 3-benzyl chloride chlorine, 4-benzyl chloride chlorine, 2-methyl benzyl chlorine, 3-methyl benzyl chlorine, 4-methyl benzyl chlorine, 2-trifluoromethyl benzyl chlorine, 3-trifluoromethyl benzyl chlorine, 4-trifluoromethyl benzyl chlorine react and can distinguish compound in synthetic table 1
12-19.
(2) compound in table 1
12-19be dissolved in chloroform, add methylsulfonic acid, in microwave reactor, reaction can synthesize three products respectively, is specially compound in table 1
21-28with compound in table 1
48-55, and 2-(4-hydroxyl-3-methoxyphenyl)-5,7-dimethoxy-4 's
h-benzopyran-4-one.
(3) compound in table 1
21-28be dissolved in methylene dichloride, two products can be synthesized respectively under boron tribromide effect, be specially compound in table 1
30-37with compound in table 1
39-46.
(4) compound in table 1
48-55be dissolved in methylene dichloride, two products can be synthesized respectively under boron tribromide effect, be specially compound in table 1
57-64with compound in table 1
66-73.
The present invention synthesis general formula (
i) in the chemical structure of target product in table 1.Nucleus magnetic hydrogen spectrum and mass spectrometer system characterize the chemical structure of target product, and its concrete data are in table 2.
Table 1 general formula (
i) middle target compound structure
Table 2 general formula (
i) in target compound hydrogen spectrum and mass-spectrometric data
embodiment 74:Bcl-2, Bcl-x
l
test with Mcl-1 protein affinity
experimental technique:with reference to previous work and pertinent literature (
bioorg Med Chem Lett 2012,22,39-44; ChemMedChem 2011,6,904-21), with gossypol acetate (AT-101) and luteolin (contrast 1) medicine in contrast, fluorescence polarization (FP) method is adopted to investigate target compound Competitive assays Bcl-2, Bcl-x
lthe ability combined with the BH3 peptide section (fluorescein-labelled) of Mcl-1 albumen and pro apoptotic protein Bim or Bid is to evaluate the avidity of itself and target protein.Fluorescence polarization signal is detected under excitation wavelength 485nm and wavelength of transmitted light are the condition of 535nm by spectrophotofluorometer.By the BH3 peptide section of series concentration target compound and fluorescein-labeled Bim or Bid and Bcl-2, Bcl-x
lor Mcl-1 albumen is at room temperature cultivated after 20 minutes together, detects its fluorescence polarization signal, calculate this compound
iC 50value.And according to the total protein concentration, the total concn of fluorescent polypeptide, the dissociation constant of albumen-polypeptide complex and the detection compound that use in measuring
iC 50 value, calculates the competitive inhibition constant of detection compound
k i .(test-results is in table 3)
Table 3 general formula (
i) in sample segment and Bcl-2, Bcl-x
lwith Mcl-1 protein affinity
IR: inhibiting rate
Result shows, flavonoid compound of the present invention shows and Bcl-2, Bcl-x
lbinding ability good with Mcl-1 albumen, particularly part of compounds Mcl-1 albumen shows better binding ability.Therefore these compounds have the medicine of the preparation disease relevant to Bcl-2 protein family anti-apoptotic members high expression level, and prepare the potential use that synergistic agent and other antitumor drug or radiotherapy share to treat tumour.
embodiment 75: anti tumor activity in vitro testing experiment
1, experimental strain:
This experiment adopts tumour cell strain to be respectively: A549(human lung carcinoma cell), HL-60(human leukemia cell) (purchased from Shanghai Institute of Pharmaceutical Industry).
2, sample preparation:
After dissolving with DMSO (Merck), add PBS (-) and be made into the solution of 1000mg/mL or uniform suspension, then dilute with the PBS (-) containing DMSO.Positive control drug is ABT-737, luteolin (contrast 1) and 2-(3-methoxyl group-4-benzyloxy) phenyl that Abbott develops)-5,7-dimethoxy-4 's
h-benzopyran-4-one (contrast 2).
