CN104230869B - Substituted flavonoids and its production and use - Google Patents

Substituted flavonoids and its production and use Download PDF

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CN104230869B
CN104230869B CN201410376529.3A CN201410376529A CN104230869B CN 104230869 B CN104230869 B CN 104230869B CN 201410376529 A CN201410376529 A CN 201410376529A CN 104230869 B CN104230869 B CN 104230869B
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phenyl
benzopyran
dihydroxy
benzyl
methyl
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CN104230869A (en
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郑灿辉
周有骏
朱驹
张猛
王重庆
蒋骏航
吕加国
田巍
杨超
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Second Military Medical University SMMU
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    • C—CHEMISTRY; METALLURGY
    • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to biomedicine technical field, provide firstly a class and lead to the flavone compound shown in formula (I) and the purposes in preparing antitumor drug thereof, present invention also offers the pharmaceutical composition containing this compounds in addition.The flavone compound of the present invention can be with competitive binding Bcl 2, Bcl xLWith Mcl 1 albumen, specifically cause apoptosis of tumor cells, be expected to be developed to the safe and efficient cancer therapy drug into targeting Bcl 2 family protein.In addition the compound of the present invention also has good antifungal activity, and data above all imply that the compound of the present invention has good DEVELOPMENT PROSPECT.

Description

Substituted flavonoids and its production and use
Technical field
The present invention relates to pharmaceutical technology field, more particularly it relates to flavonoid compound, the present invention is also Relate to the compositions of this compounds, preparation method and become with Bcl-2 protein family anti-apoptotic for treatment in preparation Purposes in disease that member's high expressed is relevant or the medicine of symptom, antineoplastic agent and synergist.
Background technology
Apoptosis be cell by the programmed cell death carried out after certain signal stimulus, be that the one of cell is the most biological Learn phenomenon.And Bcl-2 protein family plays important regulation effect at apoptosis path.It can be divided into anti-apoptotic member (as Bcl-2、Bcl-xL, Mcl-1 etc.) and promote apoptosis member two class.Research shows that Bcl-2 protein family anti-apoptotic members is excessive Expression may result in normal apoptosis path and is obstructed, and the generation to numerous disease (such as tumor, autoimmune disease etc.) is relevant, Particularly one of tumor generation and the major reason that drug 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 tumors, in difference Expression in tumor and different tumors subtypes different (Oncogene 2003, 22, 8590-607; Oncogene 2008, 27, 6398-406).By the Anti-G value of the anti-apoptotic members of overexpression in suppression tumor cell, can To recover its normal apoptosis pathway, increase its sensitivity to chemotherapy radiotherapy, be the New Policy for the treatment of tumor.Bcl-2 albumen Family anti-cell anti-apoptotic member is by the hydrophobic groove on its surface and the Bcl-2 protein family conservative region promoting apoptosis member (BH) 3 combine and interact, regulate the normal Apoptosis of cell.Micromolecular inhibitor is by being incorporated into anti-apoptotic Member's surface hydrophobicity groove, can disturb in combination the playing in rush apoptosis member BH3 region to promote apoptotic effect.(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 researcher, be found that a series of little point by different approaches Sub-inhibitor, wherein has four (ABT-199, ABT-263, AT-101, GX15-07) to enter clinic as oral antitumor drug Research.Result of study shows that Bcl-2 protein family anti-apoptotic members micromolecular inhibitor shows preferable antitumor and makees With with to other antitumor drug or radiocurable potentiation synergism, there is 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 invention aims to provide the novel flavone compound of class or its pharmaceutically acceptable salt.The present invention is same Time disclose the preparation method of this compounds, medical application and compositions.
The wood with Bcl-2 protein family anti-apoptotic members inhibitory activity that the present invention finds with this laboratory early stage The flavone compounds such as rhinoceros grass element are lead compound, use Computer-Aided Drug Design technology, design, to have synthesized a class complete The flavonoid Bcl-2 protein family anti-apoptotic members micromolecular inhibitor of new construction, the activity survey to kinds of tumor cells Taking temperature bright, this compounds shows good anti-tumor activity, is expected to be developed into the anti-cancer agent of a class brand new.
In a first aspect of the present invention, it is provided that the flavone compound shown in a kind of logical formula I or its pharmaceutically can connect Salt, solvate, prodrug or the polymorph being subject to:
In formula, R1a、R1b、R1c、R1d、R1e、R1fIndependently be any sort in following groups: a) hydrogen；B) hydroxyl；c) Amino；D) the straight or branched alkoxyl of substituted C1-8；e) –O(CH2)nR2；f) -(CH2)nR2；G) substituted C1-8 Straight or branched alkyl；H) the straight or branched thiazolinyl of substituted C2-6；I) alkynyl of the straight or branched of substituted C2-6；j) The straight or branched alkanoyloxy of substituted C1-8；
N is 1-8, R2For substituted phenyl or 3-8 unit heterocyclic aryl；
Described replacement refers to be replaced by following one or more substituent groups: hydrogen, C1-8 alkyl, C2-6 thiazolinyl, C2-6 Alkynyl, halo C1-8 alkyl, C1-8 alkoxyl, 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, R1a、R1bHydrogen or-(CH can be independently be2)nR2, but the two is different Time be hydrogen or-(CH2)nR2；R1c、R1e、R1fHydroxyl, amino, the straight or branched alkoxyl of C1-8, O (CH can be independently be2)nR2, R1dThe straight or branched alkoxyl of hydroxyl, amino, C1-8 can be independently be；
N is 1-8, R2For substituted phenyl or 3-8 unit heterocyclic aryl；
Described replacement refers to be replaced by following one or more substituent groups: hydrogen, C1-8 alkyl, halo C1-8 alkyl, C1-8 alkoxyl, halogen, trifluoromethyl, nitro, cyano group, sulfonic group, carboxyl.
In another preference, in described compound, R1a、R1bHydrogen or substituted benzyl can be independently be, but the two is different Time be hydrogen or substituted benzyl；；R1c、R1e、R1fHydroxyl, amino, the straight or branched alkoxyl of C1-8 can be independently be, replace benzyl Epoxide, R1dThe straight or branched alkoxyl of hydroxyl, amino, C1-8 can be independently be；Described replacement refer to 2 on phenyl ring, 3 or One or more positions in 4 be following arbitrary group replace: hydrogen, C1-8 alkyl, halo C1-8 alkyl, C1-8 alkoxyl, 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, it is provided that a kind of compositions, it contains the compound described in first aspect present invention Or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
In another preference, described compositions is pharmaceutical composition.
