CN106279089A - Formoononetin aliphatic ether analog derivative, its preparation method and medical usage - Google Patents
Formoononetin aliphatic ether analog derivative, its preparation method and medical usage Download PDFInfo
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- C07D311/34—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 3 only
- C07D311/36—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 3 only not hydrogenated in the hetero ring, e.g. isoflavones
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Abstract
The present invention relates to medicinal chemistry art, relate to formoononetin aliphatic ether analog derivative, its preparation method and medical usage, being specifically related to a class formula is the formoononetin aliphatic ether analog derivative of (I), their preparation method, the pharmaceutical composition containing these compounds and their medical usage, especially as prevention or the purposes of the medicine for the treatment of hyperlipemia, obesity or type ii diabetes.
Description
Technical field:
The present invention relates to medicinal chemistry art, be specifically related to formoononetin aliphatic ether analog derivative.The invention also discloses they preparation method and
Pharmacologically active, Pharmaceutical composition containing these compounds and their medical usage especially as prevention or treatment hyperlipemia, obesity,
The purposes of type ii diabetes medicine.
Background technology:
Dyslipidemia refers to plasma cholesterol, the rising of triglyceride levels that Human Lipid Metabolism obstacle causes.China determines hyperlipemia clinically
Index is as follows: cholesterol ＞ 5.2mmol/L (200mg/dl), and triglyceride ＞ 1.6mmol/L (140mg/dl) can behave as cell lactone on pathology
Fat is piled up and is formed fat vacuole, can developing deeply be " foam cell ", and developing deeply is fat stricture of vagina, fibrous plaque, atheromatous plaque.Therefore generally believe blood fat
Extremely it is the Major Risk Factors causing human atherosclerosis's property disease, the Atherosclerosis of the organ such as the heart, brain can be accelerated, cause brain
The generation of the cardiovascular and cerebrovascular diseases such as apoplexy, coronary heart disease, myocardial infarction, sudden death, is also the important risk factor of fatty liver generation.
Obesity refers to that too much and (or) local content increases and abnormal distribution body fat total content, is that one is drawn jointly by factors such as h and Es
Rise, and health is caused the chronic metabolic disease of certain impact.The fat global epidemic diseases become including China, gives society's band
Carry out huge financial burden.More seriously, there are chronic inflammatory disease, type ii diabetes, fatty liver, cardiovascular disease, tumor etc. in obese patient
The risk of disease significantly increases.The fat basic reason occurred is that lipostasis is unbalance, thus causes the excess accumulation of fat in adipose cell.From
The angle of cytobiology, obesity is owing to the increase of adipocyte number and the big dual function that becomes of adipose cell volume cause.Adipose cell
Increasing of quantity is to be realized by the propagation of PECTORAL LIMB SKELETON cell and differentiation, and nuclear receptor transcription factor PPAR γ is regulation Adipocyte Differentiation
Important regulatory factor.
Formoononetin (Formononetin) is a kind of phytoestrogen compounds, be present in Herba Trifolii Pratentis, alfalfa, the Radix Astragali, Radix Glycyrrhizae and
The root of Radix vernoniae asperae is the highest with content in Herba Trifolii Pratentis.Research shows that formoononetin has multiple biological activity, makees including significant estrogen-like
With and antioxidant activity；Good blood fat reducing and Hepatocyte protection；By promote Early gowth response factor-1 expression and regulation ERK1/2 and
MAPK path promotes endothelium reparation and wound healing；Promote the healing isoreactivity of fracture.There are some researches show, formoononetin can raise hamster body
The expression of interior SR-B1 albumen, it substantially reduces the T-CHOL (TC) of experimental hyperlipidemia hamster, triglyceride (TG), low-density lipoprotein
White cholesterol (LDL-C), and raise and high density lipoprotein increasing cholesterol (HDL-C).And can prevent and delay atherosclerotic
Formation and development.