3, test method
Experimentally detect and pertinent literature (
bioorg Med Chem Lett 2012,22,39-44; Nature. 2005,437,677-681), adopt mtt assay.It is 4 ~ 5 × 10 that the 96 every holes of orifice plate add concentration
4cell suspension 100 mL of individual/mL, puts 37 DEG C, 5% CO
2in incubator.After 24 h, add sample liquid, 10 mL/ holes, if duplicate hole, 37 DEG C, 5% CO
2act on 72 h.Every hole adds MTT solution 20 mL of 5 mg/mL, adds lysate after acting on 4 h, and 100 mL/ holes, put in incubator, surveys 570 nm OD values after dissolving by the full-automatic microplate reader of MK-2.(anti tumor activity in vitro is in table 4)
Table 4 general formula (
i) in sample segment to the in-vitro multiplication restraining effect of human body tumour cell
IR: inhibiting rate
As known from Table 4, flavonoid compound of the present invention shows good broad-spectrum anti-tumor activity to human solid tumor's (lung cancer) and neoplastic hematologic disorder (leukemia), particularly part of compounds shows better cytotoxic activity to human leukemia cell line, imply that compound of the present invention is expected good DEVELOPMENT PROSPECT.
embodiment 76: extracorporeal antifungal activity testing experiment
1, experimental strain
This experiment has selected following 2 kinds of common human body cause illness's standard fungal bacterial strains as screening object, and fungal bacterial strain provides by Changhai hospital Mycology Lab.Comprise Candida glabrata (
candida glabrata) and cryptococcus neoformans (
cryptococcus neoformans).
2, test method
Adopt conventional antibacterial experiment in vitro method (referring to: Antimicrob Agents Chemother 1995,39 (5): 1169).
Bacterium solution preparation: coccus cultivates 16h at YEPD liquid nutrient medium 35 ° of C, activation twice, with blood cell counting plate counting, with RPMI RPMI-1640 adjustment bacterial concentration to 1 × 103 ~ 5 × 103/ml; Thread fungus is seeded to SDA inclined-plane, 35 DEG C, cultivates one week, activation twice, makes bacterial strain cover SDA inclined-plane, adds appropriate RPMI1640 nutrient solution, blow and beat bacterium colony with suction pipe, make fungal spore be free in RPMI1640 nutrient solution, then filter through four layers of sterile gauze.Nutrient solution, after blood cell counting plate counting, adds RPMI1640 nutrient solution adjustment spore concentration to 1 × 103 ~ 5 × 103/ml.
Prepared by liquid: test medicine is made into 6.4 gL with DMSO respectively
-1
Inoculation: 96 No. 1, orifice plate holes add RPMI1640 100 μ l and make blank, and 3-12 hole respectively adds bacteria suspension 100 μ l, and No. 2 holes add bacteria suspension 180 μ l and liquid 20 μ l, 2-11 hole moral drug level makes 10 grades of doubling dilutions, and each hole drug level is respectively 64,32,16,8,4,2,1,0.5,0.25,0.125 μ g/mL.No. 12 holes do not add liquid, do positive control, and drug control is fluconazole and luteolin (contrast 1).
Cultivate and detect: Candida cultivates 24 hours measurement results.Each hole OD value is surveyed in 630 nm with enzyme micro-plate reader.With positive control boring ratio, with the drug level in the minimum concentration hole of OD value decline more than 80% for MIC
80.(antibacterial experiment in vitro the results are shown in Table 5)
Table 5 general formula (
i) middle sample segment In Vitro Anti fungi minimal inhibitory concentration value (MIC, mgL
-1)
As known from Table 5, flavonoid compound of the present invention has certain broad-spectrum antifungal activity in vitro, particularly part of compounds shows better inhibit activities to Candida glabrata, illustrates that the compounds of this invention has the present purposes of the medicine preparing anti-fungal infection.
To sum up, the invention provides the flavonoid compound that a class replaces, there is good anti-tumor activity and anti-mycotic activity, there is good DEVELOPMENT PROSPECT.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the prerequisite not departing from the inventive method; can also make some improvement and supplement, these improve and supplement and also should be considered as protection scope of the present invention.
Claims (12)
1. a class general formula (
i) shown in flavonoid compound or its pharmacy acceptable salt, solvate, prodrug or polymorphic form:
（
Ⅰ）
In formula, R
1a, R
1b, R
1c, R
1d, R
1e, R
1fbe the arbitrary class in following groups independently: a) hydrogen; B) hydroxyl; C) amino; The straight or branched alkoxyl group of the C1-8 d) replaced; E) – O (CH
2)
nr
2; F)-(CH
2)
nr
2; The straight or branched alkyl of the C1-8 g) replaced; The straight or branched thiazolinyl of the C2-6 h) replaced; The alkynyl of the straight or branched of the C2-6 i) replaced; The straight or branched alkanoyloxy of the C1-8 j) replaced;
N is 1-8, R
2for phenyl or the 3-8 unit heterocyclic aryl of replacement;
Described replacement to refer to replace by following one or more substituting group: hydrogen, C1-8 alkyl, C2-6 thiazolinyl, C2-6 alkynyl, halo C1-8 alkyl, C1-8 alkoxyl group, halogen, trifluoromethyl, nitro, cyano group, sulfonic group, carboxyl, hydroxyl, amino.
