CN104119221A - Beta-elemene 14-site ramification and application of beta-elemene 14-site ramification in treating atherosclerosis - Google Patents

Beta-elemene 14-site ramification and application of beta-elemene 14-site ramification in treating atherosclerosis Download PDF

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CN104119221A
CN104119221A CN201410377535.0A CN201410377535A CN104119221A CN 104119221 A CN104119221 A CN 104119221A CN 201410377535 A CN201410377535 A CN 201410377535A CN 104119221 A CN104119221 A CN 104119221A
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acid
elemi
alcohol ester
compound
beta
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尚靖
徐进宜
许海
王若妍
段文丽
陈继超
白仁仁
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DALIAN YUANDA PHARMACEUTICAL TECHNOLOGY AND DEVELOPMENT Co Ltd
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DALIAN YUANDA PHARMACEUTICAL TECHNOLOGY AND DEVELOPMENT Co Ltd
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Priority to CN201410377535.0A priority Critical patent/CN104119221A/en
Publication of CN104119221A publication Critical patent/CN104119221A/en
Priority to PCT/CN2015/075326 priority patent/WO2016015480A1/en
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Abstract

The invention relates to the field of organic synthesis and medicinal chemistry, and particularly relates to a beta-elemene 14-site ramification (I) or (II), wherein R1 and R2 are defined in the specification. The invention also discloses a preparation method of the beta-elemene 14-site ramification and application of the beta-elemene 14-site ramification on the aspect of resisting atherosclerosis. The ramifications I and II are as shown in the specification.

Description

Beta-elemene 14 bit derivants and treat atherosclerotic purposes
Technical field
The present invention relates to organic synthesis and pharmaceutical chemistry field, be specifically related to a class beta-elemene 14-bit derivant, the invention also discloses preparation method and the application aspect atherosclerosis thereof of these beta-elemenes 14-bit derivant.
Background technology
Cardiovascular and cerebrovascular diseases comprises coronary artery disease and palsy, it is the main fatal disease in the whole world, in recent years along with the change with food habits that improves constantly of people's living standard, its sickness rate has ascendant trend year by year, it is reported and have every year 100006007 million peoples to die from cardiovascular diseases, AS is the common pathophysiological basis that cardiocerebrovasculaevents events occurs, and is to cause cardiovascular and cerebrovascular diseases and a dead important factor.Recent study shows, the generation development of AS and oxidative stress close relation, the Hazard Factor that AS occurs, as hypercholesterolemia, diabetes, hypertension, smoking etc. all can inducing endothelial cell, vascular smooth muscle cell etc. produces excess of oxygen free radical (ROS), and these ROS participate in the whole evolution of atherosclerosis from fat line pathology to plaque rupture, and mediated vascular endothelial cell, smooth muscle cell and mononuclear macrophage changing function and damage, promoted again inflammatory reaction simultaneously.Therefore find novel antioxidant with strong points and remain the atherosclerotic top priority of control.
Beta-elemene, is the main active ingredient of Elemenum, studies and shows, beta-elemene has anti oxidative damage, has potential study of anti-atherogenic effect.But about beta-elemene derivatives, in the research aspect treatment atherosclerosis, but rarely has report at present, therefore by beta-elemene structure is optimized, finds the obvious lead compound of novel anti oxidative damage treatment atherosclerosis relative disease is had great importance.
Feature in view of beta-elemene structure, when its derivatize is modified, 13 of monosubstituted beta-elemene and 14 bit derivants are because polarity is close, particularly 14-bit derivant content is much lower compared with 13-bit derivant, by simple column chromatography, be difficult to separation respectively and obtain, thereby the research before researcher mainly concentrates on the modification of 13 bit derivants of beta-elemene.But, in order to probe into the 14-bit derivant of beta-elemene, whether still there is anti-oxidant activity, and then play study of anti-atherogenic effect, further analyze the structure activity relationship of beta-elemene simultaneously, we prepare separated method by HPLC, 13-β-elemol and 14-β-elemol have been carried out to successful separated (proportion is about 5:1), and take 14-β-elemol as primer synthetic 14 carboxylic acids of serial beta-elemene and the ester derivative prepared first, and disclosed it at anti-oxidative damage, and then the effect aspect treatment atherosclerosis.