Fatty acid (fatty acid), refers to the hydrocarbon chain compound of aliphatic of the length containing a carboxyl in one end, is neutral fat, phospholipid and glycolipid
Main component.Fatty acid, in the case of having sufficient oxygen supply, oxidable is decomposed into CO2And H2O, discharges big energy, and therefore fatty acid is machine
One of body main energy sources.Fatty acid radical can be classified as again short-chain fatty acid according to the difference of carbon chain fatty acid metabolism length, and (carbon in its carbochain is former
Subnumber is less than 6), medium-chain fatty acid (carbon number is 6-12) and long-chain fatty acid (carbon number is more than 12).According to degree of saturation, fatty acid
Satisfied fatty acid, monounsaturated fatty acid (containing a double bond) and polyunsaturated fatty acid (containing multiple double bonds) can be divided into.Research shows, part
Medium-chain fatty acid and long-chain unsaturated fatty acid can improve organism metabolic disorder or symptom, have important regulation effect to lipid metabolism, have anti-
Control dyslipidemia and the effect of cardiovascular disease generation.
Finding in zoopery, formoononetin oleate (OF) can significantly reduce obese rat body weight and the fat content of diet induced.Send out simultaneously
Existing, OF can reduce TC and the content of free fatty (FFA) in blood plasma, also has certain reduction effect to TG, LDL-C, and it can
Significantly raised blood plasma middle-high density lipoprotein cholesterol (HDL-C) content, illustrates that it has useful Adjust-blood lipid activity (WO2011/106924).But
Being that pharmacokinetics experiment shows that the OF half-life in vivo is comparatively short, metabolism is than very fast.Reason is owing to the ester bond in OF structure is unstable
Fixed, cause it to be easily hydrolyzed metabolism.In the formoononetin aliphatic ether analog derivative that the present invention comprises, institute's ether-containing key is more stable than ester bond, has more excellent
Good metabolic stability and pharmacokinetic property.7 connected alkoxyls of the formoononetin derivant that the present invention is comprised are by C8-C30Saturated or
Slough proton after undersaturated fatty acid reduction to be formed.Owing to middle long-chain fatty acid has certain Adjust-blood lipid effect, so the compound in the present invention
It is connected with simple C than 71-C4The isoflavone analog of class alkoxyl is compared has more excellent pharmacodynamic properties.
Summary of the invention:
The invention discloses a class formoononetin aliphatic ether analog derivative of formula I, through Preliminary Animal Experiment research display, the compounds of this invention has
Adjust-blood lipid, slimming effect, also have certain removing free radical, anti-oxidative damage, reduction insulin resistance, regulation blood glucose are put down simultaneously
The effect of weighing apparatus, in vitro in experiment, the compounds of this invention can substantially suppress differentiation and the propagation of PECTORAL LIMB SKELETON.So, the compounds of this invention has
There are potential Adjust-blood lipid and anti-obesity activity.
Wherein R1O represents C8-C30Fat alkoxyl, described alkoxyl is by C8-C30Proton shape is sloughed after saturated or undersaturated fatty acid reduction
Become.
R2Represent H, OH, OR ', SR ', NHR ', N (CH3)2、NO2, halogen, CF3Or C (O) R ', wherein R ' represents C1-C4Alkyl.
Wherein R1O preferably represents oleic acid, linoleic acid, undecylenic acid, linolenic acid, conjugated linoleic acid, stearic acid, palmitoleic acid, Eicosatetraenoic
Proton is sloughed after the fatty acid reduction such as acid, eicosapentaenoic acid, 20 carbonic acid, docosahexenoic acid, lauric acid, certain herbaceous plants with big flowers acid, octanoic acid, E-10-hydroxy-2-decylenic acid
The fatty alkoxyl formed.
R1O more preferably represents oil ether, sub-oil ether, Petiolus Trachycarpi oil ether, tallow ether or hendecene ether.