In a third aspect of the present invention, it is provided that compound or its pharmaceutically acceptable salt described in first aspect are being made Application in the medicine of the standby disease relevant to Bcl-2 protein family anti-apoptotic members high expressed.
In another preference, described disease is tumor.More specificly, described tumor is leukemia or pulmonary carcinoma.
In a third aspect of the present invention, additionally provide the compound described in first aspect or its pharmaceutically acceptable salt exists Prepare the application in antifungal agent.
In a fourth aspect of the present invention, it is provided that the preparation method of two class particular compound described in first aspect.
First, it is provided that the preparation method of a kind of substituted benzyl substituted flavone compound IV, V, it is characterised in that bag Include the following step:
(1) chromocor compound II is in the basic conditions, in atent solvent, with phenyl ring on be that the substituted benzyl chloride of R reacts, raw Become compound III；
(2) compound III, in acid condition, refluxes in atent solvent, reacting generating compound IV；
(3) as the R in compound IV1d, R1e、R1fIn one or more for alkoxyl time, in atent solvent, add BBr3, the alkyl sloughing one or more alkoxyl generates hydroxyl, and other group is constant, and compound IV is further converted to chemical combination Thing V；
In compound IV and compound V, the replacement position at substituted benzyl place is R1aOr R1b；R1d、R1e、R1fSuch as claim Described in 1；R1d、R1e、R1fIn be not the group of alkoxyl, constant after reaction；The position of substitution of R refer to 2 on phenyl ring, 3 or 4 In one or more positions, R be following arbitrary group replace: hydrogen, C1-8 alkyl, halo C1-8 alkyl, halogen.
In another preference, the alkali used in the synthesis of described compound (III) is inorganic base.Preferably, described Inorganic base be K2CO3。
In another preference, the reaction condition used in the synthesis of described compound (III) is common heating or micro- Ripple.
In another preference, in the synthesis of described compound (III) use atent solvent be DMF, DMSO or its Combination.
In another preference, the acid used in the synthesis of described compound (IV) is organic acid.Preferably, used Acid be methanesulfonic acid or trifluoroacetic acid.
In another preference, the atent solvent used in the synthesis of described compound (IV) is chloroform.
In another preference, the atent solvent used in the synthesis of described compound (V) is dichloromethane.
Secondly, additionally providing the preparation method of a kind of substituted benzyl substituted flavone compound VIII, IX, its feature exists In, comprise the following steps:
(1) chromocor compound VI is in the basic conditions, in atent solvent, with phenyl ring on be that the substituted benzyl chloride of R reacts, raw Become compound VII；
(2) compound VII, under acid condition, refluxes in atent solvent, reacting generating compound VIII；
(3) as the R in compound VIII1c、R1d、R1fIn one or more for alkoxyl time, in atent solvent, add Entering BBr3, the alkyl sloughing one or more alkoxyl generates hydroxyl, and other group is constant, and compound VIII is further converted to Compound IX；
R1c, R1d、R1fAs claimed in claim 1；R1c、R1d、R1fIn be not the group of alkoxyl, constant after reaction；R takes Subrogate the one or more positions put in 2,3 or 4 referred on phenyl ring, R be following arbitrary group replace: hydrogen, C1-8 alkyl, Halo C1-8 alkyl, halogen.
In another preference, the alkali used in the synthesis of described compound (VII) is inorganic base.Preferably, made Inorganic base be K2CO3。
In another preference, the reaction condition used in the synthesis of described compound (VII) is common heating or micro- Ripple.
In another preference, in the synthesis of described compound (VII) use atent solvent be DMF, DMSO or its Combination.
In another preference, the acid used in the synthesis of described compound (VIII) is organic acid.Preferably, made Acid be methanesulfonic acid or trifluoroacetic acid.
In another preference, the atent solvent used in the synthesis of described compound (VIII) is chloroform.
In another preference, the atent solvent used in the synthesis of described compound (IX) is dichloromethane.
The Pharmaceutical composition that the present invention relates to, can be solid form or liquid form, and described pharmaceutical dosage form is permissible It is tablet, capsule, powder agent, granule, suspensoid or injection.When the compounds of this invention is for such use, can be with one Kind or multiple pharmaceutically acceptable carrier or excipient mixing, such as solvent, diluent etc., and can be oral by following form It is administered: tablet, pill, capsule, dispersible powder, granule or suspension (containing such as from about 0.05-5% suspending agent), syrup (contain Have such as from about 10-50% sugar) and elixir (containing about 20-50% ethanol), or be administered in external mode: ointment, gel, pastille glue Cloth etc., or carry out non-with sterile injectable solution or form of suspension (containing about 0.05-5% suspending agent in isotonic medium) Enteral administration.Such as, these pharmaceutical preparatioies can be containing about 0.01-99%, the more preferably about 0.1%-90% (weight mixed with carrier Amount) active component.
" safe and effective amount " refers to: the amount of compound be enough to improve the state of an illness, and is unlikely to produce serious side effect.Peace Full effective dose determined according to age for the treatment of target, the state of an illness, the course for the treatment of etc..
" pharmaceutically acceptable carrier " refers to: one or more biocompatible solid or liquid filler or gelatinous mass, They are suitable for people and use and it is necessary to have enough purity and of a sufficiently low toxicity." compatibility " herein means generation be in compositions Each component energy and the compound of the present invention and they between mutually admix, and significantly reduce the curative effect of compound.Pharmaceutically Acceptable carrier partial example has sugar (such as glucose, sucrose, lactose etc.), starch (such as corn starch, potato starch etc.), Cellulose and its derivates (such as sodium carboxymethyl cellulose, ethyl cellulose sodium, cellulose ethanoate etc.), gelatin, Pulvis Talci, Gu Body lubricant (such as sodium stearate, magnesium stearate), calcium sulfate, vegetable oil (such as Oleum Glycines, Oleum sesami, Oleum Arachidis hypogaeae semen, olive oil etc.) is many Unit's alcohol (such as propylene glycol, glycerol, mannitol, sorbitol etc.), emulsifying agent (such as Tweens), wetting agent are (such as dodecyl sodium sulfonate Sodium), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, apirogen water etc..
The flavone compound of the present invention shows and Bcl-2, Bcl-xLBinding ability preferable with Mcl-1 albumen, special It not that part of compounds Mcl-1 albumen shows more preferable binding ability.Therefore these compounds have preparation and Bcl-2 albumen The medicine of the disease that family's anti-apoptotic members high expressed is relevant, and prepare synergist and other antitumor drug or Radiotherapy share to treat the potential use of tumor.