Summary of the invention
The invention discloses a kind of is that raw material is prepared 14 carboxylic acids of beta-elemene or ester derivative with beta-elemene, and pharmaceutical research shows that derivative of the present invention has certain effect in anti-oxidant and treatment atherosclerosis relative disease.The invention provides a series of have general formula (I) or (II) preparation methods of the compound of structural performance, general formula (I) or (II) expanded this type of derivant structure feature and range of structures.And further provide anti oxidative damage wherein excellent, there is the compound of potential treatment atheromatosis effect.
Structural formula of compound of the present invention is as follows:
R wherein 1represent carboxyl, the C replacing arbitrarily 6-10aryl or C 4-9aromatic heterocyclic, heteroatoms is selected from N, O or S, and described substituting group is selected from halogen, OH, NO 2, CF 3, C 1-3alkyl or C 1-3alkoxyl group;
R 2represent 1 of replacement arbitrarily, 2-benzene two bases, 1,3-benzene two bases, Isosorbide-5-Nitrae-benzene two bases, 1,8-naphthalene two bases or 2,6-naphthalene, two bases, described substituting group is selected from halogen, OH, NO 2, CF 3, C 1-3alkyl, C 1-3alkoxyl group;
R 2expression-(CH also 2) n-, wherein n=0-10 ,-(CH 2) a-CHX-(CH 2) b-, X is selected from C 1-3straight-chain paraffin ,-(CH 2) a-(CH=CH) c-(CH 2) b-,-(CH 2) a-(CCH 3=CH) c-(CH 2) b-,-(CH 2) a-(CH=CCH 3) c-(CH 2) b-or-(CH 2) a-(C ≡ C) c-(CH 2) b-, a=0-10 wherein, b=0-10, c=0-10.
R 2preferably represent CH 2, CH 2cH 2, CH 2cH 2cH 2, CH 2cH 2cH 2cH 2, CH 2cH 2cH 2cH 2cH 2, CH=CH, CH=CHCH 2, CH=CHCH 2cH 2, CH 2cH=CH, CH 2cH=CHCH 2, CH 2cH 2cH=CH, CH=C (CH 3), CH=C (CH 3) CH 2cH 2or replace arbitrarily 1,2-benzene two bases, 1,3-benzene two bases or Isosorbide-5-Nitrae-benzene two bases, described substituting group is selected from Cl, F, OH, NO 2, CF 3, CH 3or OCH 3.
R 2more preferably represent CH 2, CH 2cH 2, CH=CH, CH 2cH 2cH 2or 1,2-benzene, two bases.
R wherein 1preferably represent carboxyl, replace arbitrarily phenyl, pyridyl or furyl, described substituting group is selected from Cl, F, OH, NO 2, CF 3, CH 3or OCH 3.
R 1more preferably represent carboxyl, phenyl, 2-chloro-phenyl-, 4-chloro-phenyl-, 3-fluorophenyl, 4-fluorophenyl, 2-nitrophenyl, 4-nitrophenyl, 2-hydroxy phenyl, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, pyridyl or furyl.