Wherein R2Preferably represent H, OH, OCH3、OCH2CH3、SCH3、NHCH3、N(CH3)2、NO2, halogen, CF3Or C (O) CH3。
R2More preferably represent H, OCH3、OCH2CH3、Br、NO2。
The structure of the part of compounds of the present invention is as follows:
| Compound number | R1 | R2 |
| I-1 | (9Z)-CH3-(CH2)7-CH=CH-(CH2)8 | H |
| I-2 | (9Z)-CH3-(CH2)7-CH=CH-(CH2)8 | Br |
| I-3 | CH2=CH-(CH2)9 | H |
In pharmacological evaluation and embodiment, the code name of compound is equal to the compound structure corresponding to code name herein below.
The compound of formula of the present invention can be prepared by following methods:
Ra=(9Z)-CH3-(CH2)7-CH=CH-(CH2)7
Rb=CH2=CH-(CH2)8
(a)Br2, AcOH, rt, 2h；(b)BF3-Et2O, 75 DEG C, 90min；(c) DMF, PCl5, rt, 1h；(d)LiAlH4, THF, rt, 12h；(e)SOCl2,
Toluene, DMF, 75 DEG C, 5h；(f) DMF, K2CO3, KI, 75 DEG C, 12h.
The pharmacologically active of the part of compounds that the present invention is presented herein below detects:
1 compound is to 3T3-L1 cell growth inhibition assay
1.1 experiment material
DMEM (Dulbecco ' s Modified Eagle ' s Medium) culture medium, penicillin, calf serum (FBS) are purchased from Gibco BRL of
Invitrogen Corporation (Carlsbad, CA)；Trypsin, 3-isobutyl-1-methylxanthine (IBMX), tetramethyl azo azoles salt (MTT)
And other reagent are domestic analytical pure.
1.2 experimental technique
1.2.1 cell is cultivated
3T3-L1 cell respectively with DMEM culture medium (containing 10% calf serum, the penicillin of 100U/mL and the streptomycin of 100 μ g/mL) in
5%CO2, 37 DEG C of incubators are cultivated.Pass on when cell length to degree of converging is about 80%.During passage cell, outwell old culture medium, PBS (phosphorus
Phthalate buffer) wash twice.Add a small amount of 0.25% trypsin, at the bottom of paving bottle, digest at 37 DEG C and observe under about 1-2min, inverted microscope
Cell rounding, outwells pancreatin, adds fresh culture, piping and druming mixing, implants in new culture bottle, continues to cultivate.Cell counting, takes a small amount of thin
Born of the same parents' suspension and the mixing of 0.4% trypan blue solution equal-volume, with suction pipe piping and druming mixing, take a little mixed liquor and instill the space, top of counting chamber and coverslip
In, be careful not to produce bubble, observe under 100 times of low power microscope, dead cell can by Trypan Blue, living cells then will not, mobile meter
Number plate, to seeing counting grid, counts the cell number of being unstained of four big lattice, and record includes that the cell pressed right line He reach the standard grade, left line are disregarded with rolling off the production line,
Big lattice total cellular score/4 × 10 of cell number/mL=tetra-4。
During freeze-stored cell, results exponential phase cell (before collecting cell, 24h changes liquid), frozen stock solution (5%DMSO, 95%DMEM) is resuspended carefully
Born of the same parents, adjusting cell density is 5 × 106～1 × 107Individual/mL, is distributed in aseptic cryopreservation tube, and often pipe adds 1.5mL cell suspension, carries out labelling and note
Record, cryopreservation tube 4 DEG C place 20min ,-20 DEG C place 20min, move into the most afterwards in liquid nitrogen container at-70 DEG C of ultra cold storage freezers.Cell recovery,
From liquid nitrogen container, take out cryopreservation tube, put into rapidly in the beaker filling 40 DEG C of water, frequently shake, be allowed to melt as early as possible, freeze with cotton ball soaked in alcohol sterilization
Deposit tube-surface, sucking-off cell suspension, move in centrifuge tube, add cell culture fluid and cultivate to 10mL, continuation.
