CN109893522A - Amurensin H derivative is treating and preventing the application in Chronic Obstructive Pulmonary Disease - Google Patents
Amurensin H derivative is treating and preventing the application in Chronic Obstructive Pulmonary Disease Download PDFInfo
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Abstract
The invention discloses the application of a kind of Amurensin H derivative or its pharmaceutically acceptable salt in preparation treatment and/or prevention Chronic Obstructive Pulmonary Disease (COPD) product.The preparation method of Amurensin H derivative of the present invention or its pharmaceutically acceptable salt is simple, has apparent anti-inflammatory activity, and changing to COPD model mice lung tissue's inflammatory pathologies has reverse effect；The indices of COPD airway inflammation can be improved: significantly inhibiting the recruitment of total white blood cells in BALF, neutrophil leucocyte, macrophage, the generation for significantly reducing inflammatory factor TNF-α, IL-6, IL-1 β etc. in BALF is horizontal.
Description
Technical field
The present invention relates to biomedicine fields, and in particular to a kind of Amurensin H (7,8- dehydrogenation grapevine, penta element) is spread out
Biology or its medically acceptable salt, and the Pharmaceutical composition containing the derivative or its medically acceptable salt, are being controlled
Treat and/or prevent the application in Chronic Obstructive Pulmonary Disease.
Background technique
Chronic Obstructive Pulmonary Disease (Chronic obstructive pulmonary disease, COPD) be it is a kind of with
The respiratory disease that not fully reversible flow limitation is characterized has very high incidence, disability rate and the death rate, the whole world 40 years old
The above disease incidence has been up to 9%-10%, and still in trend is increased year by year, has seriously endangered global human health.
COPD flow limitation is anti-to the abnormal chronic inflammatory of toxic granular or gas with air flue and lungs in progress sexual development
It should be related.Chronic airway inflammation is the important feature of COPD, research shows that airway inflammation and COPD flow limitation degree are in positive
Close, COPD pathogenesis along with lasting chronic airway inflammation, suck toxic gas, particulate matter or secondary intrapulmonary bacterium,
A variety of predisposing factors such as virus infection can activate inflammatory response cascade in respiratory tract, and generate a large amount of inflammatory factors, chemotactic factor (CF)
With enzyme etc., lead to the damage and destruction of lung tissue.COPD airway inflammation is related between various kinds of cell and acellular components
Interaction mainly includes human airway epithelial cells, neutrophil leucocyte, eosinophil, macrophage, lymphocyte etc..?
During inflammatory reaction, pro-inflammatory cytokine causes local vessel expansion, capillary permeability to increase, and leukocyte infiltration generates white
The inflammatory mediators such as triolefin, cell factor；Between inflammatory mediator, phase between inflammatory mediator and inflammatory cell and between inflammatory cell
Interaction damages tissue or cell further, aggravates inflammatory reaction, extends inflammatory process.Therefore, control airway inflammation is
One of the necessary means of COPD clinical treatment, however, so far, still without ideal drug controlling for COPD airway inflammation
It treats.The inhalation therapy of cortin anti-inflammatory drugs is that Present clinical is unanimously recommended to use prescription for the treatment of COPD airway inflammation
Case, still, the study found that corticorubral neuron is treated for airway inflammation there are drug resistance, the patient of 70%-80% sucks skin
The matter hormone therapy state of an illness, which has no, to be significantly improved.Cortin long-time service there is a problem of more, dramatically increase infectious pneumonia
Equal adverse reactions occurrence risk.Moreover, and the non-steroid anti-inflammatory drug clinically applied there is also cause heart disease or whole body is solidifying
The adverse reactions problem such as blood obstacle disease.Therefore, finding safer effective anti-airways anti-inflammatory drugs is still current COPD
The vital task of inflammation treatment.
Amurensin H (penta element of 7,8- dehydrogenation grapevine) derivative is from folk medicinal plants V. amurensis (Vitis
Amurensis) one isolated in the root resveratrol dimer compound with benzofuran ring.Pharmacological research hair
Existing, which has significant anti-inflammatory activity and significant anti-COPD airway inflammation, improves COPD mouse lung tissue inflammation
The effect of disease pathology damage, and natural products activity is strong, toxicity is smaller, and being one has the activity of further investigation value first
Lead compound.Therefore, to obtain safer effective reactive compound, we are right using Amurensin H as lead compound
Its structure optimizes transformation, obtains a series of derivatives.The pharmacological results of further system show that the analog derivative has
There are significant anti-inflammatory activity and treatment COPD airway inflammation, further investigation revealed that, the derivative is in COPD
Application study has no document report so far.This patent is related to such compound and is treating and/or preventing Chronic Obstructive Pulmonary Disease
In application.
Summary of the invention
For overcome the deficiencies in the prior art, the technical problem to be solved in the present invention is to provide a kind of Amurensin H to spread out
Biology or combinations thereof object is preparing drug and/or health care product for preventing, treating or assisting in the treatment of Chronic Obstructive Pulmonary Disease
In application.
One of the objects of the present invention is to provide a kind of such as logical formula (I), (IA), (IAa), (IAb), (IB) and (II),
(IIA), (IIAa), (IIAb), (IIB) is acceptable on Amurensin H derivative shown in (IIC) and its pharmacodynamics
Salt is preparing the application in drug and/or health care product for preventing, treating or assisting in the treatment of Chronic Obstructive Pulmonary Disease.
It is another object of the present invention to provide a kind of pharmaceutical compositions, including at least one as led to formula (I),
(IA), (IAa), (IAb), (IB) and (II), (IIA), (IIAa), (IIAb), (IIB), Amurensin H shown in (IIC)
Derivative and its pharmaceutically acceptable salt are preparing the medicine for preventing, treating or assisting in the treatment of Chronic Obstructive Pulmonary Disease
Application in object and/or health care product.
The third aspect of the present invention is to provide the preparation method of derivative described in first aspect.
Above-mentioned purpose to realize the present invention obtains the drug candidates of better pharmacodynamic profile and smaller toxicity, this
Invention has been synthesized a series of using Amurensin H as lead compound by the semi-synthetic and structural modification method of synthesis
Amurensin H derivative, and the structure-activity relationship of such compound anti-inflammatory activity is had studied, especially in treatment chronic obstructive
Application in terms of lung disease.
Specifically, the present invention relates to a kind of Amurensin H derivatives in preparation treatment and/or prevention chronic obstructive
Application in lung disease product, it is characterised in that: such as logical formula (I) of the structure and (II) are shown:
Wherein, R1Selected from H,R2、R10Selected from H,
R9Selected from H,
R6、R7、R8、R14、R15、R16、R17、R18、R19、R20It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group,
C1-6Alkoxy acyl, Glu, SO3H、PO3H2；
R3、R4、R5、R11、R12、R13It is each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, phenyl, methylamine
Base, dimethylamino, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkoxy acyl, C2-6Insatiable hunger
With alkyl, C3-6Naphthenic base, C1-6Alkylthio group, F, Cl, Br, I, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
, according to the invention it is preferred to logical formula (I) compound represented including but not limited to chemical combination shown in general formula (IA)
The application of object and its pharmaceutically acceptable salt, which is characterized in that shown in the compound such as general formula (IA):
Wherein, R4、R5It is each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, phenyl, methylamino, dimethylamine
Base, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkoxy acyl, C2-6Unsaturated alkyl, C3-6
Naphthenic base, C1-6Alkylthio group, F, Cl, Br, I, Glu, SO3H、PO3H2；
R6、R7、R8、R17、R18It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alkoxy acyl,
Glu、SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
, according to the invention it is preferred to general formula (IA) compound represented including but not limited to shown in general formula (IAa) change
Close the application of object and its pharmaceutically acceptable salt, which is characterized in that shown in the compound such as general formula (IAa):
Wherein, R6、R7、R8、R17、R18It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alcoxyl acyl
Base, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
, according to the invention it is preferred to general formula (IA) compound represented including but not limited to shown in general formula (IAb) change
Close the application of object and its pharmaceutically acceptable salt, which is characterized in that shown in the compound such as general formula (IAb):
Wherein, R6、R7、R8、R17、R18It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alcoxyl acyl
Base, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
, according to the invention it is preferred to logical formula (I) compound represented including but not limited to chemical combination shown in general formula (IB)
The application of object and its pharmaceutically acceptable salt, which is characterized in that shown in the compound such as general formula (IB):
Wherein, R6、R7、R8、R19、R21It is each independently selected from C1-6Alkyl, C1-6Acyl group, C1-6Alkoxy acyl,
Glu、SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
, according to the invention it is preferred to logical formula (II) compound represented including but not limited to shown in general formula (IIA) change
Close the application of object and its pharmaceutically acceptable salt, which is characterized in that shown in the compound such as general formula (IIA):
Wherein, R12、R13It is each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, phenyl, methylamino, diformazan
Amido, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkoxy acyl, C2-6Unsaturated alkyl,
C3-6Naphthenic base, C1-6Alkylthio group, F, Cl, Br, I, Glu, SO3H、PO3H2；
R14、R15、R16、R17、R18It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alkoxy acyl,
Glu、SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
, according to the invention it is preferred to general formula (IIA) compound represented including but not limited to shown in general formula (IIAa)
The application of compound and its pharmaceutically acceptable salt, which is characterized in that shown in the compound such as general formula (IIAa):
R14、R15、R16、R17、R18It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alkoxy acyl,
Glu、SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
, according to the invention it is preferred to general formula (IIA) compound represented including but not limited to shown in general formula (IIAb)
The application of compound and its pharmaceutically acceptable salt, which is characterized in that shown in the compound such as general formula (IIAb):
R14、R15、R16、R17、R18It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alkoxy acyl,
Glu、SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
, according to the invention it is preferred to logical formula (II) compound represented including but not limited to shown in general formula (IIB) change
Close the application of object and its pharmaceutically acceptable salt, which is characterized in that shown in the compound such as general formula (IIB):
Wherein, R14、R15、R16、R19、R22It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alcoxyl acyl
Base, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
, according to the invention it is preferred to logical formula (II) compound represented including but not limited to shown in general formula (IIC) change
Close the application of object and its pharmaceutically acceptable salt, which is characterized in that shown in the compound such as general formula (IIC):
Wherein, R14、R15、R16、R20、R22It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alcoxyl acyl
Base, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
Specifically, logical formula (I), (IA), (IAa), (IAb), (IB) and (II), (IIA), (IIAa), (IIAb),
(IIB), Amurensin H derivative and its pharmaceutically acceptable salt shown in (IIC), which is characterized in that the chemical combination
Object is selected from following group (compound numbers correspond to the compound numbers in embodiment):
In order to complete the purpose of the present invention, that there is provided one kind is effective containing drug for the second aspect of technical solution of the present invention
Dosage as lead to formula (I), (IA), (IAa), (IAb), (IB) and (II), (IIA), (IIAa), (IIAb), (IIB), (IIC) are each
The pharmaceutical composition of compound described in situation and pharmaceutically acceptable carrier is in preparation for preventing, treating or assisting in the treatment of
The drug of Chronic Obstructive Pulmonary Disease and/or the application in health care product.
According to the present invention, the compounds of this invention can exist in the form of isomers, and usually described " of the present inventionization
Conjunction object " includes the isomers of the compound.