Human solid tumor's (pulmonary carcinoma) and neoplastic hematologic disorder (leukemia) are shown the widest by the flavone compound of the present invention Spectrum anti-tumor activity, particularly part of compounds show more preferable cytotoxic activity to human leukemia cell line.Therefore, this Bright compound is expected there is good DEVELOPMENT PROSPECT.
Additionally, the flavone compound of the present invention has certain broad-spectrum antifungal activity, particularly partization in vitro Compound shows more preferable inhibitory activity to Candida glabrata, illustrates that the compounds of this invention has and prepares anti-fungal infection The present purposes of medicine.
In should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and having in below (eg embodiment) Can be combined with each other between each technical characteristic that body describes, thus constitute new or preferred technical scheme.As space is limited, exist This tires out the most one by one states.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is expanded on further.Should be understood that these embodiments are merely to illustrate the present invention Rather than restriction the scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, generally according to conventional strip Part, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage ratio and number are percentage by weight and weight Number.
Embodiment 1-6:2-((3-benzyl-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 'H-benzo pyrrole Mutter-4-ketone (compound 1 in table 1), 2-((2-benzyl-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 'sH-benzo Pyrans-4-ketone (compound 5 in table 1), 2-((3-benzyl-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-.alpha.-5:6-benzopyran-4 Ketone (compound 3 in table 1), 2-((3-benzyl-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl groups-4H-.alpha.-5:6-benzopyran-4 Ketone (compound 4 in table 1), 2-((2-benzyl-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-.alpha.-5:6-benzopyran-4 ketone (table Compound 7 in 1) and 2-((2-benzyl-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl groups-4H-.alpha.-5:6-benzopyran-4 ketone The preparation of (compound 8 in table 1):
1, the preparation of 2-hydroxyl-4,6-dimethoxy-1-Phenylethanone.
By 2,4,6-trihydroxy-acetophenone monohydrates (3.72g, 20mmol) join in acetone (60ml), add under stirring Enter potassium carbonate (6.06g, 40mmol), undissolved, it is slowly added dropwise dimethyl sulfate (4ml, 42mmol), drips and finish, be stirred at room temperature 4 little Time, the extent of reaction is monitored by TLC.Question response terminates, and filters solid insoluble, is slowly added to water (100ml), repeatedly vibrates, quiet Put half an hour, have white solid to separate out.Filter, be dried to obtain 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 potassium carbonate (4.56g, 33mmol) and benzyl chloride (4.18g, 33mmol), be heated to reflux 6 hours, and the extent of reaction is monitored by TLC.Question response is tied Bundle, is cooled to room temperature, filters solid insoluble, is quickly slowly added to water (150ml) under stirring, stands a moment, have white solid Separate out, filter, be dried to obtain white solid (5.8g), yield 80%.
3、(E)-3-(4-(benzyloxy)-3-anisyl)-1-(2-hydroxyl-4,6-Dimethoxyphenyl) acrylate-2-alkene-1- The preparation of ketone
By intermediate 2-hydroxyl-4,6-dimethoxy-1-Phenylethanone. (2g, 10.2mmol) and intermediate 4-benzyloxy-3-first Epoxide benzaldehyde (2.5g, 10.2mmol) is dissolved in methanol (50ml), is slowly added dropwise the potassium hydroxide aqueous solution of 50% under stirring (6ml), solution colour gradually turns yellow, and drips and finishes, is stirred at room temperature 36 hours, and the extent of reaction is monitored by TLC.After question response terminates, stir Mix the hydrochloric acid solution of lower dropping 1mol/L, be adjusted to PH=5, stand a moment, be filtrated to get yellow oily solid, with methanol (30ml) Washing, filters, is dried to obtain yellow solid (3.0g), yield about 70%.
4,2-((4-benzyloxy-3-methoxyl group) phenyl)-5,7-dimethoxy-4 'HThe preparation of-benzopyran-4-one
By intermediate (E)-3-(4-(benzyloxy)-3-anisyl)-1-(2-hydroxyl-4,6-Dimethoxyphenyl) acrylate- 2-alkene-1-ketone (0.42g, 1mmol) is dissolved in pyridine (15ml), adds iodine (0.3g, 1.2mmol), be heated to reflux, instead after dissolving Degree is answered to be monitored by TLC.After reaction terminates, stirring is lower adds enough saturated sodium thiosulfate solution, has solid to separate out, mistake Filter, re-crystallizing in ethyl acetate, obtain white solid 0.3g, yield 71%.
5,2-((3-benzyl-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 'H-benzopyran-4-one (1) With 2-((2-benzyl-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 'sHThe preparation of-benzopyran-4-one (5)
By intermediate 2-((4-benzyloxy-3-methoxyl group) phenyl)-5,7-dimethoxy-4 'H-benzopyran-4-one (1.25g, 3mmol) is dissolved in chloroform (16ml), adds methanesulfonic acid (4ml), is positioned in microwave reactor, under the conditions of 300W, It is heated to reflux 13 minutes.After reaction terminates, washing (50ml), stratification, aqueous phase washs with a small amount of dichloromethane again, is associated with Machine phase, is dried and concentrates, anti-phase (C18) column chromatography purification (MeOH:H2O), isolated and purified compound 1 and 5 sterling that obtains, and 2- (4-hydroxyl-3-anisyl)-5,7-dimethoxy-4 'H-benzopyran-4-one sterling.
6,2-((3-benzyl-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-.alpha.-5:6-benzopyran-4 ketone (3) and 2-((3- Benzyl-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4HThe preparation of-.alpha.-5:6-benzopyran-4 ketone (4)
By 2-((3-benzyl-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 'sH-benzopyran-4-one (1) (0.5g, 1.19mmol) is dissolved in anhydrous methylene chloride (10ml), and-30oUnder C stirring, it is slowly added dropwise the Boron tribromide dichloro of 1M Dichloromethane (10ml), solution slowly turns yellow, and drips and finishes, warms naturally to room temperature, and TLC monitors reaction process.After reaction terminates, to Reactant liquor is slowly added into water (30ml), is extracted with ethyl acetate, collect organic facies, concentrate, anti-phase (C18) column chromatography purification (MeOH:H2O), isolated and purified compound 3 and 4 sterling is obtained.