1.2.2 cell growth inhibition assay
3T3-L1 cell is inoculated in 96 porocyte culture plates.After cellar culture 1 day, change into containing 1 × 10-4The target compound of mol/L and OF
DMEM culture fluid, matched group is the culture fluid of the DMSO containing 0.1% (V/V), and often group sets 3 multiple holes, processes 2 days.Discard Kong Zhongpei
Nutrient solution, every hole adds 20 μ l MTT liquid (5mg/mL), cultivates 4h, abandons liquid in hole for 37 DEG C, and every hole adds 150 μ l DMSO, shake well,
Measuring absorbance (Optical density, OD) immediately on enzyme-linked immunosorbent assay instrument, mensuration wavelength is 570nm.Suppression ratio is calculated as follows:
1.3 experimental result
| Compound number | Suppression ratio (%) |
| I-1 | 17.55 |
| I-2 | 82.91 |
| I-3 | 77.23 |
2 compounds are on high fat KM lipid of mice and the impact of body weight
" pharmacological experimental methodology " (third edition) that the laboratory reference refined cloud of Xu etc. is write, the method for People's Health Publisher 2002:1189-1201,
Change slightly.
2.1 experimental technique
KM mice (body weight 40～50g, male, cleaning grade), it is randomly divided into following group by body weight:
Blank group (normal diet group)；Model control group (high lipid food group)；Atorvastatin, 1mg/kg；High dose group, compound I-1
1mg/kg；Low dose group, compound I-10.5mg/kg.
Except blank group, all raise with high lipid food two months for remaining each group.Three month, respectively organize gastric infusion on request, blank group and
Model control group gives proper volume excipient, once a day, continuous one month.After administration terminates, KM mice sacrificed by exsanguination, abdominal cavity, life
Grow device to enclose fat and all take off, claim its weight in wet base, and measure body weight.
2.2 experimental result
3 instantaneous effect experiments
3.1 experimental design
With poloxamer188 induction SD rat form instantaneous hyperlipidemia model, lumbar injection P407 after 3 hours according to dosage gavage to rat compound
I-3 (25mg/kg) and positive control drug atorvastatin (25mg/kg), and after injection P407 within 3,24,30,48 hours, take a blood sample and to measure blood fat each
Item concentration, the lipid-lowering effect of preliminary assessment I-3.
3.2 experimental result
3.2.1 rat blood serum T-CHOL (TC) content (mmol/L) change
Comparing with model group, after 24h, I-3 group and statin group TC content are remarkably decreased (P ＜ 0.05).
3.2.2 rat blood serum triglyceride (TG) content (mmol/L) change
Comparing with model group, after 24h, I-3 group and statin group TG content are remarkably decreased (P ＜ 0.05).
3.2.3 rat blood serum low density lipoprotein, LDL (LDL) content (mmol/L) change
Comparing with model group, after 48h, I-3 group and statin group LDL content are remarkably decreased (P ＜ 0.05).
Fat activity research is adjusted in 4 rabbit bodies
4.1 experimental design
New zealand rabbit 5, body weight 1.8-2.0kg, male.Rabbit buys rear adaptability and raises one week, starts to high lipid food after one week,
Within 8th week, start to be administered, oral administration of compound I-1, continuous 5 weeks of 22mg/kg, continue to give high lipid food simultaneously.Weigh and quiet in ear edge on an empty stomach weekly
Arteries and veins takes blood 0.5ml, 8000r/min, centrifugal 10min, takes supernatant and measures blood fat.
4.2 experimental result
After giving high lipid food, rabbit body weight is continuously increased, and after being administered 2 weeks, body weight begins to decline, and after being administered 5 weeks, body weight relatively peak declines 12.5%.
TC, TG and LDL-C are beginning to decline after 2 weeks to I-1, and after being administered 5 weeks, each lipid composition relatively top level declines 39.3%, 54.2% and respectively
30.5%.After giving high lipid food, the 3rd week HDL-C irritability raises, after gradually steady, slowly rise after I-1 being administered orally every day, after 5 weeks
HDL-C raises 32.7% before relatively giving I-1.