According to an embodiment of the invention, the compounds of this invention further includes its pharmaceutically acceptable salt, salt
Hydrate or pro-drug.
The invention further relates to containing as the compounds of this invention and customary pharmaceutical excipients of active constituent or the medicine of adjuvant
Compositions.Usual pharmaceutical composition of the present invention contains the compounds of this invention of 0.1~95% weight.This hair in unit dosage form
The bright general content of compound is 0.1~100mg, and preferred unit dosage form contains 4~50mg.
The pharmaceutical composition of the compounds of this invention can be prepared according to method well known in the art.When for this purpose, if
It needs, can be by the compounds of this invention in conjunction with one or more solids or liquid pharmaceutical excipients and/or adjuvant, being made can be used as
The administration form or dosage form appropriate that people's medicine or veterinary drug use.
Inflammation is one of basic illness of Chronic Obstructive Pulmonary Disease, and anti-inflammatory treatment is the important means of its clinical treatment.
The present invention induces Primary mouse peritoneal macrophage inflammatory cell model using LPS, preliminary assessment Amurensin H derivative
Anti-inflammatory activity, result of study show that Amurensin H derivative 10,12,13,8 is huge to LPS induction Primary mouse abdominal cavity in vitro
The generation of phagocyte inflammatory factor NO has significant inhibiting effect, IC50It is respectively as follows: 8.6 × 10-6mol/l、6.1×10- 6mol/l、9.5×10-6Mol/l and 9.2 × 10-6mol/l；Further using croton oil inducing mouse otitis model to activation
It closes object and carries out non-specific anti-inflammatory activity evaluation in vivo, the single-dose under 50mg/kg dosage hypodermis, result of study is shown, is spread out
10,12,13,8 pairs of croton oil inducing mouse otitis of biology, which have, significantly inhibits effect.
Long-term smoking is the most common mankind COPD pathogenic factor, and the COPD model of simulation mouse is induced with LPS+ cigarette.
The Amurensin H derivative 10,12,13,8 for choosing significant anti-inflammatory activity investigates its therapeutic effect to mouse COPD.Research
The results show that continuous gavage is administered 14 days at 100 μm of ol//kg, 12,13,8 can significantly inhibit COPD mouse bronchoalveolar lavage fluid
(BALF) recruitment of total white blood cells, neutrophil leucocyte and macrophage in, inhibit BALF in inflammatory cytokine TNF-α,
The generation of IL-6, IL-1 β；13,8 can significantly mitigate COPD mouse lung inflammatory pathologies degree of injury.
The present invention has the advantages that carrying out structure optimization conjunction on the basis of (1) derivative Amurensin H structure of the present invention
At having better pharmacodynamic profile, and relatively small toxic side effect；(2) Amurensin H derivative of the present invention has significant
Anti-inflammatory activity；(3) Amurensin H derivative of the present invention can effectively treat COPD airway inflammation, mitigate its inflammatory pathologies damage
Wound；(4) this product raw material is easy to get, and preparation process is simple, and be easy to standardize production.
The preparation method of pharmaceutical composition is further related to according to the present invention.When for this purpose, if it is desired, can by activity at
Divide in conjunction with one or more solids or liquid pharmaceutical excipients and/or adjuvant, is made and can be used as the appropriate application that people's medicine uses
Form or dosage form.
Pharmaceutical composition of the invention can be administered in a unit, and administration route can be enteron aisle or non-bowel, such as mouth
Clothes, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum etc..
The administration route of pharmaceutical composition of the invention can be drug administration by injection.Injection includes intravenous injection, intramuscular injection, skin
Lower injection, intracutaneous injection and acupoint injection therapy etc..Form of administration can be liquid dosage form, solid dosage forms.As liquid dosage form can be
True solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form.Other dosage forms for example tablet, capsule, dripping pill, aerosol,
Pill, pulvis, solution, suspension, emulsion, granule, suppository, freeze drying powder injection etc..
Composition of the invention can be made ordinary preparation, be also possible to sustained release preparation, controlled release preparation, targeting preparation and each
Kind particulate delivery system.
In order to which tablet is made in unit dosage forms for administration, various carriers well known in the art can be widely used.About carrier
Example be such as diluent and absorbent, such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, grape
Sugar, urea, calcium carbonate, white bole, microcrystalline cellulose, alumina silicate etc.；Wetting agent and adhesive, Ru Shui, Gan Bo, polyethylene glycol,
Ethyl alcohol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, carboxymethylcellulose sodium,
Lac, methylcellulose, potassium phosphate, polyvinylpyrrolidone etc.；Disintegrating agent, for example, dry starch, alginate, agar powder,
Laminaran, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol aliphatic ester, dodecyl sodium sulfate, methyl
Cellulose, ethyl cellulose etc.；Disintegration inhibitor, such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil and fat etc.；It absorbs and promotees
Into agent, such as quaternary ammonium salt, sodium lauryl sulfate etc.；Lubricant, such as talcum powder, silica, cornstarch, stearic acid
Salt, boric acid, atoleine, polyethylene glycol etc..Tablet can also be further made to coating tablet, such as sugar coated tablet, film packet
Garment piece, enteric coated tablets or double-layer tablets and multilayer tablet.
In order to which pill is made in administration unit, various carriers well known in the art can be widely used.Example about carrier
Son is, such as diluent and absorbent, as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone,
Gelucire, kaolin, talcum powder etc.；Adhesive, as Arabic gum, bassora gum, gelatin, ethyl alcohol, honey, liquid sugar, rice paste or
Batter etc.；Disintegrating agent, such as agar powder, dry starch, alginate, dodecyl sodium sulfate, methylcellulose, ethyl cellulose
Deng.
In order to which suppository is made in administration unit, various carriers well known in the art can be widely used.Example about carrier
Son is, such as enzyme, gelatin, semi-synthetic glycerol enzyme of polyethylene glycol, lecithin, cocoa butter, higher alcohol, higher alcohol etc..
In order to which capsule is made in administration unit, effective component is mixed with above-mentioned various carriers, and will be thus obtained
Mixture is placed in hard gelatine capsule or soft capsule.Microcapsules can also be made in effective component, be suspended in shape in aqueous medium
At suspension, injection application also can be fitted into hard capsule or is made.
For example, injection preparation is made in composition of the invention, such as solution, suspension solution, emulsion, freeze-dried powder
Injection, this preparation can be it is aqueous or non-aqueous, can contain acceptable carrier in a kind of and/or a variety of pharmacodynamics, diluent,
Adhesive, lubricant, preservative, surfactant or dispersing agent.As diluent can be selected from water, ethyl alcohol, polyethylene glycol, 1,3-
Propylene glycol, the isooctadecanol of ethoxylation, polyoxygenated isooctadecanol, polyoxy ethylene sorbitol fatty acid enzyme etc..In addition, in order to
Isotonic injection is prepared, suitable sodium chloride, glucose or glycerol can be added into injection preparation, further, it is also possible to add
Add conventional cosolvent, buffer, pH adjusting agent etc..These auxiliary materials are commonly used in the art.
Furthermore if desired, can also be added into pharmaceutical preparation colorant, preservative, fragrance, corrigent, sweetener or its
Its material.
The dosage of Pharmaceutical composition of the present invention depends on many factors, such as to be prevented or be treated the property of disease
And severity, gender, age, weight, personality and the individual reaction of patient or animal, administration route, administration number of times etc., therefore
Therapeutic dose of the invention can have large-scale variation.In general, the dosage of Chinese pharmacology ingredient of the present invention is ability
Well known to field technique personnel.It can actually active drug number contained in preparation last in Pharmaceutical composition according to the present invention
Amount, is subject to adjustment appropriate, to reach the requirement of its therapeutically effective amount, completes the purpose for the treatment of diseases associated with inflammation of the invention.
Usually to about 75 kilogram patient of weight, the daily dose of given extract is 0.001mg/kg weight~500mg/kg weight, preferably
3mg/kg weight~30mg/kg weight.Above-mentioned dosage with single dose form or can be divided into several, such as two, three or four agent
The administration of amount form, this is limited to the clinical experience and dosage regimen of administration doctor.
The third aspect of the present invention is to provide the preparation method of derivative described in first aspect.
It is used to prepare the raw material of the compounds of this invention, resveratrol can by commercially available acquisition, isorhapontigenin
It is prepared according to the method for document [J.Asian Nat.Prod.Res., 2014,16 (5): 511-521].
The basic synthetic route of compound 1-8 in the present invention is as follows:
The basic synthetic route of compound 9-19 in the present invention is as follows:
The basic synthetic method of compound of the present invention includes the following steps:
Step 1: resveratrol (or isorhapontigenin) carries out dimerization reaction and synthesizes the benzo two containing styrene double bond
Hydrogen furan type talan dimer derivate.
4- styrene substitution coumaran type resveratrol dimer synthesis: resveratrol in methyl alcohol with
FeCl3·6H2O is that catalyst carries out polymerization reaction, and reaction product is concentrated under reduced pressure, and obtained solid obtains target through chromatographic separation and purification
Product 4- styrene replaces coumaran type resveratrol dimer (such as compound 1).
5- styrene substitution coumaran type resveratrol dimer synthesis: resveratrol in anhydrous propanone with
Ag2O (or horseradish peroxidase) is that oxidant carries out oxidative coupling reaction, and reaction solution filtering is concentrated to dryness gained slightly
Product obtains target product 5- styrene through chromatographic separation and purification and replaces coumaran type resveratrol dimer (such as compound
9)。
The synthesis of 5- styrene substitution coumaran type isorhapontigenin dimer: isorhapontigenin monomer exists
With horseradish peroxidase (HRP) and H in the mixed solution of acetone and water2O2For oxidant (or Ag2O is oxidant) carry out oxygen
Change coupling reaction, reaction mixture is concentrated under reduced pressure after being further processed, and gained crude product obtains target product through chromatographic separation and purification
5- styrene replaces coumaran type isorhapontigenin dimer (such as compound 14).
Step 2: it is permethylated that phenolic hydroxyl group talan dimer derivate obtained by step 1 carries out methylation reaction synthesis
Talan dimer derivate.
The anhydrous propanone solution of phenolic hydroxyl group talan dimer derivate is in K2CO3In the presence of, with CH3I (or (CH3)2SO4Or CH2N2) methylation reaction is carried out, reaction product obtains the permethylated hexichol second of phenolic hydroxyl group through recrystallization or chromatographic isolation
Alkene dimer derivate.
Step 3: phenolic hydroxyl group talan dimer derivate obtained by step 1 carries out acetylating reaction and synthesizes full acetyl
The talan dimer derivate of change.
Step 1 products therefrom carries out acetylization reaction with aceticanhydride in dry pyridine, after reaction solution removes pyridine, decompression
It is concentrated to give the full acetylated talan dimer derivate of target product.
Step 4: permethylated or full acetylated dihydrofuran type talan dimer derivate is aoxidized by DDQ
Synthesize furan type talan dimer derivate.
Permethylated or full acetylated dihydrofuran type talan dimer derivate obtained by step 2 and step 3
In anhydrous dioxane with DDQ carry out oxidative dehydrogenation, reaction product through recrystallization or chromatographic isolation obtain it is permethylated or
Full acetylated furan type talan dimer derivate.