7,2-((2-benzyl-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-.alpha.-5:6-benzopyran-4 ketone (7) and 2- ((2-benzyl-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4HThe preparation of-.alpha.-5:6-benzopyran-4 ketone (8)
By intermediate 2-((2-benzyl-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-.alpha.-5:6-benzopyran-4 Ketone (5) (0.5g, 1.19mmol) is dissolved in anhydrous methylene chloride (10ml), and-30oUnder C stirring, it is slowly added dropwise the Boron tribromide of 1M Dichloromethane solution (10ml), solution slowly turns yellow, and drips and finishes, warms naturally to room temperature, and TLC monitors reaction process.Reaction terminates After, in reactant liquor, it is slowly added into water (30ml), is extracted with ethyl acetate, collect organic facies, concentrate, anti-phase (C18) column chromatography Purification (MeOH:H2O), isolated and purified compound 7 and 8 sterling is obtained.
Embodiment 7-8:2-((3-benzyl-4-hydroxy-5-methyl epoxide) phenyl)-5-hydroxyl-7-methoxyl group-4H-benzo Pyrans-4-ketone (compound 2 in table 1) and 2-((2-benzyl-4-hydroxy-5-methyl epoxide) phenyl)-5-hydroxyl-7-methoxyl groups- 4HThe preparation of-benzopyran-4-one (compound 6 in table 1):
1,2-((4-benzyloxy-3-methoxyl group) phenyl)-5-hydroxyl-7-methoxyl group-4HThe preparation of-benzopyran-4-one
By intermediate (E)-3-(4-(benzyloxy)-3-anisyl)-1-(2-hydroxyl-4,6-Dimethoxyphenyl) acrylate- 2-alkene-1-ketone (0.42g, 1mmol) is dissolved in pyridine (15ml), adds iodine (0.5g, 2mmol), be heated to reflux after dissolving, reaction Degree is monitored by TLC.After reaction terminates, stirring is lower adds enough saturated sodium thiosulfate solution, has solid to separate out, filters, Re-crystallizing in ethyl acetate, obtains white solid (0.25g), yield 59%.
2,2-((3-benzyl-4-hydroxy-5-methyl epoxide) phenyl)-5-hydroxyl-7-methoxyl group-4H-benzopyran-4-one (2) and 2-((2-benzyl-4-hydroxy-5-methyl epoxide) phenyl)-5-hydroxyl-7-methoxyl groups-4H-benzopyran-4-one (6) Preparation
By intermediate 2-((4-benzyloxy-3-methoxyl group) phenyl)-5-hydroxyl-7-methoxyl group-4H-benzopyran-4-one (1.25g, 3mmol) is dissolved in chloroform (16ml), adds methanesulfonic acid (4ml), is positioned in microwave reactor, under the conditions of 300W, It is heated to reflux 13 minutes.After reaction terminates, washing (50ml), stratification, aqueous phase washs with a small amount of dichloromethane again, is associated with Machine phase, is dried and concentrates, anti-phase (C18) column chromatography purification (MeOH:H2O), isolated and purified compound 2 and 6 sterling that obtains, and 2- (4-hydroxyl-3-anisyl)-5-hydroxyl-7-methoxyl group-4H-benzopyran-4-one sterling.
Embodiment 9-12:2-(3,4-Dimethoxyphenyl)-5-benzyloxy-7-methoxyl group-4H-benzopyran-4-one (compound 9 in table 1), 2-((2-benzyl-4,5-dimethoxy) phenyl)-5-hydroxyl-7-methoxyl groups-4H-.alpha.-5:6-benzopyran-4 Ketone (compound 10 in table 1), 2-((2-benzyl-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-.alpha.-5:6-benzopyran-4 ketone (compound 7 in table 1) and 2-((2-benzyl-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl groups-4H-.alpha.-5:6-benzopyran-4 The preparation of ketone (compound 8 in table 1):
1、(E) system of-3-(3,4-dimethoxy phenyl)-1-(2-hydroxyl-4,6-Dimethoxyphenyl) acrylate-2-alkene-1-ketone Standby
By 2-hydroxyl-4,6-dimethoxy-1-Phenylethanone. (0.5 g, 2.5mmol) is dissolved in 9ml methanol, adds 3,4-bis- Methoxybenzaldehyde (0.42g, 2.5mmol), after Veratraldehyde dissolves, the potassium hydroxide of addition 50% is water-soluble Liquid (4.5ml), is stirred at room temperature 36 hours.After question response terminates, regulate PH < 7 with the hydrochloric acid solution of 1mol/L.Reactant liquor Bu Shi Funnel filters, and collects yellow solid.Filtrate extracts by ethyl acetate (30ml × 2).Merging organic facies, anhydrous MgSO4 is dried, and subtracts Pressure distillation.Merge yellow solid, be added thereto to methanol (50ml), 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-4HThe preparation of-benzopyran-4-one
By intermediate (E)-3-(3,4-dimethoxy phenyl)-1-(2-hydroxyl-4,6-Dimethoxyphenyl) acrylate-2-alkene-1- Ketone (0.6 g, 1.7mmol) is dissolved in 8ml pyridine, is subsequently added into iodine (0.86g, 3.4mmol), is heated to reflux stirring 13 hours. After completion of the reaction, adding hypo solution 30ml, filter, crude product ethyl acetate (20ml) is recrystallized to give yellow solid 0.41g, yield 72%.
3,2-(3,4-Dimethoxyphenyl)-5-benzyloxy-7-methoxyl group-4HThe preparation of-benzopyran-4-one (9)
By 2-(3,4-dimethoxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-benzopyran-4-one (1.72 g, 5.2mmol) it is dissolved in 30mlDMF, is subsequently added into potassium carbonate (0.8 g, 5.72mmol), add benzyl chloride (1.33g, 10.4mmol) It is heated to reflux stirring 6 hours.Reaction terminate after, in reactant liquor add 100ml water, filter, filtrate with ethyl acetate (20ml × 3) extraction.Merging organic facies, anhydrous MgSO4 is dried, decompression distillation.Merging crude product silica gel column chromatography (ethyl acetate/normal hexane= 1:4) obtain 9 sterlings.
4,2-((2-benzyl-4,5-dimethoxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-.alpha.-5:6-benzopyran-4 ketone (10) Preparation
By intermediate 2-(3,4-Dimethoxyphenyl)-5-benzyloxy-7-methoxyl group-4H-benzopyran-4-one (1g, 2.4mmol) it is dissolved in 8ml chloroform, pours in the microwave reaction bottle of 30ml, add methanesulfonic acid 2ml, react 1 under the conditions of 65 DEG C little Time.Adding 20ml dichloromethane in reaction bulb, 20ml water washs, and organic facies is dried with anhydrous MgSO4, and decompression distillation obtains Crude product, anti-phase (C18) column chromatography purification (MeOH:H2O), isolated and purified compound 10 sterling and 2-(3,4-dimethoxy) are obtained Phenyl)-5-hydroxyl-7-methoxyl group-4H-benzopyran-4-one sterling.