The present invention is following arbitrary compound or its pharmacy acceptable salt preferably:
4-(14-beta-elemene oxygen base)-4-ketobutyric acid;
5-(14-beta-elemene oxygen base)-4-oxopentanoie acid;
2-(14-beta-elemene oxygen base carbonyl) phenylformic acid;
14-(acetic acid)-β-elemi alcohol ester;
14-(propionic acid)-β-elemi alcohol ester;
14-(butyric acid)-β-elemi alcohol ester;
14-(Sorbic Acid)-β-elemi alcohol ester;
14-(phenylformic acid)-β-elemi alcohol ester;
14-(4-tolyl acid)-β-elemi alcohol ester;
14-(4-methoxybenzoic acid)-β-elemi alcohol ester;
14-(2-chloro-benzoic acid)-β-elemi alcohol ester;
14-(4-chloro-benzoic acid)-β-elemi alcohol ester;
14-(3-fluorobenzoic acid)-β-elemi alcohol ester;
14-(4-fluorobenzoic acid)-β-elemi alcohol ester;
14-(4-nitrobenzoic acid)-β-elemi alcohol ester;
14-(styracin)-β-elemi alcohol ester;
14-(4-fluoro cinnamic acid)-β-elemi alcohol ester;
14-(Whitfield's ointment)-β-elemi alcohol ester;
14-(nicotinic acid)-β-elemi alcohol ester;
14-(γ-picolinic acid)-β-elemi alcohol ester;
14-(furancarboxylic acid)-β-elemi alcohol ester;
Succinic acid two (14-β-elemol) ester;
Phthalic acid two (14-β-elemol) ester.
Be below formula of of the present invention (I) or (II) shown in the preparation method of compound.
General formula (I) or (II) shown in the preparation of compound, all need through 14-β-elemol intermediate.The preparation method of 14-β-elemol is as reacted as shown in the of one.First take beta-elemene as raw material, with clorox generation chlorination, generate the chloro-beta-elemene of 14-, the chloro-beta-elemene of 14-and the chloro-beta-elemene mixture of 13,14-bis-.The mixture of all chloro-products and unreacted beta-elemene be take to sherwood oil and pass through silica gel column chromatography as eluent, can realize the separated of single chloro-product and two chloro-products.Monochloro then reacts with sodium acetate, anhydrous and generates 13 and 14 ethyl ester product mixtures for mixture, further in KOH Water Under solution, can make 14-β-elemol and 14-β-elemol mixture.Finally, by HPLC, prepare separated method, successful separation obtains 14-β-elemol (proportion approximately 17%).
Reaction one:
In general formula (I), containing carboxyl can be according to reaction two preparation with the derivative (II).Under the catalysis of DMAP and EDCI, 14-β-elemol reacts with corresponding ring dicarboxylic anhydride, can make corresponding product.
Reaction two:
As react as shown in the of three, under the catalysis of DMAP and EDCI, 14-β-elemol reacts with corresponding aliphatic carboxylic acid or aromatic carboxylic acid, can make other corresponding derivatives as shown in general formula (II).
Reaction three:
The compounds of this invention pharmacy acceptable salt, is characterized in that: refer to conventional acid salt or base addition salt, it has the pharmacy effect same with compound, and the salt becoming with suitable non-toxicity organic acid or mineral acid or organic bases or mineral alkali.
The invention also discloses a kind of pharmaceutical composition, containing compound of the present invention or its pharmacy acceptable salt, can add pharmaceutically acceptable carrier and make common medicinal preparations, as tablet, capsule, pulvis, syrup, liquor, suspension agent, injection, can add the conventional excipient substances such as spices, sweeting agent, liquid or solid stopping composition or thinner.
The modes such as that compound of the present invention administering mode clinically can adopt is oral, injection.
The clinical dosage used of compound of the present invention is 0.01mg～1000mg/ days, also can depart from this scope according to the difference of the weight of the state of an illness or formulation.
Be pharmacodynamics test and the result of the compounds of this invention below, in pharmacodynamics test, the chemical structure of compound used therefor code name is shown in embodiment:
One, Antioxidation in vitro evaluation
The HUVEC cell of taking the logarithm vegetative period, with 10 5the cell suspension inoculation of individual/mL, in 6 well culture plates, is cultivated after 24h, inhales and abandons nutrient solution, and blank group and damage group add fresh serum-free DMEM high glucose medium, cellar culture.It is the various medicines of 5 μ mol/L or 50 μ mol/L that administration group adds respectively concentration on this basis, continues to cultivate after 24h, adds containing H 2o 2final concentration is the DMEM serum free medium of 0.5mmol/L, processes after 2h, detects reactive oxygen species (ROS), the content of mda (MDA) and superoxide-dismutase (SOD).