Step 5: the talan dimer derivate of the double bond containing styrene synthesizes corresponding double bond hydrogen by hydro-reduction
Change derivative.
The talan dimer derivate of the double bond containing styrene obtained by above step is in ethyl acetate solvent, with Pd/C
(10%) it is catalyst, carries out double bond reduction reaction in a hydrogen atmosphere.Reaction mixture is filtered to remove Pd/C, filtrate decompression
It is concentrated to give the benzofuran or coumaran type talan dimer derivate of the hydrogenation of styrene double bond.
Step 6: it is derivative that full acetylated talan dimer derivate removing acetyl group synthesizes corresponding phenolic hydroxyl group
Object.
Mixed solution of the full acetylated talan dimer derivate in methylene chloride and methanol obtained by above step
In with NH4OAc is reacted.Reaction product is added water and is extracted with ethyl acetate, and organic phase evaporated under reduced pressure obtains corresponding phenolic hydroxyl group
Talan dimer derivate.
Advantageous effects
The activity research process of the present inventor natural products amurensin H isolated in V. amurensis
In, it is found that the compound has stronger anti-oxidant and anti-inflammatory activity on animal model.On this basis, with Amurensin
H is lead compound, and the method by synthesizing semi-synthetic integrated structure modification has been synthetically prepared a series of Amurensin H,
And the inflammation inhibitory activity for having carried out inside and outside to obtained derivative is evaluated, such compound inflammation inhibitory activity is had studied
Structure-activity relationship, further confirm the anti-inflammatory activity of such compound.The experimental results showed that such compound induces LPS
The generation of Primary mouse peritoneal macrophage NO has stronger inhibitory activity, causes mouse otitis to have significant suppression croton oil
System activity；Further animal experiments show that, such compound has the murine chronic obstructive disease of lung that cigarette induces aobvious
The inhibiting effect of work has the potential value further developed.
Currently, other than 7, the 8- dehydrogenation grapevine penta plain (amurensin H) of this group report, to benzofuran or benzene
And the anti-inflammatory activity structure activity study of the talan dimer class system of compounds of dihydrofuran structure is there is not yet document report
Road.Other than 7,8- dehydrogenation grapevine penta plain (amurensin H), have no in existing literature and technology about benzofuran or
Coumaran type talan dimer derivate or its medically acceptable salt and such compound are used to prepare and control
Treat and/or prevent the relevant report of Chronic Obstructive Pulmonary Disease.
Detailed description of the invention:
The various terms and phrase that the present invention uses have well known to a person skilled in the art general senses, nonetheless,
The present invention remains desirable to that these terms and phrase are described in more detail and are explained at this, the term and phrase referred to if any with
Common art-recognized meanings are inconsistent, the meaning that the present invention of being subject to is stated.Here is the definition of a variety of terms used in the present invention, these
Definition is suitable for term used in the application the whole instruction, unless otherwise indicated in concrete condition.
Term mentioned by the present invention " alkyl " refers to specifying number the alkyl of carbon atom number, can for straight chain or
The alkyl of branch, such as " C referred to3-6Naphthenic base " refer to carbon atom number be 3,4,5,6 substituted or unsubstituted cycloalkanes
Base may include C3-5Naphthenic base, C3-4Naphthenic base, C4-6Naphthenic base, C4-5Naphthenic base, C5-6The subrange of the expressions such as naphthenic base
Group, and preferred specific group, such as cyclopropyl alkyl, pentamethylene base and cyclohexyl.
Term " C mentioned by the present invention1-6Alkyl " refer to carbon atom number be 1,2,3,4,5,6 linear chain or branched chain alkane
Base may include C1-5Alkyl, C1-4Alkyl, C2-5Alkyl, C2-4Alkyl, C2-3Alkyl, C3-5The base of the subrange of the expressions such as alkyl
Group, and preferred specific group, such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, tert-butyl etc..
Term " C mentioned by the present invention1-6Alkoxy " refers to that carbon atom number is 1,2,3,4,5,6 alkoxy, including
C1-5Alkoxy, C1-2Alkoxy, C2-4Alkoxy, C2-3Alkoxy, C3-4The group of the subrange of the expressions such as alkoxy, Yi Jiyou
Specific group such as methoxyl group, ethyoxyl, n-propyl oxygroup, isopropyl oxygroup, normal-butyl oxygroup, the sec-butyl oxygroup, uncle of choosing
Butyl oxygroup etc..
Term " C mentioned by the present invention2-6Unsaturated alkyl " refers to that carbon atom number is 2,3,4,5,6 unsaturated alkyl,
It may include C1-5Unsaturated alkyl, C1-4Unsaturated alkyl, C2-5Unsaturated alkyl, C2-4Unsaturated alkyl etc. indicate
Subrange group, and preferred specific group, such as vinyl, acetenyl, isopropenyl, isopropynyl, isobutene
Base, isopentene group, 1,4- dibutene base.
Term " C mentioned by the present invention1-6Acyl group " refer to carbon atom number be 1,2,3,4,5,6 acyl group, may include
C1-5Acyl group, C1-3Acyl group, C2-5Acyl group, C2-3Acyl group, C3-4The group of the subrange of the expressions such as acyl group, and preferred specific base
Group, such as formoxyl, acetyl group, propiono etc..
" C mentioned by the present invention1-6Acyloxy " refer to carbon atom number be 1,2,3,4,5,6 linear chain or branched chain acyl-oxygen
Base may include C1-5Acyloxy, C1-3Acyloxy, C2-5Acyloxy, C2-3Acyloxy, C3-4The subrange of the expressions such as acyloxy
Group, and preferred specific group, such as formyloxy, acetoxyl group, propionyloxy etc..
" C mentioned by the present invention1-6Alkoxy acyl " refer to that carbon atom number is 1,2,3,4,5,6 alkoxy acyl, can be with
Including C1-5Alkoxy acyl, C1-3Alkoxy acyl, C2-5Alkoxy acyl, C2-3Alkoxy acyl, C3-4The subrange of the expressions such as alkoxy acyl
Group, and preferred specific group, such as methoxy acyl group, ethoxy acyl group etc.；
Term " C mentioned by the present invention1-6Alkylthio group " refer to carbon atom number be 1,2,3,4,5,6 linear chain or branched chain
Alkylthio group may include C1-5Alkylthio group, C1-3Alkylthio group, C2-5Alkylthio group, C2-3Alkylthio group, C3-4The sub- model of the expressions such as alkylthio group
The group enclosed, and preferred specific group, such as methyl mercapto, ethylmercapto group etc..
Detailed description of the invention
Influence of Figure 1A murensin H anti-inflammatory activity derivative to COPD mouse lung tissue pathological change；
Specific embodiment
In order to which the present invention is furture elucidated, a series of embodiments are given below.These embodiments be entirely it is illustrative, it
Only be used to the present invention is specifically described, be not construed as limitation of the present invention.
The basic synthetic route of compound 1-8 in the present invention is following, and (compound numbers correspond to the chemical combination in embodiment
Object code name):
The basic synthetic route of compound 9-19 in the present invention is as follows:
Embodiment 1:
5- [2- (4- hydroxy phenyl) -4- [2- (4- hydroxy phenyl) vinyl -6- hydroxyl] -2,3- dihydro -3- benzofuran
Base] -1,3- benzenediol (1)
The synthetic route of compound 1:
100g resveratrol (438.6mmol) stirs lower dropwise addition FeCl with the dissolution of 1000mL anhydrous methanol3Aqueous solution
[116.7g FeCl3·6H2O (432.619mmol) is dissolved in 67mL water, and 100mL methanol dilution is added].Reaction solution is stirred at room temperature
Stop reaction after 3d.Decompression boils off solvent and obtains black medicinal extract.The medicinal extract is with petroleum ether: acetone=6:3 carries out silica gel (100-200
Mesh) column chromatography for separation obtains 1 30.5g of gray solid compound (67.181mmol), yield 10.2%.
Compound 1,1H NMR(CD3COCD3,500MHz)δ:8.41(OH),8.38(OH),8.33(OH),8.17(2H, 2
× OH), 7.20 (2H, d, J=9.0Hz, H-2a, 6a), 7.16 (2H, d, J=8.5H, H-2b, 6b), 6.90 (1H, d, J=
16.0 Hz, H-7b), 6.82 (2H, d, J=9.0Hz, H-3a, 5a), 6.73 (2H, d, J=8.5Hz, H-3b, 5b), 6.72
(2H, d, J=2.0 Hz, H-10a, 14a), 6.70 (1H, d, J=16.0Hz, H-8b), 6.32 (1H, d, J J=2.0Hz, H-
12b), 6.23 (2H, br s, H-12a, 14b), 5.41 (1H, d, J=5.5Hz, H-7a), 4.47 (1H, d, J=5.5Hz, H-
8a)。0 (c=1.103, MeOH)；ESI-MS m/z:455.2[M+H]+,477.1[M+Na]+.
Embodiment 2:
2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -4- [2- (4- methoxyphenyl) vinyl] -6- first
Oxygroup -2,3- Dihydro-benzofuran (2)
The synthetic route of compound 2:
1522mg K is added portionwise with the dissolution of 10ml anhydrous propanone in 500mg compound 1 (1.10mmol) under stirring2CO3Gu
Body (11.013mmol) instills 3907mg CH after 30min is stirred at room temperature3I (27.525mmol), continues to be stirred to react 48h.Instead
Liquid is answered to dilute with water, ethyl acetate extraction, organic phase merges, and successively with saturated salt solution, water washing, anhydrous sodium sulfate is dry,
It is concentrated to dryness to obtain white-yellowish solid compound 2 (489mg, 0.933mmol), yield 84.7%, m.p.58-59 DEG C.
Compound 2:1H NMR(CD3COCD3, 500MHz) and δ: 7.31 (2H, d, J=9.0Hz, H-2a, 6a), 7.26 (2H,
D, J=8.5Hz, H-2b, 6b), 7.03 (1H, d, J=16.5Hz, H-7a), 6.93 (2H, d, J=8.5Hz, H-3b, 5b),
6.82 (2H, d, J=9.0Hz, H-3a, 5a), 6.81 (1H, br s, H-14b), 6.78 (1H, d, J=16.5Hz, H-8a),
6.47 (2H, d, J=2.0Hz, H-10a, 14a), 6.45 (1H, d, J=1.5Hz, H-12b), 6.38 (1H, t, J=2.0Hz,
), H-12a 5.56 (1H, d, J=6.0Hz, H-7a), 4.66 (1H, d, J=6.0Hz, H-8a), 3.84 (3H, s, OCH3),
3.79(3H,s,OCH3),3.76(3H,s,OCH3), 3.71(6H,s,OCH3)；13C NMR(CD3COCD3,125MHz)δ:
162.3(4×C),160.58,160.51,147.2,136.2, 134.7,130.9,130.2,128.6(2×C),127.8(2
×C),123.9,121.0,114.83(2×C),114.77(2×C),106.6 (2×C),102.9,99.3,95.7,93.6,
57.2,55.8(OCH3),55.5(4×OCH3),36.4,35.9；ESI-MS m/z:547.3 [M+Na]+.