5,2-((2-benzyl-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-.alpha.-5:6-benzopyran-4 ketone (7) and 2-((2-benzyl Base-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4HThe preparation of-.alpha.-5:6-benzopyran-4 ketone (8)
By intermediate 2-((2-benzyl-4,5-dimethoxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-.alpha.-5:6-benzopyran-4 Ketone (0.4g, 0.96mmol) is dissolved in 10ml DCM, and solution cools to-30 DEG C, takes 1mlBBr3 and is dissolved in 9mlDCM, will join Good BBr3 solution is added drop-wise in above-mentioned solution, and reactant liquor is stirred at room temperature 3 hours.It is subsequently added 30ml water, adds 20ml Ethyl acetate, merges organic facies, and anhydrous MgSO4 is dried, decompression distillation, crude product anti-phase (C18) column chromatography purification (MeOH:H2O), Isolated and purified obtain compound 7 and 8 sterling.
Embodiment 13-19:2-((3 methoxyl group-4-(2-chlorobenzyl)) phenyl)-5,7-dimethoxy-4 'H-benzo pyrrole Mutter-4-ketone (compound 11 in table 1), 2-((3-(2-chlorobenzyl)-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxys- 4H-benzopyran-4-one (compound 20 in table 1), 2 ((2-(2-chlorobenzyl)-4-hydroxy-5-methyl epoxide) phenyl)-5,7- Dimethoxy-4 'H-benzopyran-4-one (compound 47 in table 1), 2 ((3 (2-chlorobenzyl)-4,5-dihydroxy) phenyl)- 5,7-dihydroxy-4H-benzopyran-4-one (compound 29 in table 1), 2 ((3-(2-chlorobenzyl)-4,5-dihydroxy) benzene Base)-5-hydroxyl-7-methoxyl group-4H-benzopyran-4-one (compound 38 in table 1), 2 ((2 (2-chlorobenzyl)-4,5-two Hydroxyl) phenyl)-5,7-dihydroxy-4H-benzopyran-4-one (compound 56 in table 1) and 2 ((2-(2-chlorobenzyl)-4,5- Dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4HThe preparation of-benzopyran-4-one (compound 65 in table 1):
1,2-((3 methoxyl group-4-(2-chlorobenzyl)) phenyl)-5,7-dimethoxy-4 'H-benzopyran-4-one (11) Preparation
By intermediate 2-(4-hydroxyl-3-anisyl)-5,7-dimethoxy-4 'H-benzopyran-4-one (0.98g, 3mmol) it is dissolved in DMF(15ml) in, under stirring, adding potassium carbonate (0.46g, 3.3mmol), solid is the most molten.Add 2-benzyl chloride chlorine (0.53g, 3.3mmol) is heated to reflux 2 hours, TLC point plate monitoring reaction process.Reaction terminates, and filters solid insoluble, quickly It is slowly added to 75ml water under stirring, stands a moment, have white solid to separate out, filter, be dried to obtain white solid 2-(4-(2-chlorine Benzyloxy)-3-anisyl)-5,7-dimethoxy-4 '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, -CH2-), 3.89 (s, 3H, -OCH3), 3.89 (s, 3H, -OCH3) , 3.82 (s, 3H, -OCH3). MS (ESI): m/z 453.43 (M +H)+。
2,2 ((3-(2-chlorobenzyl)-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 'H-.alpha.-5:6-benzopyran- 4-ketone (9) and 2-((2-(2-chlorobenzyl)-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 'sH-.alpha.-5:6-benzopyran-4- The preparation of ketone (12)
By intermediate 2-(4-(2-benzyl chloride epoxide)-3-anisyl)-5,7-dimethoxy-4 'H-benzopyran-4-one (1.36g, 3mmol) is dissolved in 16ml anhydrous chloroform, adds 4ml methanesulfonic acid, is positioned in microwave reactor, under the conditions of 300W, It is heated to reflux 13 minutes.After reaction terminates, washing (50ml), stratification, aqueous phase washs with a small amount of dichloromethane again, is associated with Machine phase, is dried and concentrates, anti-phase (C18) column chromatography purification (MeOH:H2O), isolated and purified compound 9 and 12 sterling that obtains, and 2- (4-hydroxyl-3-anisyl)-5,7-dimethoxy-4 'H-benzopyran-4-one sterling.
3,2 ((3 (2-chlorobenzyl)-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-benzopyran-4-one (10) With 2 ((3-(2-chlorobenzyl)-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4HThe system of-benzopyran-4-one (11) Standby
By intermediate 2-(3-(2-chlorobenzyl)-4-hydroxy-5-methyl phenyl)-5,7-dimethoxy-4 'H-benzo pyrrole -4-ketone (0.6g, 1.32mmol) of muttering is dissolved in 10ml anhydrous methylene chloride, and-30oUnder C stirring, it is slowly added dropwise the Boron tribromide of 1M Dichloromethane solution (10ml), solution slowly turns yellow, and drips and finishes, warms naturally to room temperature, and TLC monitors reaction process.Reaction terminates After ,-30oC downhill reaction liquid is slowly added into water (30ml), drips and finish, be extracted with ethyl acetate, collect organic facies, concentrate, instead Phase (C18) column chromatography purification (MeOH:H2O), isolated and purified compound 10 and 11 sterling is obtained.
4,2 ((2 (2-chlorobenzyl)-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-benzopyran-4-one (13) With 2 ((2-(2-chlorobenzyl)-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4HThe system of-benzopyran-4-one (14) Standby
By intermediate 2-(2-(2-chlorobenzyl)-4-hydroxy-5-methyl phenyl)-5,7-dimethoxy-4 'H-benzo pyrrole -4-ketone (0.6g, 1.32mmol) of muttering is dissolved in 10ml anhydrous methylene chloride, and-30oUnder C stirring, it is slowly added dropwise the Boron tribromide of 1M Dichloromethane solution (10ml), solution slowly turns yellow, and drips and finishes, warms naturally to room temperature, and TLC monitors reaction process.Reaction terminates After ,-30oC downhill reaction liquid is slowly added into water (30ml), drips and finish, be extracted with ethyl acetate, collect organic facies, concentrate, instead Phase (C18) column chromatography purification (MeOH:H2O), isolated and purified compound 13 and 14 sterling is obtained.
Embodiment 20-73
Repeating embodiment 13-19, difference is: use different raw materials, thus prepare compound 12-19 in table 1, 21-28、48-55、30-37、39-46、57-64、66-73.Specific as follows:
(1) by intermediate 2-(4-hydroxyl-3-anisyl)-5,7-dimethoxy-4 'H-benzopyran-4-one and 3-chlorine Benzyl 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, The reaction of 4-trifluoromethyl benzyl chlorine can be respectively synthesized compound 12-19 in table 1.