Experiment conclusion
Test result indicate that, part of compounds is to PECTORAL LIMB SKELETON proliferation function, and shows good Adjust-blood lipid effect in animal body.
The invention further relates to the compound of formula and the Pharmaceutical composition of pharmaceutically acceptable carrier composition.
The compounds of this invention individually or can make preparation for administration with one or more pharmaceutically acceptable carrier combinations.Can use
Oral dosage form, such as conventional tablet and capsule, slow releasing tablet and capsule, controlled release tablet and capsule, drop pill, dispersibles powder, granule etc.；
Also ejection preparation can be prepared as.Can be more conventional containing the active component with such as 0.05% to 90% total amount of carrier combinations in these pharmaceutical formulations
The active component of weight between about 15% to 60%.The compounds of this invention dosage can be 0.001～100mg/kg/ days, it is also possible to according to disease degree
Difference or the difference of dosage form deviate this dosage range.
Detailed description of the invention
The preparation of part of compounds is implemented as follows:
Fusing point XRC-1 micro-meldometer measures (thermometer is the most calibrated), and IR Nicolet iS10 type Fourier transformation infrared spectrometer measures (KBr
Tabletting),1H-NMR nuclear magnetic resonance, NMR is by Bruker AV300 type (300MHz) nmr determination (TMS is internal standard substance), and mass spectrum is respectively by Shimadzu
GC/MS-QP2010 type mass spectrograph (EI-MS), Agilent1 100LC-MSD-Trap/SL type mass spectrograph (ESI-MS) measure.
Column chromatography silica gel is 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel (Haiyang Chemical Plant, Qingdao), and eluant is petroleum ether-acetic acid second
Ester system or chloroform-methanol system.Thin layer chromatography (TLC) GF254 thin layer chromatography board (Yantai Jiang You silica gel development corporation, Ltd.)；TLC expanding body
System is petroleum ether-ethyl acetate system or chloroform-methanol system, adds a small amount of acetic acid if desired；TLC at ZF7 type ultraviolet analysis instrument for three purposed, (consolidate by Henan
Yi Yuhua Instrument Ltd.) under irradiate display.Part of compounds purity uses Shimadzu HPLC to detect under 254nm, and flowing is methanol/water system mutually
System.
Embodiment 1
The preparation of 7-hydroxyl-3-(4-methoxyphenyl)-4H-benzopyran-4-one (3a)
In first reaction bulb, add resorcinol (0.72g, 6.5mmol), homoanisic acid (1；1.0g, 6.0mmol), BF3/Et2O
(10ml), stirring reaction 90min at 75 DEG C.Reaction terminates, and is cooled to less than 10 DEG C, under stirring, is slowly added to DMF (10mL).At second
In reaction bulb, add DMF (20mL), be cooled to less than 10 DEG C, be dividedly in some parts PCl5(2.0g, 9mmol), stirring reaction 30min at 55 DEG C.
Reaction terminates, and is cooled to less than 10 DEG C, is slowly added in first reaction bulb, room temperature reaction 1h.Reaction terminates, and under stirring, is poured into by reactant liquor
In the dilute hydrochloric acid (0.1N) of heat, separate out solid, sucking filtration, washing, dry.Crude product recrystallizing methanol, obtains product 1.0g, yield 62.5%.
mp 256-258℃；MS (ESI): m/z=269 [M+H]+.