Embodiment 3:
5- [2- (4- acetoxyl group phenyl)-4- [(1E)-2- (4- acetoxyl group phenyl) vinyl] acetoxyl group-2-6-,
3- dihydro -3- benzofuranyl] -1,3- diacetic ester (3)
The synthetic route of compound 2:
10g compound 1 (22.026mmol) is slowly added to aceticanhydride 56.2g with the dissolution of 150ml dry pyridine under stirring
(550.980 mmol), is stirred overnight at room temperature.After having reacted, 60ml water is slowly dropped under ice bath, reaction solution is transferred to 1000ml
In separatory funnel, with the dilution of 300ml water, ethyl acetate is extracted three times, merges organic phase, successively to be saturated CuSO4Solution is washed, satisfies
After saline solution, water washing, evaporated under reduced pressure obtains white-yellowish solid 3 (12.3g, 18.524mmol), yield 84.1%, m.p.
147-149℃。
Compound 3:1H NMR(CD3COCD3, 500MHz) and δ: 7.43 (2H, d, J=8.5Hz, H-2a, 6a), 7.36 (2H,
D, J=8.5Hz, H-2b, 6b), 7.15 (2H, d, J=8.5Hz, H-3a, 5a), 7.09 (1H, d, J=16.5Hz, H-7b),
7.07 (1H, d, J=2.0Hz, H-12b), 7.02 (2H, d, J=8.5Hz, H-3b, 5b), 7.01 (2H, d, J=2.0Hz, H-
10a, 14a), 6.91 (1H, t, J=2.0Hz, H-12a), 6.81 (1H, d, J=16.5Hz, H-8b), 6.70 (1H, d, J=
2.0Hz, H-14b), 5.71 (1H, d, J=6.0Hz, H-7a), 4.93 (1H, d, J=6.0Hz, H-8a), 2.29 (3H, s,
OCOCH3),2.28(3H,s, OCOCH3),2.24(15H,s,OCOCH3)；ESI-MS m/z:687.3[M+Na]+,703.2[M+
K]+.
Embodiment 4:
2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -4- [2- (4- methoxyphenyl) vinyl] -6- first
Oxygroup-benzofuran (4)
The synthetic route of compound 4:
350mg compound 2 (0.668mmol) is added 227mg DDQ (1.00mmol), is added with the dissolution of 15ml dioxane
Stop reaction after heat reflux 48h, reaction solution is concentrated under reduced pressure, and residue carries out silica gel (200-300 by eluant, eluent of methylene chloride
Mesh) column chromatography for separation obtains light yellow solid 4 (277.5mg, 0.532mmol), yield 79.6%, and m.p.61-62 DEG C.
Compound 4:1H NMR(CD3COCD3, 500MHz) and δ: 7.54 (2H, d, J=8.5Hz, H-2a, 6a), 7.18 (1H,
D, J=2.0Hz, H-14b), 7.08 (1H, d, J=2.0Hz, H-12b), 7.06 (2H, d, J=8.5Hz, H-3a, 5a), 7.05
(1H, d, J=16.0Hz, H-7b), 6.89 (2H, d, J=9.0Hz, H-2b, 6b), 6.87 (1H, d, J=16.0Hz, H-8b),
6.84 (2H, d, J=9.0Hz, H-3b, 5b), 6.75 (1H, t, J=2.0Hz, H-12a), 6.67 (2H, d, J=2.0Hz, H-
10a,14a),3.91(3H, s,OCH3),3.80(6H,s,OCH3),3.794(3H,s,OCH3),3.789(3H,s,OCH3)；13C
NMR(CD3COCD3, 125MHz)δ:162.8(2×C),160.5,160.4,159.3,155.8,150.3,137.8,132.9,
131.0,129.4,128.4(2×C), 128.2(2×C),124.1,123.2,122.6,117.3,114.8(4×C),
109.5(2×C),107.3,100.7,95.6,56.1(OCH3), 55.9(2×OCH3),55.6(2×OCH3)；m/z:545.3
[M+Na]+.
Embodiment 5:
5- [2- (4- acetoxyl group phenyl)-4- [(1E)-2- (4- acetoxyl group phenyl) vinyl]-6- acetoxy-3-
Benzofuranyl] -1,3- diacetic ester (5)
The synthetic route of compound 5:
7.8g compound 3 (11.76mmol) is dissolved in the dry methylene chloride of 300ml, and 4.0g DDQ solid is added
(17.621 mmol), is heated to reflux 48h under stirring.Reaction solution evaporated under reduced pressure, remaining mixture are carried out by solvent of methylene chloride
Silica gel column chromatography (200-300 mesh) separates to obtain yellowish crude product.Crude product with acetone recrystallization obtain light yellow crystal 5 (5.9g,
8.912mmol), yield 75.8%.
5:m.p.107-109 DEG C of compound；1H NMR(CD3COCD3, 500MHz) and δ: 7.61 (2H, d, J=9.0Hz, H-
2a, 6a), 7.42 (1H, d, J=2.0Hz, H-14b), 7.36 (1H, d, J=2.0Hz, H-12b), 7.27 (2H, d, J=
2.0Hz, H-10a, 14a), 7.26 (1H, t, J=2.0Hz, H-12a), 7.23 (2H, d, J=9.0Hz, H-2b, 6b), 7.12
(2H, d, J=9.0Hz, H-3a, 5a), 7.15 (1H, d, J=17.0Hz, H-7b), 7.02 (2H, d, J=9.0Hz, H-3b,
5b), 6.98 (1H, d, J=17.0 Hz, H-8b), 2.32 (3H, s, OCOCH3),2.25(6H,s,OCOCH3),2.24(6H,s,
OCOCH3)；ESI-MS m/z: 685.3[M+Na]+,701.4[M+K]+.
Embodiment 6:
5- [2- (4- hydroxy phenyl) -4- [2- (4- hydroxy phenyl) ethyl] -2,3- dihydro -3- benzofuranyl] -1,3-
Benzenediol (6)
The synthetic route of compound 6:
100mg compound 1 (0.220mmol) is dissolved in 7ml ethyl acetate, is added 8.8mg Pd/C (10%).In hydrogen
Under atmosphere, atmospheric pressure at room stirs 4h, is filtered to remove Pd/C, and filtrate decompression is concentrated to give yellow solid 6 (98.0mg, 0.215mmol),
Yield is 97.7%, m.p.107-109 DEG C.
Compound 6:UV λmax(MeOH,logε):227(4.67),282.8(4.25),351(3.90)nm；1H NMR
(CD3COCD3, 500MHz) and δ: 8.15 (5H, br s, OH), 7.08 (2H, d, J=9.0Hz, H-2a, 6a), 6.78 (2H, d, J=
8.5Hz, H-2b, 6b), 6.76 (2H, d, J=9.0Hz, H-3a, 5a), 6.60 (2H, d, J=8.5Hz, H-3b, 5b), 6.23
(2H, d, J=2.0Hz, H-14b), 6.21 (1H, t, J=1.5Hz, H-12a), 6.20 (1H, d, J=1.5Hz, H-12b),
6.13 (2H, d, J=1.5Hz, H-10a, 12a), 5.28 (1H, d, J=6.0Hz, H-7a), 4.13 (1H, d, J=6.0Hz, H-
8a),2.46-2.50(1H,m, H-7b×1),2.35-2.39(3H,m,H-7b×1,8b×2)；13C NMR(CD3COCD3,
125MHz)δ:162.0,159.8 (2×C),159.5,158.1,156.3,147.4,141.0,133.8,133.4,130.2(2
×C),128.1(2×C),120.2,116.1 (2×C),115.7(2×C),109.2,107.0(2×C),102.0,95.5,
94.0,57.1,36.5,36.1；ESI-MS m/z:457.3 [M+H]+,479.2[M+Na]+,485.5[M+K]+；HR-ESI-MS
m/z:457.1653[M+H]+(calcd.for C28H25O6, 457.1646).
Embodiment 7:
2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -4- [2- (4- methoxyphenyl) ethyl] -6- methoxy
Base -2,3- Dihydrobenzofuranes (7)
The synthetic route of compound 7:
100mg compound 2 (0.191mmol) is dissolved in 6ml ethyl acetate, and 7.6mg Pd/C (10%) solid is added,
Under hydrogen atmosphere, 1h is stirred at room temperature in middle pressure, is filtered to remove Pd/C, and it is light yellow to obtain 98.1mg (0.187mmol) for filtrate decompression concentration
Sticky shape compound 7, yield 97.6%.
Compound 7:1H NMR(CD3COCD3, 500MHz) and δ: 7.20 (2H, d, J=9.0Hz, H-2a, 6a), 6.90 (2H,
D, J=9.0Hz, H-3a, 5a), 6.85 (2H, d, J=8.5Hz, H-2b, 6b), 6.72 (2H, d, J=8.5Hz, H-3b, 5b),
6.42 (1H, br t, J=1.5Hz, H-12a), 6.36 (4H, br s, H-10a, 13a, 12b, 14b), 5.43 (1H, d, J=
6.0Hz, H-7a), 4.25 (1H, d, J=6.0Hz, H-8a), 3.79 (3H, s, OCH3),3.74(6H,s,OCH3),3.71(6H,
s,OCH3),2.58-2.61 (1H,m,H-7b×1),2.43-2.48(3H,m,H-7b×1,8b×2)；13C NMR
(CD3COCD3,125MHz)δ:162.3 (2×C),162.2,162.0,160.5,158.9,147.0,140.8,134.6,
134.4,130.2(2×C),127.5(2×C)121.2,114.7 (2×C),114.3(2×C),108.2,106.9(2×
C),99.3,94.3,93.7,57.3,55.6(3×OCH3),55.4(2×OCH3), 36.4,35.9；ESI-MS m/z:527.3
[M+H]+,549.3[M+Na]+,565.2[M+K]+.
Embodiment 8:
5- [2- (4- acetoxyl group phenyl)-4- [2- (4- acetoxyl group phenyl) ethyl]-6- acetoxy-3-benzo furan
Mutter base] -1,3- diacetic ester (8)
The synthetic route of compound 8:
210mg compound 3 (0.316mmol) is dissolved in 10ml ethyl acetate, and 12.7mg Pd/C (10%) solid is added.
In a hydrogen atmosphere, 2h is stirred at room temperature in middle pressure, is filtered to remove Pd/C, filtrate decompression concentration, obtain shallow white solid 8 (207mg,
0.206 mmol), yield 98.2%, m.p.82-83 DEG C.
Compound 8:UV λmax(MeOH,logε):279(4.22),348.8(4.02)nm；1H NMR(CD3COCD3,500
MHz) δ: 7.33 (2H, d, J=8.5Hz, H-2a, 6a), 7.13 (2H, d, J=8.5Hz, H-3a, 5a), 6.96 (2H, d, J=
8.5 Hz, H-2b, 6b), 6.95 (1H, br s, H-12a), 6.92 (2H, d, J=2.0Hz, H-10a, 14a), 6.89 (2H, d, J
=8.5Hz, H-3b, 5b), 6.63 (1H, d, J=1.5Hz, H-14b), 6.61 (1H, br s, H-12b), 5.58 (1H, d, J=
6.0Hz, H-7a), 4.48 (1H, d, J=6.0Hz, H-8a), 2.62-2.65 (1H, m, H-7b × 1), 2.51-2.56 (3H, m,
H-7b×1,8b×2)；13C NMR(CD3COCD3,125MHz)δ:169.62(OCOCH3),169.59(OCOCH3),169.5
(OCOCH3),169.5 (2×C,OCOCH3),161.3,153.2,152.7(2×C),151.9,150.1,146.0,140.0,
139.6,139.1,130.2(2×C), 127.6(2×C),125.6,122.9(2×C),122.3(2×C),119.5(2×
C),116.1,115.7,102.5,93.3,56.5,36.4, 35.4,21.0(OCOCH3),20.94(2×C,OCOCH3),
20.90(2×C,OCOCH3)；ESI-MS m/z:689.3[M+Na]+, 705.2[M+K]+；HR-ESI-MS m/z:689.2004
[M+Na]+(calcd.for C38H34NaO11,689.1993).