ROS reduced rate=(damage group-administration group)/damage group * 100%
SOD increment rate=(administration group-model group)/administration group * 100%
MDA reduced rate=(model group-administration group)/administration group * 100%.
Experimental result is in Table 1.
14 carboxylic acids of table 1 beta-elemene or ester derivative are on the impact of oxidative damage endotheliocyte oxidation index (n=3)
Antioxidation activity in vitro evaluation demonstration, by 14 of beta-elemenes are carried out to esterification modification, gained derivative has shown good anti-oxidant activity to damaging rear HUVEC.Experimental data also further confirms the invention provides a kind of effective ways of preparing Elemenum derivative anti-oxidation medicine.
Two, the effect research of the compounds of this invention to Atherosclerotic quail animal pattern
1. the foundation of Atherosclerotic quail model and grouping
120 of healthy male quails, weight 110 ± 20g/, sub-cage rearing.Quantitatively feeding (20g/ pcs/day), freely drinks water, 20 ℃-25 ℃ of room temperatures, illumination 12 hours/day.Normal diet was fed after one week, and Normal group is raised with common quail special feed, and all the other are fed with high lipid food (1% cholesterol, 6% peanut oil, 14% lard and 79% basal feed).Set up Atherosclerotic quail model.The modeling of the high fat atherosclerosis of quail is after 3 weeks, and the quail feeding with high lipid food is divided into 7 groups at random by serum total cholesterol (TC) level, 15 every group.Experiment is grouped as follows: 1. normal group; 2. model group; 3. solvent control group; 4. positive drug group: Simvastatin (6.5mg/kg); 5. 23 groups of compounds (100mg/kg); 6. compound 24 (100mg/kg).When feeding with feed, every morning respectively gavage give relative medicine, normal group and model group give the physiological saline of equivalent.By body weight, adjust dosage, administration 7 weeks weekly.
In feeding process, note the observation to generalized cases such as the animal mental status, diet, activity, stool colour and proterties, and weigh weekly the weight of animals, check feed high lipid food and the impact of medicine gavage on animal bodies situation.
2. compound 23,24 is on the morphologic impact of Atherosclerotic Quail arterial wall
2.1 collecting sample
After last administration, fasting (can't help water) 16h, quail is put to death, and takes out aorta, with normal saline flushing blood, with filter paper, blots.After aorta numbering, with 10% neutral formalin, fix, carry out HE dyeing, the pathology situation of rear observation endarterium, carries out arterial disease degree analyzing by atherosclerosis lesion type method.
2.2 experimental results are shown in Fig. 1, and as seen from the figure, Normal group endarterium is smooth.Model group patch merges in flakes, the whole tube chamber of nearly cover.The visible patch of solvent control group is projection obviously, merges in flakes.23,24 groups of endarterium of positive drug Simvastatin and compound thicken, but have no the obviously protruding AS patch to tube chamber.Mottling formation is significantly improved.23,24 pairs of atheromatosiss of prompting compound have good therapeutic action.