Embodiment 2
The preparation of 3-(4-methoxyphenyl)-7-(3-(4-methoxyphenyl) propoxyl group)-4H-benzopyran-4-one (4a)
Add 7-hydroxyl-3-(4-methoxyphenyl)-4H-benzopyran-4-one (3a, 5g, 1.3mmol), K2CO3(1.0g), KI (0.2g), 1-(3-chlorine
Propyl group)-4-methoxybenzene (1.65mmol), DMF (10mL), at 75 DEG C stir 5h.Reaction terminates, and is cooled to room temperature, under stirring, by reactant liquor
Pour in frozen water, separate out solid, sucking filtration, washing, dry, obtain crude product.Column chromatography (petrol ether/ethyl acetate: 5/1, V/V), obtains white solid
Body 450mg, yield 83.2%.mp 178-180℃；IR(cm-1): 3416,2909,2838,1631,1609,1566,1515,1445,1250,1183,
1024,827,812；1H-NMR(CDCl3, 300MHz)；δ 8.21 (d, 1H, J=8.82Hz, H-5), 7.91 (s, 1H, H-2), 7.50 (d, 2H, J=
8.28Hz, H-2 ', H-6 '), 7.13 (d, 2H, J=8.37Hz, H-2 ", H-6 "), 6.98 (m, 3H, Ar-H), 6.83 (m, 3H, Ar-H), 4.04 (t, 2H, J
=6.06Hz ,-OCH2-), 3.84 (m, 3H ,-OCH3), 3.79 (m, 3H ,-OCH3), 2.78 (t, 2H, J=7.5Hz, Ar-CH2-), 2.13 (m, 2H,
-OCH2CH2-)；MS (EI): m/z=416；Anal.Calcd for C26H24O5: C, 74.98%；H, 5.81%；Found:C, 74.65%；H,
5.81%.
Embodiment 3
The preparation of 9Z-oleyl alcohol (6a)
Add tetrahydrochysene lithium aluminum (0.35g, 9.15mmol), anhydrous tetrahydro furan (THF, 10mL), under stirring, be slowly added dropwise dissolved with oleic acid (29g,
THF solution (10ml) 6.1mmol).Drip complete, room temperature reaction 12h.Terminate reaction, by remaining LiAlH4Go out by a small amount of water extraction, add
Appropriate ethyl acetate, stirring, filter solid, solution decompression is concentrated to dryness, obtain colourless transparent liquid 1.28g, yield 78%.
Embodiment 4
The preparation of undecylenic alcohol (6b)
Use the synthetic method identical with compound (6a), yield 82%.
Embodiment 5
(Z) preparation of-1-chloro-9-octadecylene (7a)
Add 9Z-oleyl alcohol (6a, 1.28g, 7.22mmol), toluene (10ml), thionyl chloride (2ml), react 5h at 75 DEG C, with petroleum ether post layer
Analysis purification obtains sterling oily liquids, yield 69%.
Embodiment 6
The preparation of 1-chloro-10-hendecene (7b)
Use the synthetic method identical with compound (7a), obtain colourless transparent liquid, yield 74%.
Embodiment 7
(Z) preparation of-3-(4-methoxyphenyl)-7-(9-octadecylene epoxide)-4H-benzopyran-4-one (I-1)
Add 7-hydroxyl-3-(4-methoxyphenyl)-4H-benzopyran-4-one (4a, 25g, 1.3mmol), K2CO3(1.0g)、KI(0.2g)、(Z)-1-
Chloro-9-octadecylene (7a, 31g, 1.65mmol), DMF (10mL), stirring reaction 12h at 75 DEG C.Reaction terminates, and is cooled to room temperature, under stirring,
Reactant liquor is poured in frozen water, separate out solid, sucking filtration, washing, dry, obtain crude product.Column chromatography (petrol ether/ethyl acetate: 5/1, V/V),
White solid 489mg, yield 72.5%.mp 106-108℃；IR(cm-1): 3451,2920,2851,1633,1610,1516,1447,1267,1179,
1033,830；1H-NMR(CDCl3, 300MHz): δ 8.20 (d, 1H, J=8.88Hz, H-2), 7.91 (s, 1H, H-5), 7.50 (d, 2H, J=8.52
Hz, H-2 ', H-6 '), 6.97 (m, 3H, H-6, H-3 ', H-5 '), 6.83 (d, 1H, J=1.59Hz, H-8), 5.35 (m, 2H ,-CH=CH-), 4.05 (t,
2H, J=6.48Hz ,-OCH2-), 3.84 (s, 3H ,-OCH3), 2.02 (m, 4H ,-CH2-CH=CH-CH2-), 1.81 (m, 2H,
-CH2-CH2-O-), 1.48 (m, 2H ,-CH2-CH2-CH2-O-), 0.88 (m, 3H ,-CH3)；MS (EI): m/z=518；Anal.Calcd for
C34H46O4·0.5H2O:C, 77.38%；H, 8.98%；Found:C, 77.47%；H, 8.57%.