2. compound as claimed in claim 1, it is characterized in that, n is 1-3.
3. compound as claimed in claim 1, is characterized in that, R
1a, R
1bcan be hydrogen or-(CH independently
2)
nr
2, but be hydrogen or-(CH when the two is different
2)
nr
2; R
1c, R
1e, R
1fcan be the straight or branched alkoxyl group, – O (CH of hydroxyl, amino, C1-8 independently
2)
nr
2, R
1dcan be the straight or branched alkoxyl group of hydroxyl, amino, C1-8 independently;
N is 1-8, R
2for phenyl or the 3-8 unit heterocyclic aryl of replacement;
Described replacement to refer to replace by following one or more substituting group: hydrogen, C1-8 alkyl, halo C1-8 alkyl, C1-8 alkoxyl group, halogen, trifluoromethyl, nitro, cyano group, sulfonic group, carboxyl.
4. compound as claimed in claim 1, is characterized in that, R
1a, R
1bcan be hydrogen or substituted benzyl independently, but be hydrogen or substituted benzyl when the two is different; R
1c, R
1e, R
1fcan be hydroxyl, amino, the straight or branched alkoxyl group of C1-8, substituted benzyloxy independently, R
1dcan be the straight or branched alkoxyl group of hydroxyl, amino, C1-8 independently; Described replacement refers to that the one or more positions in 2,3 or 4 on phenyl ring are that following arbitrary group replaces: hydrogen, C1-8 alkyl, halo C1-8 alkyl, C1-8 alkoxyl group, halogen, trifluoromethyl, nitro, cyano group, sulfonic group, carboxyl.
5. compound as claimed in claim 1, it is characterized in that, described compound is any one in following compounds:
。
6. a composition, containing compound according to claim 1 or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
7. a compound as claimed in claim 1 or the application of its pharmacy acceptable salt in the medicine for the preparation of the disease relevant to Bcl-2 protein family anti-apoptotic members high expression level.
8. apply as claimed in claim 7, it is characterized in that, this disease is tumour.
9. apply as claimed in claim 8, it is characterized in that, this tumour is leukemia or lung cancer.
10. a compound as claimed in claim 1 or its pharmaceutically acceptable salt are for the preparation of the application in antifungal drug.
The preparation method of flavonoid compound IV, V of 11. 1 kinds of substituted benzyl replacements, is characterized in that, comprise the following steps:
(1) chromocor compound II in the basic conditions, in inert solvent, reacts with the benzyl chloride that phenyl ring replaces for R, generates compound III;
(2) compound III, in acid condition, refluxes in inert solvent, reacting generating compound IV;
(3) as the R in compound IV
1d, R
1e, R
1fin one or more when being alkoxyl group, in inert solvent, add BBr3, the alkyl sloughing one or more alkoxyl group generates hydroxyl, and other group is constant, and compound IV is further converted to compound V;
In compound IV and compound V, the replacement position at substituted benzyl place is R
1aor R
1b; R
1d, R
1e, R
1fas claimed in claim 1; R
1d, R
1e, R
1fin be not the group of alkoxyl group, constant after reaction; The position of substitution of R refers to the one or more positions in 2,3 or 4 on phenyl ring, and R is that following arbitrary group replaces: hydrogen, C1-8 alkyl, halo C1-8 alkyl, halogen.