(2) in table 1, compound 12-19 is dissolved in chloroform, adds methanesulfonic acid, and in microwave reactor, reaction can be respectively synthesized three Compound 48-55 in compound 21-28 and table 1 in individual product, specially table 1, and 2-(4-hydroxyl-3-anisyl)-5,7- Dimethoxy-4 'H-benzopyran-4-one.
(3) in table 1, compound 21-28 is dissolved in dichloromethane, can be respectively synthesized two products under Boron tribromide effect, It is specially in table 1 compound 39-46 in compound 30-37 and table 1.
(4) in table 1, compound 48-55 is dissolved in dichloromethane, can be respectively synthesized two products under Boron tribromide effect, It is specially in table 1 compound 66-73 in compound 57-64 and table 1.
In the logical formula I of present invention synthesis, the chemical constitution of target product is shown in Table 1.Nucleus magnetic hydrogen spectrum and mass spectrometer system characterize The chemical constitution of target product, its concrete data are shown in Table 2.
Table 1 leads to target compound structure in formula I
Table 2 leads to hydrogen spectrum and the mass spectrometric data of target compound in formula I
Embodiment 74:Bcl-2, Bcl-xLTest 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), adopt using gossypol acetate (AT-101) and luteolin (comparison 1) as compareing medicine Target compound Competitive assays Bcl-2, Bcl-x is investigated by fluorescence polarization (FP) methodLWith Mcl-1 albumen and pro apoptotic protein The ability that the BH3 peptide fragment (fluorescein labelling) of Bim or Bid combines is to evaluate the affinity of itself and target protein.Fluorescence polarization signal Detected under conditions of excitation wavelength 485nm and wavelength of transmitted light are 535nm by spectrofluorophotometer.By series concentration mesh The BH3 peptide fragment of mark compound and fluorescein-labeled Bim or Bid and Bcl-2, Bcl-xLOr Mcl-1 albumen is the most at room temperature After cultivating 20 minutes, detect its fluorescence polarization signal, calculate this compoundIC 50Value.And according to the albumen used in measuring Total concentration, the total concentration of fluorescent polypeptide, the dissociation constant of albumen-polypeptide complex and detection compoundIC 50 Value, calculates inspection Survey the competitive inhibition constant of compoundK i .(result of the test is shown in Table 3)
Table 3 leads to sample segment and Bcl-2, Bcl-x in formula ILWith Mcl-1 protein affinity
IR: suppression ratio
Result shows, the flavone compound of the present invention shows and Bcl-2, Bcl-xLPreferably tie with Mcl-1 albumen Conjunction ability, particularly part of compounds Mcl-1 albumen show more preferable binding ability.Therefore these compounds have preparation with The medicine of the disease that Bcl-2 protein family anti-apoptotic members high expressed is relevant, and it is anti-with other to prepare synergist Tumour medicine or radiotherapy share to treat the potential use of tumor.
Embodiment 75: anti tumor activity in vitro testing experiment
1, experimental strain:
This experiment use tumor cell strain be respectively as follows: A549(human lung carcinoma cell), HL-60(human leukemia cell) (purchase From Shanghai Institute of Pharmaceutical Industry).
2, sample preparation:
After dissolving with DMSO (Merck), addition PBS (-) it is made into the solution of 1000mg/mL or uniform suspension, then With containing DMSO PBS (-) dilution.Positive control drug is ABT-737, luteolin (comparison 1) and the 2-(3-that Abbott develops Methoxyl group-4-benzyloxy) phenyl)-5,7-dimethoxy-4 'H-benzopyran-4-one (comparison 2).
3, test method
According to experiment detection and pertinent literature (Bioorg Med Chem Lett 2012, 22, 39-44; Nature. 2005, 437, 677- 681), use mtt assay.It is 4～5 × 10 that the 96 every holes of orifice plate add concentration4The cell suspension of individual/mL 100 mL, put 37 DEG C, 5% CO2In incubator.After 24 h, addition sample liquid, 10 mL/ holes, if duplicate hole, 37 DEG C, 5% CO2 Act on 72 h.Every hole adds MTT solution 20 mL of 5 mg/mL, adds lysate, 100 mL/ holes, put incubator after acting on 4 h In, survey 570 nm OD values by the full-automatic microplate reader of MK-2 after dissolving.(anti tumor activity in vitro is shown in Table 4)
Table 4 leads to the sample segment in-vitro multiplication inhibitory action to human body tumour cell in formula I
IR: suppression ratio
As known from Table 4, human solid tumor's (pulmonary carcinoma) and neoplastic hematologic disorder (leukemia) are shown by the flavone compound of the present invention Preferable broad-spectrum anti-tumor activity, particularly part of compounds show that to human leukemia cell line more preferable cell toxicant is lived Property, imply that the compound of the present invention is expected to have good DEVELOPMENT PROSPECT.
Embodiment 76: extracorporeal antifungal activity testing experiment
1, experimental strain
This experiment selected following 2 kinds of common human body cause illness's standard fungal bacterial strains as screening object, fungal bacterial strain by Changhai hospital Mycology Lab provide.Including Candida glabrata (Candida glabrata) and neogenesis cryptococcus (Cryptococcus neoformans).
2, test method
Conventional antibacterial experiment in vitro method is used (to refer to: Antimicrob Agents Chemother 1995,39 (5): 1169).
Prepared by bacterium solution: coccus cultivates 16h at 35 ° of C of YEPD fluid medium, activates twice, counts with blood cell counting plate, With RPMI RPMI-1640 adjustment bacterial concentration to 1 × 103～5 × 103/ml；Filamentous bacteria is seeded to SDA inclined-plane, 35 DEG C, Cultivate one week, activate twice, make bacterial strain cover SDA inclined-plane, add appropriate RPMI1640 culture fluid, blow and beat bacterium colony with suction pipe, make true Bacterium spore is free in RPMI1640 culture fluid, then filters through four layers of sterile gauze.Culture fluid counts through blood cell counting plate After, add RPMI1640 culture fluid and adjust spore concentration to 1 × 103～5 × 103/ml.