Embodiment 8
The preparation of 3-(4-methoxyphenyl)-7-(10-hendecene epoxide)-4H-benzopyran-4-one (I-3)
Use the synthetic method identical with compound (I-1), obtain white solid, yield 77.3%.1H-NMR(CDCl3, 300MHz): δ 8.20 (d,
1H, H-2), 7.93 (s, 1H, H-5), 7.52 (d, 2H, H-2 ', H-6 '), 7.01 (m, 3H, H-6, H-3 ', H-5 '), 6.85 (d, 1H, H-8), 5.82 (m, 1H,
-CH=CH2), 4.98 (m, 2H ,-CH=CH 2 ), 4.07 (t, 2H ,-OCH 2 -), 3.86 (s, 3H ,-OCH3), 2.08 (m, 2H ,-CH 2 -CH=CH2),
1.87 (m, 2H ,-CH 2 -CH2-O-), 1.34 (m, 10H ,-CH2-).MS (ESI): m/z=421 [M+H]+。
Embodiment 9
The preparation of 3-bromo-4-methoxyphenylacetic acid (2)
Add homoanisic acid (1,23g, 6.02mmol), acetic acid (5ml), under stirring, be slowly added dropwise dissolved with Br2(0.5ml, 9.03mmol)
Acetic acid (5ml).Drip complete, reaction 2h is stirred at room temperature.Reaction terminates, and pours in frozen water by reactant liquor under stirring, precipitation solid, sucking filtration,
Washing, dries.Obtain white solid 1.17g, yield 79.3%.mp 114-116℃.
Embodiment 10
The preparation of 7-hydroxyl-3-(3-bromo-4-methoxyphenyl)-4H-benzopyran-4-one (4b)
Use the synthetic method identical with compound (4a), yield 40%.Mp 284-287℃；1H-NMR (DMSO, 300MHz): δ 10.85 (d,
1H, OH), 8.43 (s, 1H, H-2), 7.98 (d, 1H, J=8.97Hz, H-5), 7.82 (s, 1H, H-2 '), 7.58 (d, 1H, J=8.58Hz, H-6 '),
7.18 (d, 1H, J=8.64Hz, H-5 '), 6.96 (d, 1H, J=8.97Hz, H-6), 6.89 (s, 1H, H-8), 3.88 (s, 3H ,-OCH3)。
Embodiment 11
(Z) preparation of-3-(3-bromo-4-methoxyphenyl)-7-(9-octadecylene epoxide)-4H-benzopyran-4-one (I-2)
Use the synthetic method identical with compound (I-1), yield 80.3%.mp 46-48℃；IR(cm-1): 3425,2923,2852,1635,1602,
1502,1446,1263,1050,828；1H-NMR(CDCl3, 300MHz): δ 8.19 (d, 1H, J=8.91Hz, H-5), 7.92 (s, 1H, H-2),
7.75 (d, 1H, J=1.95Hz, H-2 '), 7.53 (dd, 1H, H-6 '), 6.98 (m, 2H, H-6, H-5 '), 6.84 (d, 1H, J=2.07Hz, H-8), 5.35
(m, 2H ,-CH=CH-), 4.05 (t, 2H, J=6.48Hz ,-OCH2-), 3.93 (s, 3H ,-OCH3), 2.03 (m, 4H ,-CH2-CH=CH-CH2-),
1.84 (m, 2H ,-CH2-CH2-O-), 1.48 (m, 2H ,-CH2-CH2-CH2-O-), 0.88 (m, 3H ,-CH3)；MS (EI): m/z=598；
Anal.Calcd for C34H45BrO4: C, 68.33%；H, 7.59%；Found:C, 67.98%；H, 7.53%.