Embodiment 9:
5- [2- [4- hydroxy phenyl] -3- [3,5- dihydroxy phenyl] -2,3- dihydro -5- benzofuranyl] vinyl -1,
3- benzenediol (9)
The synthetic route of compound 9:
67.8g Ag is added with the dissolution of 1500ml anhydrous propanone in 60g resveratrol (263.158mmol)2O is heated to reflux
3d, reaction solution are filtered with diatomite, and filtrate is evaporated to obtain reaction mixture.The mixture is with petroleum ether: acetone=3:2 carries out silica gel
(200-300 mesh) column chromatography for separation, obtaining yellow solid is compound 9 (6.7g, 14.758mmol), yield 11.2%, m.p.
154-156℃。
Compound 9:1H NMR(CD3COCD3,500MHz)δ:8.42(1H,s,OH),8.18(2H,s,OH),8.14(2H,
S, OH), 7.42 (1H, br d, J=8.5Hz, H-6b), 7.26 (1H, br s, H-2b), 7.23 (2H, d, J=8.0Hz, H-
2a, 6a), 7.05 (1H, d, J=16.0Hz, H-7b), 6.90 (1H, d, J=16.0Hz, H-8b), 6.86 (1H, d, 8.5Hz,
), H-5b 6.84 (2H, d, J=8.0Hz, H-3a, 5a), 6.53 (2H, d, J=2.0Hz, H-10b, 14b), 6.27 (1H, t, J
=2.0Hz, H-12b), 6.25 (1H, t, J=2.0Hz, H-12a), 6.18 (2H, d, J=2.0Hz, H-10a, 14a), 5.44
(1H, d, J=8.0Hz, H-7a), 4.46 (1H, d, J=8.0Hz, H-8a)；ESI-MS m/z:455.1[M+H]+,477.2[M
+Na]+,493.1[M+K]+；0 (c=1.018, MeOH)
Embodiment 10:
5- [2- (4- acetoxyl group phenyl) -3- (3,5- diacetoxy phenyl) -5- [(1E) -2- (4- acetyloxy phenyl
Base) vinyl] -2,3- dihydro -3- benzofuranyl] -1,3- diacetic ester (10)
The synthetic route of compound 10:
4g compound 9 (8.810mmol) is added 22.5g aceticanhydride (220.564mmol) with the dissolution of 57.2ml dry pyridine,
It is stirred overnight at room temperature, TLC detects fully reacting.Reaction solution is slowly dropped into ice water under ice bath, and it is dilute to continuously add 3 times of volume of water
It releases, three times with ethyl acetate extraction, organic phase merges, successively to be saturated CuSO4After solution, saturated salt solution, water washing, decompression
Be evaporated to obtain crude product, the crude product is with petroleum ether: acetone=3:1 progress silica gel (200-300 mesh) column chromatography for separation obtains white solid
Body be compound 10 (5.6g, 8.434mmol), yield 95.7%, m.p.182-183 DEG C.
Compound 10:1H NMR(CD3COCD3, 500MHz) and δ: 7.53 (1H, br d, J=8.0Hz, H-6b), 7.43 (2H,
D, J=8.5Hz, H-2a, 6a), 7.32 (1H, br s, H-2b), 7.25 (1H, d, J=16.5Hz, H-7b), 7.19 (2H, d, J
=1.5Hz, H-10b, 14b), 7.15 (2H, d, J=8.5Hz, H-3a, 5a), 7.05 (1H, d, J=16.5H, H-8b), 6.97
(1H, d, J=8.0 Hz, H-5b), 6.94 (1H, t, J=1.5Hz, H-12b), 6.93 (2H, d, J=2.0Hz, H-10a,
14a), 6.73 (1H, t, J=2.0 Hz, H-12a), 5.67 (1H, d, J=8.0Hz, H-7a), 4.72 (1H, d, J=8.0Hz,
H-8a),2.252(6H,s,OCOCH3), 2.248(6H,s,OCOCH3),2.23(3H,s,OCOCH3)；13C NMR
(CD3COCD3,125MHz)δ:169.6 (OCOCH3),169.35(2×C,OCOCH3),169.30(2×C,OCOCH3),
160.7,152.60(2×C),152.56(2×C), 152.0,144.9,140.9,138.6,131.8,131.4,131.1,
129.4,127.9(2×C),125.5,124.3,122.9(2×C), 119.6(2×C),117.5(2×C),
115.8.115.2,110.6,92.9,57.4,20.9(5×C,OCOCH3)；ESI-MS m/z:687.1 [M-H]-,703.1[M+
Na]+.
Embodiment 11:
2- (4- methoxyphenyl) -3- (3,5- Dimethoxyphenyl) -5- [(1E) -2- (3,5- Dimethoxyphenyl) second
Alkenyl]-benzofuran (11)
The synthetic route of compound 11:
250mg compound 9 (0.551mmol) is dissolved in 6ml anhydrous propanone, and 761mg K is added portionwise2CO3
(5.507mmol) instills 1955mg CH after stirring 30min352h, TLC detection is stirred at room temperature in I (13.775mmol), reaction solution
End of reaction.Reaction solution filtering, filtrate are diluted with ethyl acetate, and saturated salt solution, water washing, organic phase evaporated under reduced pressure obtain pale yellow
231.9 mg of color solid.It takes gained compound 150mg to be dissolved in the dry dioxane of 8ml, 97.3mg DDQ is added
(0.429mmol) stops reaction after being heated to reflux 48h.Remove reaction solution under reduced pressure, gained medicinal extract using methylene chloride as eluant, eluent into
It is compound 11 (122.9mg, 0.235mmol), yield that row silica gel (200-300 mesh) column chromatography for separation, which obtains shallow white solid,
82.3%, m.p.104-106 DEG C.
Compound 11:1H NMR(CD3COCD3, 500MHz) and δ: 6.65 (1H, dd, J=9.0Hz, 1.5Hz, H-6b), 7.63
(2H, d, J=8.5Hz, H-2a, 6a), 7.62 (1H, br s, H-2b), 7.57 (1H, d, J=9.0Hz, H-5b), 7.38 (1H,
D, J=17.0Hz, H-7b), 7.15 (1H, d, J=17.0Hz, H-8b), 6.96 (2H, d, J=8.5H, H-3a, 5a), 6.79
(2H, d, J=2.5Hz, H-10b, 14b), 6.66 (2H, d, 2.5Hz, H-10a, 14a), 6.60 (1H, t, J=2.5Hz, H-
12b), 6.39 (1H, t, J=2.5Hz, H-12a)；13C NMR(CD3COCD3,125MHz)δ:162.5(2×C),162.1(2
×C),161.1,154.3, 152.2,140.6,135.5,133.9,131.6,130.1,129.2(2×C),128.5,
123.9,123.6,118.9,116.9,114.9(2×C), 111.9,108.4(2×C),105.2(2×C),100.6,
100.5,55.7(OCH3),55.65(2×OCH3),55.58(2×OCH3)； ESI-MS m/z:523.2[M+H]+,545.1[M
+Na]+.
Embodiment 12:
5- [2- (4- acetoxyl group phenyl) -5- [(1E) -2- (3,5- diacetoxy phenyl) vinyl] -3- benzo furan
Mutter base] -1,3- diacetic ester (12)
The synthetic route of compound 12:
200mg compound 10 (0.301mmol) is dissolved in the dry dioxane of 8ml, and 102.5mg DDQ (0.452 is added
Mmol), reaction solution stops reaction after being heated to reflux 48h, and evaporating solvent under reduced pressure carries out silica gel by eluant, eluent of methylene chloride
(200-300 mesh) column chromatography for separation obtain shallow white solid be compound 12 (161.4mg, 0.244mmol), yield 81.1%,
m.p.173-174℃。
Compound 12:UV λmax(MeOH,logε):237.2(3.90),300.6(4.27)nm 1H NMR(CD3COCD3,
500 MHz) δ: 7.74 (2H, d, J=9.0Hz, H-2a, 6a), 7.70 (1H, dd, J=9.0Hz, 1.5Hz, H-6b), 7.61
(1H, d, J=9.0Hz, H-5b), 7.41 (1H, d, J=16.5Hz, H-7b), 7.26 (2H, d, J=2.0Hz, H-10b,
14b), 7.24 (2H, d, J=2.0Hz, H-10a, 14a), 7.19 (2H, d, J=16.5Hz, H-8b), 7.18 (2H, d, J=
9.0Hz, H-3a, 5a), 7.08 (1H, t, J=2.0Hz, H-12b), 6.84 (1H, t, J=2.0Hz, H-12a), 2.27 (15H,
s,OCOCH3)；13C NMR(CD3COCD3, 125MHz)δ:169.43(OCOCH3),169.41(2×C,OCOCH3),169.38
(2×C,OCOCH3),154.7,152.9 (2×C),152.6(2×C),152.4,151.7,140.7,134.8,133.8,
131.4,131.0,128.8(2×C),128.1,127.2, 125.1,123.1(2×C),121.3(2×C),119.0,
117.7,116.8(2×C),116.3,115.5,112.3,20.92-20.95(5×C, OCOCH3)；ESI-MS m/z:
685.1[M+Na]+,701.1[M+K]+；HR-ESI-MS m/z:685.1684[M+Na]+ (calcd.for C38H3NaO11,
685.1680).
Embodiment 13:
2- (4- hydroxy phenyl) -3- (3,5- dihydroxy phenyl) -5- [(1E) -2- (3,5- dihydroxy phenyl) vinyl] -
Benzofuran (13)
The synthetic route of compound 13:
3ml methanol is added after dissolving with 3ml methylene chloride in 100mg compound 12 (0.151mmol), adds 1861mg
NH4OAc (24.169mmol), is stirred at room temperature 4d, and TLC detects end of reaction.Reaction solution is diluted with water, and ethyl acetate extraction has
Machine mutually merges, and crude product is obtained after evaporated under reduced pressure.Crude product is with chloroform: methanol=15:1 carries out silica gel (200-300 mesh) column chromatography
Separate yellow solid be compound 13 (57.1mg, 0.126mmol), yield 83.7%, m.p.97-99 DEG C.