The preparation method of flavonoid compound VIII, IX of 12. 1 kinds of substituted benzyl replacements, is characterized in that, comprise the following steps:
(1) chromocor compound VI in the basic conditions, in inert solvent, reacts with the benzyl chloride that phenyl ring replaces for R, generates compound VI I;
(2) compound VI I, under acidic conditions, refluxes in inert solvent, reacting generating compound VIII;
(3) as the R in compound VI II
1c, R
1d, R
1fin one or more when being alkoxyl group, in inert solvent, add BBr3, the alkyl sloughing one or more alkoxyl group generates hydroxyl, and other group is constant, and compound VI II is further converted to Compound I X;
R
1c, R
1d, R
1fas claimed in claim 1; R
1c, R
1d, R
1fin be not the group of alkoxyl group, constant after reaction; The position of substitution of R refers to the one or more positions in 2,3 or 4 on phenyl ring, and R is that following arbitrary group replaces: hydrogen, C1-8 alkyl, halo C1-8 alkyl, halogen.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104876902A (en) * | 2015-03-30 | 2015-09-02 | 大连理工大学 | 7-methylcyclohexane-5-(2'-amino) phenyl-chrysin, preparation method thereof and application thereof |
| CN105294627A (en) * | 2015-11-04 | 2016-02-03 | 江西师范大学 | Method for synthesizing flavonoid compound by using 1, 3-dialkyl imidazole oxometallate as catalyst in one step |
| CN107661333A (en) * | 2016-07-27 | 2018-02-06 | 清华大学 | Application of the compound in lung cancer is treated |
| CN109020939A (en) * | 2018-10-19 | 2018-12-18 | 海南医学院 | A kind of preparation method and applications of chain hydrocarbon chrysin derivative |
| CN110240582A (en) * | 2019-06-21 | 2019-09-17 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | A kind of chromocor derivative and the preparation method and application thereof with inhibition tumour cell |
| CN112876446A (en) * | 2021-01-19 | 2021-06-01 | 张洪胜 | Anti-osteoporosis acacetin derivative and preparation method thereof |
| WO2023146511A1 (en) * | 2022-01-25 | 2023-08-03 | Vivace Therapeutics, Inc. | Compounds and methods of use thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009103984A1 (en) * | 2008-02-20 | 2009-08-27 | Care Technologies Inc | Cancer detection methods and techniques |
| CN101591319A (en) * | 2009-06-22 | 2009-12-02 | 复旦大学 | Flavone derivative and the purposes in pharmaceutical compositions thereof |
| CN102697768A (en) * | 2012-06-07 | 2012-10-03 | 中国人民解放军第二军医大学 | Application of luteolin flavonoid compounds in preparation of anti-tumor medicaments |
| CN102698275A (en) * | 2012-06-19 | 2012-10-03 | 中国人民解放军第二军医大学 | Application of myricetin similar flavonol compound to preparation of antitumor medicament |
-
2014
- 2014-08-01 CN CN201410376529.3A patent/CN104230869B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009103984A1 (en) * | 2008-02-20 | 2009-08-27 | Care Technologies Inc | Cancer detection methods and techniques |
| CN101591319A (en) * | 2009-06-22 | 2009-12-02 | 复旦大学 | Flavone derivative and the purposes in pharmaceutical compositions thereof |
| CN102697768A (en) * | 2012-06-07 | 2012-10-03 | 中国人民解放军第二军医大学 | Application of luteolin flavonoid compounds in preparation of anti-tumor medicaments |
| CN102698275A (en) * | 2012-06-19 | 2012-10-03 | 中国人民解放军第二军医大学 | Application of myricetin similar flavonol compound to preparation of antitumor medicament |
Non-Patent Citations (2)
| Title |
|---|
| CAN-HUI，ZHENG: "Design,synthesis,and activity evaluation of broad-spectrum small-molecule inhibitors of anti-apoptotic Bcl-2 family proteins:Characteristics of broad-spectrum protein binding and its effects on anti-tumor activity", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| ZHANG, JIANGE，等: "Discovery and synthesis of novel luteolin derivatives as DAT agonists", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
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| CN104876902A (en) * | 2015-03-30 | 2015-09-02 | 大连理工大学 | 7-methylcyclohexane-5-(2'-amino) phenyl-chrysin, preparation method thereof and application thereof |
| CN105294627A (en) * | 2015-11-04 | 2016-02-03 | 江西师范大学 | Method for synthesizing flavonoid compound by using 1, 3-dialkyl imidazole oxometallate as catalyst in one step |
| CN105294627B (en) * | 2015-11-04 | 2018-11-23 | 江西师范大学 | Method for synthesizing flavonoid compound by using 1, 3-dialkyl imidazole oxometallate as catalyst in one step |
| CN107661333A (en) * | 2016-07-27 | 2018-02-06 | 清华大学 | Application of the compound in lung cancer is treated |
| CN107661333B (en) * | 2016-07-27 | 2020-12-29 | 清华大学 | Application of compound in treating lung cancer |
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| CN110240582A (en) * | 2019-06-21 | 2019-09-17 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | A kind of chromocor derivative and the preparation method and application thereof with inhibition tumour cell |
| CN110240582B (en) * | 2019-06-21 | 2022-11-01 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | Flavone derivative with tumor cell inhibiting function and preparation method and application thereof |
| CN112876446A (en) * | 2021-01-19 | 2021-06-01 | 张洪胜 | Anti-osteoporosis acacetin derivative and preparation method thereof |
| WO2023146511A1 (en) * | 2022-01-25 | 2023-08-03 | Vivace Therapeutics, Inc. | Compounds and methods of use thereof |
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