Claims (4)
1. the compound of general formula:
Wherein R1O represents C8-C30Fat alkoxyl, described alkoxyl is by C8-C30After saturated or undersaturated fatty acid reduction de-
Deprotonation is formed；
R2Represent H, OH, OR ', SR ', NHR ', N (CH3)2、NO2, halogen, CF3Or C (O) R ', wherein R ' representative
C1-C4Alkyl.
Its pharmaceutically acceptable salt of compound the most according to claim 1 or its prodrug, wherein R1O preferably represents oil
Acid, linoleic acid, undecylenic acid, linolenic acid, conjugated linoleic acid, stearic acid, palmitoleic acid, eicosatetraenoic acid, 20 carbon
Matter is sloughed after the fatty acid reduction such as five olefin(e) acids, 20 carbonic acid, docosahexenoic acid, lauric acid, certain herbaceous plants with big flowers acid, octanoic acid, E-10-hydroxy-2-decylenic acid
The fatty alkoxyl that son is formed；
R2Preferably represent H, OH, OCH3、OCH2CH3、SCH3、NHCH3、N(CH3)2、NO2, halogen, CF3
Or C (O) CH3。
Compound the most according to claim 2, its pharmaceutically acceptable salt or its prodrug, R1O more preferably represents oil ether
Base, sub-oil ether, Petiolus Trachycarpi oil ether, tallow ether or hendecene ether；
R2More preferably represent H, OCH3、OCH2CH3、Br、NO2。
Compound the most according to claim 1, its pharmaceutically acceptable salt or its prodrug, be used for preparing prevention or treatment
The purposes of the medicine of hyperlipemia, obesity or type ii diabetes.
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| CN107879942A (en) * | 2017-11-15 | 2018-04-06 | 江南大学 | A kind of bio-based primary amine cationic surfactant and preparation method thereof |
| CN110090209A (en) * | 2019-06-11 | 2019-08-06 | 中日友好医院 | Application of the formoononetin in treatment nonalcoholic fatty liver |
| CN113712970A (en) * | 2021-09-13 | 2021-11-30 | 云南大学 | Application of formononetin derivative in preparation of medicine for treating or preventing perimenopausal syndrome |
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| WO2011106924A1 (en) * | 2010-03-01 | 2011-09-09 | 中国药科大学 | Isoflavone fatty acid ester derivatives, preparation method and pharmaceutical uses thereof |
| CN102964322A (en) * | 2012-12-12 | 2013-03-13 | 中国药科大学 | Isoflavone or flavonoid aliphatic ether derivates, preparation method and medical application thereof |
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| WO2011106924A1 (en) * | 2010-03-01 | 2011-09-09 | 中国药科大学 | Isoflavone fatty acid ester derivatives, preparation method and pharmaceutical uses thereof |
| CN102964322A (en) * | 2012-12-12 | 2013-03-13 | 中国药科大学 | Isoflavone or flavonoid aliphatic ether derivates, preparation method and medical application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107879942A (en) * | 2017-11-15 | 2018-04-06 | 江南大学 | A kind of bio-based primary amine cationic surfactant and preparation method thereof |
| CN107879942B (en) * | 2017-11-15 | 2020-03-06 | 江南大学 | Bio-based primary amine cationic surfactant and preparation method thereof |
| CN110090209A (en) * | 2019-06-11 | 2019-08-06 | 中日友好医院 | Application of the formoononetin in treatment nonalcoholic fatty liver |
| CN113712970A (en) * | 2021-09-13 | 2021-11-30 | 云南大学 | Application of formononetin derivative in preparation of medicine for treating or preventing perimenopausal syndrome |
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