Compound 13:UV λmax(MeOH,logε):300.0(4.55)nm；1H NMR(CD3COCD3,500MHz)δ:8.28
(5H, br s, H-OH), 7.63 (1H, brs, H-2b), 7.58 (1H, dd, J=8.5Hz, H-6b), 7.57 (2H, d, J=
9.0Hz, H-2a, 6a), 7.52 (1H, d, J=8.5Hz, H-5b), 7.22 (1H, d, J=16.0Hz, H-7b), 7.05 (1H, d,
J=16.0Hz, H-8b), 6.86 (2H, d, J=9.0Hz, H-3a, 5a), 6.60 (2H, d, J=2.0Hz, H-10b, 14b),
6.51 (2H, d, J=2.0 Hz, H-10b, 14b) .6.44 (1H, t, J=2.0Hz, H-12b), 6.29 (1H, t, J=2.0Hz,
H-12a)；13C NMR (CD3COCD3,125MHz)δ:160.06(2×C),159.96(2×C),158.9,154.3,152.3,
140.6,135.4,131.8, 131.6,129.51,129.46(2×C),128.7,123.9,122.8,118.5,116.5,
116.28(2×C),111.8,108.9(2×C), 105.9(2×C),103.0,102.9；ESI-MS m/z:453.2[M+H]+；
HR-ESI-MS m/z:453.1333[M+H]+(calcd. for C28H21O6,453.1333).
Embodiment 14:
5- [2- (3- methoxyl group -4- hydroxy phenyl) -3- (3,5- dihydroxy phenyl) -7- methoxyl group -2,3- dihydro -5- benzene
And furyl] vinyl -1,3- benzenediol (14)
The synthetic route of compound 14:
Be added in the mixture of 900mg isorhapontigenin powder (3.48mmol) and 9.0mg HRP 54ml acetone with
The mixed solvent of 18 ml water, instills 22.5ml 3%H in batches under stirring2O21h is stirred at room temperature in aqueous solution, and reaction solution is with acetic acid second
Ester extraction, with saturated salt solution, water washing after organic phase merging, anhydrous sodium sulfate is dry, and gained medicinal extract is concentrated under reduced pressure with chloroform:
Acetone=3:1 be eluant, eluent carry out silica gel column chromatography separation, obtain sterling grey powder be compound 14 (490mg,
0.953mmol), yield 54.6%, m.p.161-163 DEG C.
Compound 14:1H NMR(CD3COCD3,500MHz)δ:7.16(1H,br s,H-2b),7.04(1H,br s,H-
2a), 7.03 (1H, d, J=16.0Hz, H-8b), 6.92 (1H, d, J=16.0Hz, H-7b), 6.84 (1H, br d, J=
9.5Hz, H-6a), 6.82 (1H, br s, H-6b), 6.81 (1H, d, J=8.0Hz, H-5a), 6.52 (2H, d, J=1.5Hz,
H-10b, 14b), 6.27 (1H, t, J=1.5Hz, H-12b), 6.25 (1H, t, J=1.5Hz, H-12a), 6.19 (2H, d, J=
1.5Hz, H-10a, 14a), 5.44 (1H, d, J=8.5Hz, H-7a), 4.51 (1H, d, J=8.5Hz, H-8a), 3.96 (3H,
s,OCH3),3.92(3H,s,OCH3)； ESI-MS m/z:515.2[M+H]+,537.2[M+Na]+,553.2[M+K]+；0
(c=0.980, MeOH)
Embodiment 15:
2- (3,4- Dimethoxyphenyl) -3- (3,5- Dimethoxyphenyl) -5- [2- (3,4- Dimethoxyphenyl) ethylene
Base] -7- methoxyl group -2,3- Dihydro-benzofuran (15)
The synthetic route of compound 15:
340.2mg K is added portionwise with the dissolution of 2.6ml anhydrous propanone in 130mg compound 14 (0.246mmol)2CO3Solid
(2.462mmol) instills 873mg CH after stirring 30min3I (6.150mmol), is stirred at room temperature 48h.Reaction solution is with ethyl acetate
Dilution, successively with saturated salt solution, water washing, light yellow solid 15 (139mg, 0.238mmol) is concentrated under reduced pressure to obtain in organic phase,
Yield 96.7%, m.p.105-107 DEG C.
Compound 15:UV λmax(MeOH,logε):235.6(3.75),285(sh,3.35),334.2(3.79)nm；1H
NMR (CD3COCD3, 500MHz) and δ: 7.20 (1H, br s, H-2b), 7.18 (1H, d, 16.0Hz, H-8b), 7.05 (1H, d, J=
1.5 Hz, H-2a), 7.00 (1H, d, J=16.0Hz, H-7b), 6.90-6.92 (2H, m, H-5a, 6a), 6.81 (1H, br s,
), H-6b 6.71 (1H, d, J=2.0Hz, H-10b, 14b), 6.43 (3H, br s, H-12b, 10a, 14a), 6.35 (1H, t, H-
12a), 5.59 (1H, d, J=8.5Hz, H-7a), 4.62 (1H, d, J=8.5Hz, H-8a), 3.94 (3H, s, OCH3),3.80
(3H,s,OCH3),3.78(9H,s, OCH3),3.74(6H,s,OCH3).13C NMR(CD3COCD3,125MHz)δ:162.2(2
×C),162.0(2×C),150.54, 150.47,149.2,145.5,144.7,140.8,133.6,133.0,132.6,
130.0,127.2,119.8,116.6,112.5,111.5, 111.0,107.3(2×C),105.0(2×C),100.3,
99.5,94.1,58.4,56.4(OCH3),56.10(OCH3),56.06 (2×OCH3),55.6(2×OCH3),55.5(OCH3)；
ESI-MS m/z:607.1[M+Na]+,623.2[M+K]+； HR-ESI-MS m/z:607.2309[M+Na]+(calcd.for
C35H36NaO8,607.2302).
Embodiment 16:
5- [2- (4- acetoxy-3-methoxyl group) phenyl-5- [2- (3,5- diacetoxy phenyl) vinyl]-7- first
Oxygroup -2,3- dihydro -3- benzofuranyl] -1,3- diacetic ester (16)
The synthetic route of compound 16:
200mg compound 14 (0.389mmol) pyridinium dissolution dry with 5ml, instills 0.9ml dropwise under stirring
(9.7mmol) aceticanhydride, is stirred overnight at room temperature.After having reacted, 3ml water is slowly dropped under ice bath, after completion of the reaction to extra aceticanhydride
It is transferred in 50 ml separatory funnels, with the dilution of 15ml water, ethyl acetate extraction, organic phase merges, successively to be saturated CuSO4Water
Solution, saturated salt solution, water washing, evaporated under reduced pressure obtain shallow white solid 16 (250mg, 0.345mmol), yield 88.9%,
m.p. 111-112℃。
Compound 16:1H NMR(CD3COCD3, 500MHz) and δ: 7.26 (1H, br s, H-2b), 7.23 (1H, d, J=
16.0Hz, H-8b), 7.19 (2H, d, J=2.0Hz, H-10b, 14b), 7.15 (1H, d, J=2.0Hz, H-2a), 7.08 (1H,
D, J=16.0Hz, H-7b), 7.05 (1H, d, J=8.0Hz, H-5a), 6.96 (1H, dd, J=8.0Hz, 2.0Hz, H-6a),
6.95 (2H, d, J=2.0 Hz, H-10a, 14a), 6.94 (1H, t, J=2.0Hz, H-12b), 6.88 (1H, br s, H-6b),
6.80 (1H, t, J=2.0Hz, H-12a), 5.65 (1H, d, J=8.0Hz, H-7a), 4.76 (1h, d, J=8.0Hz, H-8a),
3.95(3H,s,OCH3),3.79(3H, s,OCH3),2.25(3H,s,OCOCH3),2.23(12H,s,OCOCH3)；13C NMR
(CD3COCD3,125MHz)δ: 169.3(4×C,OCOCH3),168.9(OCOCH3),152.6(4×C),152.4,149.4,
145.7,144.8,140.9(2×C), 139.8,132.6,132.2,131.4,125.7,123.8,119.7(2×C),
118.9,117.5(2×C),,116.9,115.8,115.1, 112.1,111.2,93.5,57.8,56.5(OCH3),56.2
(OCH3),20.9(4×C,OCOCH3),20.6(OCOCH3)； ESI-MS m/z:747.3[M+Na]+,763.2[M+K]+.
Embodiment 17:
2- (3,4- Dimethoxyphenyl) -3- (3,5- Dimethoxyphenyl) -7- methoxyl group -5- [2- (3,5- dimethoxy
Phenyl) vinyl] benzofuran (17)
The synthetic route of compound 17:
80mg compound 15 (0.137mmol) the dioxane dissolution dry with 6ml, is added 46.6mg DDQ (0.206
Mmol), stop reaction after being heated to reflux 8h, evaporating solvent under reduced pressure carries out silica gel (200-300 mesh) by eluant, eluent of methylene chloride
Column chromatography for separation obtains crude product, and crude product obtains white, needle-shaped crystals (50mg, 0.086mmol), yield with acetone recrystallization
62%, m.p.144-146 DEG C.
Compound 17:UV λmax(MeOH,logε):222.4(4.38),278.8(3.69),312.4(3.84)nm；1H
NMR (CD3COCD3, 500MHz) and δ: 7.35 (1H, d, J=16.5Hz, H-7b), 7.30 (1H, dd, J=9.0Hz, 1.5Hz, H-
6a), 7.29 (1H, br s, H-2b), 7.20 (1H, d, J=1.5Hz, H-2a), 7.19 (1H, br s, H-6b), 7.17 (1H,
D, J=16.5Hz, H-8b), 6.98 (1H, d, J=9.0Hz, H-5a), 6.78 (2H, d, J=2.0Hz, H-10b, 14b),
6.67 (2H, d, J=2.5Hz, H-10a, 14a), 6.60 (1H, t, J=2.0Hz, H-12b), 6.38 (1H, t, J=2.5Hz,
H-12a),4.11(3H,s,OCH3), 3.83(3H,s,OCH3),3.81(6H,s,OCH3),3.80(6H,s,OCH3),3.65
(3H,s,OCH3)；162.5(2×C), 162.1(2×C),152.0,151.0,150.0,146.4,143.6,140.6,
135.1,134.9,133.0,130.5,128.5,123.7, 120.6,117.5,112.5,111.9,111.3,108.6(2×
C),105.8,105.2(2×C),100.6(2×C),56.5(OCH3),56.0 (OCH3),55.8(3×OCH3),55.6(2×
OCH3)；ESI-MS m/z:605.3[M+Na]+,520.9[M+K]+；HR-ESI-MS m/z:605.2163[M+Na]+
(calcd.for C35H34NaO8,605.2146).
Embodiment 18:
5- [2- (3- methoxyl group -4- acetoxyl group) phenyl -5- [2- (3,5- diacetoxy phenyl) vinyl] -7- first
Oxygroup -3- benzofuranyl] -1,3- diacetic ester (18)
The synthetic route of compound 18:
100mg compound 15 (0.138mmol) the dioxane dissolution dry with 5ml, is added 47.6mg DDQ (0.207
Mmol), stop reaction after being heated to reflux 32h, evaporating solvent under reduced pressure carries out silica gel (200-300 by eluant, eluent of methylene chloride
Mesh) column chromatography for separation obtains shallow white solid 18 (83.3mg, 0.115mmol), yield 83.5%, and m.p.223-224 DEG C.