Prepared by medicinal liquid: test medicine is made into 6.4 g L with DMSO respectively-1
Inoculation: 96 orifice plate 1 holes add RPMI1640 100 μ l and make blank, 3-12 hole respectively adds bacteria suspension 100 μ l, and 2 Number hole adds bacteria suspension 180 μ l and medicinal liquid 20 μ l, and 2-11 hole moral drug level makees 10 grades of doubling dilutions, and each hole drug level divides It is not 64,32,16,8,4,2,1,0.5,0.25,0.125 μ g/mL.No. 12 holes are not added with medicinal liquid, do positive control, and drug control is Fluconazol and luteolin (comparison 1).
Cultivate and detection: Candida cultivates 24 hours measurement results.Each hole is surveyed in 630 nm with enzyme micro-plate reader OD value.With positive control boring ratio, decline the drug level in the least concentration hole of more than 80% with OD value as MIC80.(external press down Bacterium experimental result is shown in Table 5)
Table 5 leads to sample segment In Vitro Anti fungus minimal inhibitory concentration value (MIC, mg L in formula I-1)
As known from Table 5, the flavone compound of the present invention has certain broad-spectrum antifungal activity, particularly portion in vitro Differentiation compound shows more preferable inhibitory activity to Candida glabrata, illustrates that the compounds of this invention has and prepares antifungal sense The present purposes of the medicine of dye.
To sum up, the invention provides a substituted flavone compound of class, there is good anti-tumor activity and antifungal Activity, has preferable DEVELOPMENT PROSPECT.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art Member, on the premise of without departing from the inventive method, it is also possible to makes some improvement and supplements, and these improve and supplement and also should be regarded as Protection scope of the present invention.

Claims (9)

1. a class leads to the flavone compound shown in formula I or its pharmaceutically acceptable salt:
In formula, R1a、R1bHydrogen or substituted benzyl can be independently be, but be hydrogen or substituted benzyl when the two is different；R1c、R1e、R1fCan be only It is on the spot hydroxyl, amino, the straight or branched alkoxyl of C1-8, substituted benzyloxy, R1dHydroxyl, amino, C1-8 can be independently be Straight or branched alkoxyl；Described replacement refers to that 2 on phenyl ring, one or more positions in 3 or 4 are following arbitrary Group replaces: hydrogen, C1-8 alkyl, halo C1-8 alkyl, C1-8 alkoxyl, halogen, trifluoromethyl.
2. flavonoid compound, it is characterised in that described compound is any one in following compounds:
1) 2-((3-benzyl-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 ' H-benzopyran-4-one；
2) 2-((3-benzyl-4-hydroxy-5-methyl epoxide) phenyl)-5-hydroxyl-7-methoxyl group-4H-benzopyran-4-one；
3) 2-((3-benzyl-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-.alpha.-5:6-benzopyran-4 ketone；
4) 2-((3-benzyl-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-.alpha.-5:6-benzopyran-4 ketone；
5) 2-((2-benzyl-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 ' H-benzopyran-4-one；
6) 2-((2-benzyl-4-hydroxy-5-methyl epoxide) phenyl)-5-hydroxyl-7-methoxyl group-4H-benzopyran-4-one；
7) 2-((2-benzyl-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-.alpha.-5:6-benzopyran-4 ketone；
8) 2-((2-benzyl-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-.alpha.-5:6-benzopyran-4 ketone；
9) 2-(3,4-Dimethoxyphenyl)-5-benzyloxy-7-methoxyl group-4H-benzopyran-4-one；
10) 2-((2-benzyl-4,5-dimethoxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-.alpha.-5:6-benzopyran-4 ketone；
11) 2-((3 methoxyl group-4-(2-chlorobenzyl)) phenyl)-5,7-dimethoxy-4 ' H-benzopyran-4-one；
12) 2-((3 methoxyl group-4-(3-chlorobenzyl)) phenyl)-5,7-dimethoxy-4 ' H-benzopyran-4-one；
13) 2-((3 methoxyl group-4-(4-chlorobenzyl)) phenyl)-5,7-dimethoxy-4 ' H-benzopyran-4-one；
14) 2-((3 methoxyl group-4-(2-methyl-benzyl)) phenyl)-5,7-dimethoxy-4 ' H-benzopyran-4-one；
15) 2-((3 methoxyl group-4-(3-methyl-benzyl)) phenyl)-5,7-dimethoxy-4 ' H-benzopyran-4-one；
16) 2-((3 methoxyl group-4-(4-methyl-benzyl)) phenyl)-5,7-dimethoxy-4 ' H-benzopyran-4-one；
17) 2-((3 methoxyl group-4-(2-trifluoromethyl benzyl)) phenyl)-5,7-dimethoxy-4 ' H-benzopyran-4-one；
18) 2-((3 methoxyl group-4-(3-trifluoromethyl benzyl)) phenyl)-5,7-dimethoxy-4 ' H-benzopyran-4-one；
19) 2-((3 methoxyl group-4-(4-trifluoromethyl benzyl)) phenyl)-5,7-dimethoxy-4 ' H-benzopyran-4-one；
20) 2-((3-(2-chlorobenzyl)-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 ' H-benzopyran-4-one；
21) 2-((3-(3-chlorobenzyl)-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 ' H-benzopyran-4-one；
22) 2-((3-(4-chlorobenzyl)-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 ' H-benzopyran-4-one；
23) 2-((3-(2-methyl-benzyl)-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 ' H-.alpha.-5:6-benzopyran-4- Ketone；
24) 2-((3-(3-methyl-benzyl)-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 ' H-.alpha.-5:6-benzopyran-4- Ketone；
25) 2-((3-(4-methyl-benzyl)-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 ' H-.alpha.-5:6-benzopyran-4- Ketone；
26) 2-((3-(2-trifluoromethyl benzyl)-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 ' H-.alpha.-5:6-benzopyran- 4-ketone；
27) 2-((3-(3-trifluoromethyl benzyl)-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 ' H-.alpha.-5:6-benzopyran- 4-ketone；
28) 2-((3-(4-trifluoromethyl benzyl)-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 ' H-.alpha.-5:6-benzopyran- 4-ketone；
29) 2 ((3 (2-chlorobenzyl)-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-benzopyran-4-one；
30) 2 ((3 (3-chlorobenzyl)-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-benzopyran-4-one；
31) 2 ((3 (4-chlorobenzyl)-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-benzopyran-4-one；
32) 2 ((3 (2-methyl-benzyl)-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-benzopyran-4-one；
33) 2 ((3 (3-methyl-benzyl)-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-benzopyran-4-one；
34) 2 ((3 (4-methyl-benzyl)-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-benzopyran-4-one；
35) 2 ((3 (2-trifluoromethyl benzyl)-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-benzopyran-4-one；
36) 2 ((3 (3-trifluoromethyl benzyl)-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-benzopyran-4-one；
37) 2 ((3 (4-trifluoromethyl benzyl)-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-benzopyran-4-one；
38) 2 ((3-(2-chlorobenzyl)-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-benzopyran-4-one；