Compound 18:1H NMR(CD3COCD3, 500MHz) and δ: 7.38 (1H, d, J=17.0Hz, H-7a), 7.37 (1H,
Dd, J=8.5Hz, 1.5Hz, H-6a), 7.35 (1H, br s, H-2b), 7.25 (1H, d, J=17.0Hz, H-8a), 7.25
(3H, d, J=1.5Hz, H-2a, 10b, 14b), 7.22 (2H, d, J=2.0Hz, H-10a, 14a), 7.19 (1H, br s, H-
6b), 7.12 (1H, d, J=8.5Hz, H-5a), 7.08 (1H, t, J=2.0Hz, H-12a), 6.83 (1H, t, J=2.0Hz, H-
12b),4.11(3H,s,OCH3), 3.65(3H,s,OCH3),2.272(6H,s,OCOCH3),2.266(6H,s,OCOCH3),
2.24(3H,s,OCOCH3)；13C NMR(CD3COCD3,125MHz)δ:169.5(2×C,OCOCH3),169.4(2×C,
OCOCH3),168.8(OCOCH3), 153.0(2×C),152.6(2×C),152.3,151.6,146.5,144.0,141.4,
140.7,135.2,134.8,132.5,131.7, 129.2,127.2,124.2,121.5(2×C),119.8,117.7(2×
C),117.3,116.6,115.4,111.8,111.6,106.8,56.6 (OCH3),56.0(OCH3),20.9(4×C,
OCOCH3),20.5(OCOCH3)；ESI-MS m/z:745.2[M+Na]+,761.2 [M+K]+.
Embodiment 19:
5- [2- (3- methoxyl group -4- hydroxy phenyl) -3- (3,5- dihydroxy phenyl) -7- methoxyl group -2,3- dihydro -5- benzene
And furyl] vinyl -1,3- benzenediol (19)
The synthetic route of compound 19:
46mg compound 18 (0.064mmol) is added 1.5ml methanol dilution, is added with the dissolution of 1.5ml methylene chloride
786 mg NH4OAc (6.116mmol), is stirred at room temperature 52h, stops upper reaction.The water of 4 times of amounts, acetic acid second are added into reaction solution
Ester extraction, organic phase washing, is concentrated under reduced pressure.Product is chromatographed through silica gel (200-300 mesh) column, with chloroform: methanol=20:1 elution
It obtains pistac solid 19 (24mg, 0.047mmol), yield 74.1%, m.p.164-166 DEG C.
Compound 19:1H NMR(CD3COCD3,500MHz)δ:7.25-7.26(2H,m,H-2a,6a),7.24(1H,br
S, H-2b), 7.21 (1H, br s, H-6b), 7.19 (1H, d, J=16.5Hz, H-7b), 7.06 (1H, d, J=16.5Hz, H-
8b), 6.86 (1H, d, J=8.5Hz, H-5a), 6.59 (2H, d, J=1.5Hz, H-10b, 14b), 6.52 (1H, d, J=
1.5Hz,H-10a,14a), 6.43(1H,br s,H-12a),6.28(1H,br s,H-12b),4.10(3H,s,3b-OCH3),
3.71(3H,s,3a-OCH3)；13C NMR(CD3COCD3,125MHz)δ:162.4(2×C),159.5(2×C),152.1,
148.2,148.1,146.3,143.6,140.6, 135.5,134.8,132.9,129.8,128.8,122.9,121.2,
117.1,116.0,111.6,111.3,108.9(2×C),106.0,105.8 (2×C),102.9,102.8,56.5
(OCH3),56.0(OCH3)；ESI-MS m/z:513.2[M+H]+,535.2[M+Na]+,551.1 [M+K]+,511.6[M-H]-.
Pharmacological evaluation
The sub- NO of the Primary mouse peritoneal macrophage inflammation that experimental example 1:Amurensin H derivative induces LPS is generated
Inhibiting effect
Macrophage executes body non-specific immune function, can produce the inflammatories such as NO under bacteria lipopolysaccharide LPS induction
The factor participates in simultaneously inducing inflammatory reaction, has higher level during inflammation immunologic process initial stage and pathological development.
It, can be in the anti-inflammatory work of external preliminary observation compound by detecting the NO production quantity of the Turnover of Mouse Peritoneal Macrophages of originally culture
Property.
Experimental method:
It takes Primary mouse peritoneal macrophage to be inoculated in 96 orifice plates, various concentration compound is added and protects 1h in advance；Then,
LPS, which is added, makes its final concentration of 1 μ g/ml, in 37 DEG C, 5%CO2After cultivating for 24 hours in incubator, supernatant is collected, using Griess
Method measures the content of NO, calculatesMeanwhile
Cell proliferation inhibition rate is measured with mtt assay；And it measures NO and generates the IC inhibited50(being calculated with Probit weighted regression analysis method).
Experimental result:
The results are shown in Table 1, compared with Amurensin H, Amurensin H derivative after structure of modification,
Outside keeping body while anti-inflammatory activity, cytotoxicity is significantly reduced.
The influence that table 1.Amurensin H derivative generates LPS induction Primary mouse peritoneal macrophage NO
* concentration: 10-5；Orientation treatment: anti-inflammatory.
Influence of the experimental example 2:Amurensin H derivative to croton oil inducing mouse otitis
Experimental method:
The male mice in kunming of 18-20g is taken, random to be grouped, groups of animals applies croton oil respectively at left ear two sides
0.02ml；After 30 minutes, 100mg/kg weight test-compound is given in groups of animals subcutaneous injection, and model control group is given
Volume solvent；After 4h is administered, takes off neck and put to death mouse, cut ears along auricle base line, diameter 6mm punch removes left and right ear respectively
The auricle of same position, assay balance weighing, calculates ear swelling (ear swelling=left auricle weight-auris dextra sheet weight) and ear
[ear swelling inhibiting rate (%)=(model group be averaged ear swelling-administration group ear swelling)/model group is average for swelling inhibiting rate
Ear swelling group × 100%].
Experimental result:
Experimental result is as shown in table 2, and Amurensin H and its derivative 12,13,8 all have the significant croton oil that mitigates and lure
The ear thickness of mouse otitis is led, and 12,13,8 interior anti-inflammatory activity of derivative is better than Amurensin H.
Influence (Mean ± Std, n=10) of the table 2.Amurensin H derivative to croton oil inducing mouse otitis
Note: compared with model group, "*" indicate p < 0.05, "**" indicate p < 0.01.
Inhibiting effect of the experimental example 3:Amurensin H derivative to LPS+ cigarette inducing mouse COPD airway inflammation
Experimental method: SPF grades of male BALB/c mouses, 18-20g are randomly divided into Normal group, model control group, sun
Property control group (dexamethasone, 1 μm of ol/kg, gastric infusion), 10 drug-treated groups (100 μm of ol/kg, gastric infusion), 12 drugs
Processing group (100 μm of ol/kg, gastric infusion), 13 drug-treated groups (100 μm of ol/kg, gastric infusion), 8 drug-treated groups (100
μm ol/kg, gastric infusion), every group 15.In addition to blank control group, groups of animals tracheae after experiment anesthesia in the 1st day drips
Enter the normal saline solution that 50 μ l/ contain only 40 μ g LPS, the 10th day tracheae instills the physiology salt that 30 μ l/ contain only 30 μ g LPS
Aqueous solution；And in experiment the 2-9 days and the 11-21 days, mouse is placed in toy flue gas sucking microenvironment preparation system (cigarette
Smog: 160-200ppm, 22-28 DEG C of temperature, oxygen >=18.0%) in carry out fumigation, 1h/ times, 1 time a day；Meanwhile administration group
1 hour gastric infusion before daily sootiness, blank control group and model control group give isometric solvent.Mouse is given in last
After medicine 24 hours, some animals lung tissue is taken, carries out histopathology.The physiology that remaining each group mouse is pre-chilled with 0.7mL
Salt water perfusion rinses 3 times, is sucked out BAL fluid (BALF), and centrifugation, supernatant is for analyzing TNF-α, IL-6 and IL-1
The content of β；Cell is resuspended in PBS buffer solution, carries out Arneth's count.
Experimental result:
(1) influence of the Amurensin H derivative to COPD mouse lung tissue inflammatory and venereal injury
As shown in 3.1 inflammatory pathologies appraisal result of Fig. 1 pathological picture and table, model group alveolar wall broadens, alveolar wall epithelium
Cellular swelling is rounded, partial exfoliation, the visible macrophage of alveolar space, bronchium and peribronchiolar stove inflammatory cell
Infiltration, the expansion of lung tissue edge alveolar space.Amurensin H derivative 10,13,8 can significantly improve COPD mouse lung tissue
Inflammatory pathologies change.As it can be seen that the gastric infusion at 100 μm of ol/kg of dosage of Amurensin H derivative 10,13,8, small to COPD
Mouse lung tissue inflammatory pathologies, which change, has significant therapeutic effect.
Influence (Mean ± Std, the n that 3.1 Amurensin H derivative of table evaluates COPD mouse lung tissue Inflammation
=4)
Remarks: compared with blank control group, #p < 0.05, ##p < 0.01；Compared with model control group,*P < 0.05,**p
< 0.01
(2) Amurensin H derivative makees the inhibition of inflammatory cell recruitment in COPD mouse bronchoalveolar lavage fluid (BALF)
With
1. influence of the Amurensin H derivative to total white blood cells in COPD mouse BALF
For COPD characterized by throughout air flue, pulmonary parenchyma and pulmonary vascular chronic inflammation, it is thin that this inflammation shows as neutral grain
Born of the same parents, T lymphocyte and macrophage increase in intrapulmonary.The inflammatory cell of activation discharges a series of inflammatory mediators and destroys lung structure
Or maintain the medium of neutrophil leucocyte inflammation.This experiment purpose is to investigate 10,12,13,8 pairs of Amurensin H derivative
The influence that total white blood cells are raised in COPD mouse BALF, the results are shown in Table 3.2.
As a result: the gastric infusion at 100 μm of ol/kg of dosage of Amurensin H derivative 10,12,13,8 can reduce COPD
Total inflammatory cell recruitment in mouse BALF, wherein 12,13,8 administration groups, compared with model group, difference has conspicuousness (p <
0.01)。
Influence (Mean ± Std, n=of the 3.2 Amurensin H derivative of table to total white blood cells in COPD mouse BALF
10)
Remarks: compared with blank control group, #p < 0.05, ##p < 0.01；Compared with model control group,*P < 0.05,**p
< 0.01
2. influence of the Amurensin H derivative to neutrophil leucocyte differential counting in COPD mouse BALF
Neutrophil leucocyte plays a significant role in COPD morbidity, it can discharge serine protease and animal is induced to produce
The pathological change of stranger's class pulmonary emphysema sample.Neutrophil leucocyte life is of short duration, it, which is recycled, recruits to air flue and crossing gap chamber
Process is very rapid.Pathological study proves neutrophil numbers increase and airflow obstruction in some COPD patient bronchial tissues
The degree of obtaining is related.Neutrophil numbers increase in the COPD patient air flue of smoking, and especially those are with chronic bronchitis
Patient.It is thin that this experiment purpose is to investigate neutral grain in 10,12,13,8 couples of COPD mouse BALF of Amurensin H derivative
The influence that born of the same parents raise, the results are shown in Table 3.3.