39) 2 ((3-(3-chlorobenzyl)-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-benzopyran-4-one；
40) 2 ((3-(4-chlorobenzyl)-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-benzopyran-4-one；
41) 2 ((3-(2-methyl-benzyl)-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-benzopyran-4-one；
42) 2 ((3-(3-methyl-benzyl)-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-benzopyran-4-one；
43) 2 ((3-(4-methyl-benzyl)-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-benzopyran-4-one；
44) 2 ((3-(2-trifluoromethyl benzyl)-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-.alpha.-5:6-benzopyran-4- Ketone；
45) 2 ((3-(3-trifluoromethyl benzyl)-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-.alpha.-5:6-benzopyran-4- Ketone；
46) 2 ((3-(4-trifluoromethyl benzyl)-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-.alpha.-5:6-benzopyran-4- Ketone；
47) 2-((2-(2-chlorobenzyl)-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 ' H-benzopyran-4-one；
48) 2-((2-(3-chlorobenzyl)-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 ' H-benzopyran-4-one；
49) 2-((2-(4-chlorobenzyl)-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 ' H-benzopyran-4-one；
50) 2-((2-(2-methyl-benzyl)-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 ' H-.alpha.-5:6-benzopyran-4- Ketone；
51) 2-((2-(3-methyl-benzyl)-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 ' H-.alpha.-5:6-benzopyran-4- Ketone；
52) 2-((2-(4-methyl-benzyl)-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 ' H-.alpha.-5:6-benzopyran-4- Ketone；
53) 2-((2-(2-trifluoromethyl benzyl)-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 ' H-.alpha.-5:6-benzopyran- 4-ketone；
54) 2-((2-(3-trifluoromethyl benzyl)-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 ' H-.alpha.-5:6-benzopyran- 4-ketone；
55) 2-((2-(4-trifluoromethyl benzyl)-4-hydroxy-5-methyl epoxide) phenyl)-5,7-dimethoxy-4 ' H-.alpha.-5:6-benzopyran- 4-ketone；
56) 2 ((2 (2-chlorobenzyl)-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-benzopyran-4-one；
57) 2 ((2 (3-chlorobenzyl)-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-benzopyran-4-one；
58) 2 ((2 (4-chlorobenzyl)-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-benzopyran-4-one；
59) 2 ((2 (2-methyl-benzyl)-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-benzopyran-4-one；
60) 2 ((2 (3-methyl-benzyl)-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-benzopyran-4-one；
61) 2 ((2 (4-methyl-benzyl)-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-benzopyran-4-one；
62) 2 ((2 (2-trifluoromethyl benzyl)-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-benzopyran-4-one；
63) 2 ((2 (3-trifluoromethyl benzyl)-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-benzopyran-4-one；
64) 2 ((2 (4-trifluoromethyl benzyl)-4,5-dihydroxy) phenyl)-5,7-dihydroxy-4H-benzopyran-4-one；
65) 2 ((2-(2-chlorobenzyl)-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-benzopyran-4-one；
66) 2 ((2-(3-chlorobenzyl)-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-benzopyran-4-one；
67) 2 ((2-(4-chlorobenzyl)-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-benzopyran-4-one；
68) 2 ((2-(2-methyl-benzyl)-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-benzopyran-4-one；
69) 2 ((2-(3-methyl-benzyl)-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-benzopyran-4-one；
70) 2 ((2-(4-methyl-benzyl)-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-benzopyran-4-one；
71) 2 ((2-(2-trifluoromethyl benzyl)-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-.alpha.-5:6-benzopyran-4- Ketone；
72) 2 ((2-(3-trifluoromethyl benzyl)-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-.alpha.-5:6-benzopyran-4- Ketone；
73) 2 ((2-(4-trifluoromethyl benzyl)-4,5-dihydroxy) phenyl)-5-hydroxyl-7-methoxyl group-4H-.alpha.-5:6-benzopyran-4- Ketone.
3. a compositions, containing the compound described in claim 1 or its pharmaceutically acceptable salt and pharmaceutically acceptable Carrier.
4. a compound as claimed in claim 1 or its pharmaceutically acceptable salt are for preparation and Bcl-2 albumen man Application in the medicine of the disease that race's anti-apoptotic members high expressed is relevant.
5. disease as claimed in claim 4, it is characterised in that this disease is tumor.
6. tumor as claimed in claim 5, it is characterised in that this tumor is leukemia or pulmonary carcinoma.
7. a compound as claimed in claim 1 or its pharmaceutically acceptable salt are for preparing in antifungal agent Application.
8. the preparation method of a substituted benzyl substituted flavone compound IV, V, it is characterised in that comprise the following steps:
(1) chromocor compound II is in the basic conditions, in atent solvent, with phenyl ring on be that the substituted benzyl chloride of R reacts, generationization Compound III；
(2) compound III, in acid condition, refluxes in atent solvent, reacting generating compound IV；
(3) as the R in compound IV1d, R1e、R1fIn one or more for alkoxyl time, in atent solvent, add BBr3, The alkyl sloughing one or more alkoxyl 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 R1aOr R1b, another now corresponding substituent group is Hydrogen；R1d、R1e、R1fAs claimed in claim 1；R1d、R1e、R1fIn be not the group of alkoxyl, constant after reaction；The replacement position of R Putting the one or more positions in 2,3 or 4 referred on phenyl ring, R is that following arbitrary group replaces: hydrogen, C1-8 alkyl, halo C1-8 alkyl, halogen.
9. the preparation method of a substituted benzyl substituted flavone compound VIII, IX, it is characterised in that include following step Rapid:
(1) chromocor compound VI is in the basic conditions, in atent solvent, with phenyl ring on be that the substituted benzyl chloride of R reacts, generationization Compound VII；
(2) compound VII, under acid condition, refluxes in atent solvent, reacting generating compound VIII；
(3) as the R in compound VIII1c、R1d、R1fIn one or more for alkoxyl time, in atent solvent, add BBr3, the alkyl sloughing one or more alkoxyl generates hydroxyl, and other group is constant, compound being further converted to of VIII Compound IX；
R1c, R1d、R1fAs claimed in claim 1；R1c、R1d、R1fIn be not the group of alkoxyl, constant after reaction；The replacement position of R Putting the one or more positions in 2,3 or 4 referred on phenyl ring, R is that following arbitrary group replaces: hydrogen, C1-8 alkyl, halo C1-8 alkyl, halogen.
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