As a result: the gastric infusion at 100 μm of ol/kg of dosage of Amurensin H derivative 10,12,13,8 can reduce COPD
Neutrophil recruitment in mouse BALF, wherein 12,13,8 administration groups, compared with model group, difference has conspicuousness (p <
0.01).3.3 Amurensin H derivative of table to neutrophil leucocyte differential counting in COPD mouse BALF influence (Mean ±
Std, n=10)
Remarks: compared with blank control group, #p < 0.05, ##p < 0.01；Compared with model control group,*P < 0.05,**p
< 0.01
3. influence of the Amurensin H derivative to macrophage differential counting in COPD mouse BALF
Smoker and COPD patient intrapulmonary macrophage increase compared with normal population level, are gathered in alveolar, bronchiole more
And small airway.The small airway disease degree of alveolar wall macrophage numbers and light moderate pulmonary emphysema and COPD patient is in positive
It closes.Lesion tissue and the visible COPD of damage location are slowly in progress and chronic disease increase for a long time with macrophage it is parallel.Macrophage
Cell may cause elastic fibrous tissue degradation capability to increase extremely by release matrix metalloproteinases, induce the generation of pulmonary emphysema.
This experiment purpose is to investigate the shadow of macrophage recruitment in 10,12,13,8 couples of COPD mouse BALF of Amurensin H derivative
It rings, the results are shown in Table 3.4.
As a result: the gastric infusion at 100 μm of ol/kg of dosage of Amurensin H derivative 10,12,13,8 can reduce COPD
Macrophage recruitment in mouse BALF, wherein 12,13,8 administration groups, compared with model group, difference has conspicuousness (p < 0.01
Or 0.05).3.4 Amurensin H derivative of table to macrophage differential counting in COPD mouse BALF influence (Mean ±
Std, n=10)
Remarks: compared with blank control group, #p < 0.05, ##p < 0.01；Compared with model control group,*P < 0.05,**p
< 0.01
(3) Amurensin H derivative makees the inhibition that inflammatory factor in COPD mouse bronchoalveolar lavage fluid (BALF) generates
With
1. the influence that Amurensin H derivative generates TNF-α in COPD mouse BALF
Pro-inflammatory cytokines TNF-α is the startup factor in the pathogenic process of COPD.The TNF-α of COPD patient is horizontal high
In normal person, the bronchial epithelial cell of culture is contacted with the smog of cigarette can TNF secretion-α.TNF-α can promote neutral grain thin
Mucomembranous cell hyperplasia and hypersecretion are played in born of the same parents' degranulation, induction, increase epithelial cell IL-8 and generate, and increase macrophage matrix gold
Proteases generate, and promote airway hyperreactivity.This experiment purpose is to investigate 10,12,13,8 pairs of Amurensin H derivative
The influence that TNF-α generates in COPD mouse BALF, the results are shown in Table 3.5.
As a result: the gastric infusion at 100 μm of ol/kg of dosage of Amurensin H derivative 10,12,13,8 can reduce COPD
The generation of TNF-α is horizontal in mouse BALF, wherein 12,13,8 administration groups, compared with model group, difference has conspicuousness (p <
0.01)。
Influence (Mean ± Std, the n=that 3.5 Amurensin H derivative of table generates TNF-α in COPD mouse BALF
10)
Remarks: compared with blank control group, #p < 0.05, ##p < 0.01；Compared with model control group,*P < 0.05,**p
< 0.01
2. the influence that Amurensin H derivative generates IL-6 in COPD mouse BALF
IL-6 is the important cytokine for participating in COPD airway inflammation, the IL-6 of high concentration can vascular endothelial cell injury,
Promote immune adherence, microvascular corrosion cast, and can inhibit endothelium reparation, make vascular injury and high penetration state delay, lung is caused to damage
Wound.Pulmonary alveolar macrophage can be activated after the particulate matter in phagocytosis smoke from cigarette, generate IL-6, amplify inflammatory reaction.Together
When smoking promote bronchial epithelial cell etc. express and release IL-6 increase, airway inflammation is further aggravated.This experiment purpose exists
In investigating the influence that IL-6 is generated in 10,12,13,8 couples of COPD mouse BALF of Amurensin H derivative, it the results are shown in Table 3.6.
As a result: the gastric infusion at 100 μm of ol/kg of dosage of Amurensin H derivative 10,12,13,8 can reduce COPD
The generation of IL-6 is horizontal in mouse BALF, wherein 12,13,8 administration groups, compared with model group, difference has conspicuousness (p <
0.05 or 0.01).
The influence (Mean ± Std, n=10) that 36 Amurensin H derivative of table generates IL-6 in COPD mouse BALF
Remarks: compared with blank control group, #p < 0.05, ##p < 0.01；Compared with model control group,*P < 0.05,**p
< 0.01
3. the influence that Amurensin H derivative generates IL-1 β in COPD mouse BALF
The inflammatory cells such as IL-1 β energy activating macrophage discharge inflammatory mediator, can cause in intrapulmonary thin with macrophage, grain
Born of the same parents infiltrate the lung inflammation being characterized.IL-1 β also can induce macrophage and generate Matrix Metalloproteinase-9, in pulmonary parenchyma of degrading
Extracellular matrix components cause the rupture of alveolar septa elastomer to lead to Airway Remodeling and airway fibrosis.This experiment purpose exists
In investigating the influence that IL-1 β is generated in 10,12,13,8 couples of COPD mouse BALF of Amurensin H derivative, the results are shown in Table
3.7。
As a result: the gastric infusion at 100 μm of ol/kg of dosage of Amurensin H derivative 10,12,13,8 can reduce COPD
The generation of IL-1 β is horizontal in mouse BALF, wherein 12,13 administration groups, compared with model group, difference has conspicuousness (p < 0.05
Or 0.01).
Influence (Mean ± Std, the n=that 3.7 Amurensin H derivative of table generates IL-1 β in COPD mouse BALF
10)
Remarks: compared with blank control group, #p < 0.05, ##p < 0.01；Compared with model control group,*P < 0.05,**p
< 0.01
To sum up result of study is shown, it is scorching that Amurensin H derivative 10,12,13,8 can improve COPD mouse lung tissue
Disease pathological change inhibits total white blood cells, neutrophil leucocyte and macrophage differential counting in BALF, reduces inflammation in BALF
The generation of factor TNF-α, IL-6, IL-1 β etc. are horizontal, wherein more significant with 12,13,8 curative effects.Moreover, Amurensin H
Derivative 10,12,13,8 is it is not yet found that any toxic side effect, it is seen that it has very wide application in the treatment of COPD
And development prospect.
Claims (15)
1. one kind Amurensin H derivative and its pharmaceutically acceptable salt are in preparation treatment and/or prevention chronic obstructive
Application in lung disease product, it is characterised in that: such as logical formula (I) of the derivative and (II) are shown:
Wherein, R1Selected from H,R2、R10Selected from H,
R9Selected from H,
R6、R7、R8、R14、R15、R16、R17、R18、R19、R20It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6's
Alkoxy acyl, Glu, SO3H、PO3H2；
R3、R4、R5、R11、R12、R13It is each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, phenyl, methylamino, two
Methylamino, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkoxy acyl, C2-6Unsaturated alkyl,
C3-6Naphthenic base, C1-6Alkylthio group, F, Cl, Br, I, Glu, SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
2. the application of Amurensin H derivative according to claim 1 and its pharmaceutically acceptable salt, which is characterized in that
Shown in the derivative such as general formula (IA):
Wherein, R4、R5Be each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, phenyl, methylamino, dimethylamino,
C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkoxy acyl, C2-6Unsaturated alkyl, C3-6Cycloalkanes
Base, C1-6Alkylthio group, F, Cl, Br, I, Glu, SO3H、PO3H2；
R6、R7、R8、R17、R18It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alkoxy acyl, Glu, SO3H、
PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
3. the application of Amurensin H derivative according to claim 2 and its pharmaceutically acceptable salt, which is characterized in that
Shown in the derivative such as general formula (IAa):
Wherein, R6、R7、R8、R17、R18It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alkoxy acyl, Glu,
SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
4. the application of Amurensin H derivative according to claim 2 and its pharmaceutically acceptable salt, which is characterized in that
Shown in the derivative such as general formula (IAb):
Wherein, R6、R7、R8、R17、R18It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alkoxy acyl, Glu,
SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
5. the application of Amurensin H derivative according to claim 1 and its pharmaceutically acceptable salt, which is characterized in that
Shown in the derivative such as general formula (IB):
Wherein, R6、R7、R8、R19、R21It is each independently selected from C1-6Alkyl, C1-6Acyl group, C1-6Alkoxy acyl, Glu,
SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
6. the application of Amurensin H derivative according to claim 1 and its pharmaceutically acceptable salt, which is characterized in that
Shown in the derivative such as general formula (IIA):
Wherein, R12、R13Be each independently selected from hydrogen, hydroxyl, nitro, cyano, amino, carboxyl, phenyl, methylamino, dimethylamino,
C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy, C1-6Alkoxy acyl, C2-6Unsaturated alkyl, C3-6Cycloalkanes
Base, C1-6Alkylthio group, F, Cl, Br, I, Glu, SO3H、PO3H2；
R14、R15、R16、R17、R18It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alkoxy acyl, Glu,
SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
7. the application of Amurensin H derivative according to claim 6 and its pharmaceutically acceptable salt, which is characterized in that
Shown in the derivative such as general formula (IIAa):
R14、R15、R16、R17、R18It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alkoxy acyl, Glu,
SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
8. the application of Amurensin H derivative according to claim 6 and its pharmaceutically acceptable salt, which is characterized in that
Shown in the derivative such as general formula (IIAb):
R14、R15、R16、R17、R18It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alkoxy acyl, Glu,
SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
9. the application of Amurensin H derivative according to claim 1 and its pharmaceutically acceptable salt, which is characterized in that
Shown in the derivative such as general formula (IIB):
Wherein, R14、R15、R16、R19、R22It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alkoxy acyl,
Glu、SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
10. the application of Amurensin H derivative according to claim 1 and its pharmaceutically acceptable salt, which is characterized in that
Shown in the derivative such as general formula (IIC):
Wherein, R14、R15、R16、R20、R22It is each independently selected from hydrogen, C1-6Alkyl, C1-6Acyl group, C1-6Alkoxy acyl,
Glu、SO3H、PO3H2；
Glu indicates β-D glucopyranosyl；SO3H indicates sulfonyl；PO3H2Indicate phosphoryl.
11. the application of Amurensin H derivative as claimed in one of claims 1-10 and its pharmaceutically acceptable salt,
It is characterized in that, the derivative is selected from following group:
12. application of a kind of pharmaceutical composition in preparation treatment and/or prevention Chronic Obstructive Pulmonary Disease product, by effective agent
The described in any item derivatives of claim 1-11 and its pharmaceutically acceptable salt and pharmaceutically acceptable carrier of amount or
Auxiliary material composition.
13. application according to claim 12, which is characterized in that the pharmaceutical composition is selected from tablet, capsule, pill, note
Penetrate agent.
14. application according to claim 12, which is characterized in that described pharmaceutical composition be selected from sustained release preparation, controlled release preparation and
Various particulate delivery systems.
15. application according to claim 12, which is characterized in that the product is selected from drug, health care product.
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