Accompanying drawing explanation
Fig. 1 is that compound 23,24 is on the morphologic impact of Atherosclerotic Quail arterial wall
Embodiment
Embodiment 1
The preparation method of intermediate 14-β-elemol (compound 1)
100mmol beta-elemene is dissolved in to (V:V=2:1) in 20mL methylene dichloride and acetic acid mixed solution, under condition of ice bath, slowly splashes into the chlorine bleach liquor of containing 180mmol reactive chlorine, ice bath reaction 4h.Separate dichloromethane layer, water layer is with dichloromethane extraction 3 times, combined dichloromethane concentrates to obtain weak yellow liquid crude product, without being further purified processing, this liquid crude product is dissolved in the anhydrous N of 15mL, in dinethylformamide (DMF), under stirring, add 200mmol sodium acetate, anhydrous, in 100 ℃ of reaction 7h.Reaction solution is with diatomite suction filtration, and filtrate adds 15mL saturated aqueous common salt, and with petroleum ether extraction 3 times.Inspissated oil ether obtains yellow liquid, with sherwood oil: ethyl acetate=30:1 (V:V) column chromatography for separation, obtains 13 and 14 ethyl ester product mixtures.Then the mixing solutions with 8mL methyl alcohol and 8mL chloroform dissolves, and adds 200mmol potassium hydroxide back flow reaction 2h.Filter, filtrate is concentrated, with sherwood oil: ethyl acetate=5:1 (V:V) column chromatography, obtains colorless liquid product, and now overall yield is 20%.Finally, adopt the separated 13-β-elemol of HPLC preparation method and 14-β-elemol mixture, chiral column model is CHIRALPAK AD-H, moving phase is normal hexane: ethanol=98:2 (V:V), flow velocity is 1mL/min, detecting wavelength is UV 214nm, separating mixture under room temperature condition, and separation obtains 14-β-elemol (proportion is about 17%).
1H?NMR(CDCl 3,300MHz)δ:1.02(s,3H),1.44-1.68(m,6H),1.76(s,3H),1.94-2.08(m,2H),4.02(q,J＝13.4Hz,2H),4.73(s,2H),4.86(s,1H),4.91(s,1H),4.95(d,J＝5.5Hz,1H),5.17(s,1H),5.79(dd,J 1＝17.8Hz,J 2＝10.5Hz,1H).
13C?NMR(CDCl 3,300MHz)δ:151.4,150.0,149.6,111.0,110.6,108.3,67.4,47.9,45.6,39.6,33.3,26.6,20.9,15.9.
Embodiment 2
The preparation method of 4-(14-beta-elemene oxygen base)-4-ketobutyric acid (compound 2)
3mmol 14-β-elemol is dissolved in 10mL anhydrous methylene chloride, adds 0.3mmol DMAP, 0.3mmol EDCI and 3.3mmol Succinic anhydried, normal-temperature reaction 10h.Reaction solution is with 10% salt acid elution 3 times, and concentrated dichloromethane layer obtains weak yellow liquid.With sherwood oil: ethyl acetate=8:1 (V:V) column chromatography, obtain colorless liquid product, productive rate is 67%.
1H?NMR(CDCl 3,300MHz)δ:0.99(s,3H),1.40-1.65(m,6H),1.74(s,3H),1.92-1.97(m,1H),2.01-2.06(m,1H),2.63-2.73(m,4H),4.51(s,2H),4.72(s,2H),4.89-4.95(m,3H),5.13(s,1H),5.75(dd,J 1＝17.8Hz,J 2＝10.4Hz,1H).
13C?NMR(CDCl 3,300MHz)δ:177.9,171.7,150.0,149.3,145.9,113.6,111.0,108.4,68.6,48.3,45.6,39.7,33.0,28.9,26.7,21.0,16.0.
Embodiment 3
The preparation method of 5-(14-beta-elemene oxygen base)-5-oxopentanoic acid (compound 3)
3mmol 14-β-elemol is dissolved in 10mL anhydrous methylene chloride, adds 0.3mmol DMAP, 0.3mmol EDCI and 3.3mmol Pyroglutaric acid, normal-temperature reaction 10h.Reaction solution is with 10% salt acid elution 3 times, and concentrated dichloromethane layer obtains weak yellow liquid.With sherwood oil: ethyl acetate=8:1 (V:V) column chromatography, obtain colorless liquid product, productive rate is 74%.
1H?NMR(CDCl 3,300MHz)δ:1.00(s,3H),1.41-1.65(m,6H),1.74(s,3H),1.92-2.06(m,4H),2.44(t,J＝7.3Hz,4H),4.49(s,2H),4.71(s,2H),4.88(s,1H),4.90(d,J＝4.7Hz,1H),4.95(s,1H),5.13(s,1H),5.75(dd,J 1＝17.8Hz,J 2＝10.4Hz,1H).
13C?NMR(CDCl 3,300MHz)δ:178.8,172.5,150.0,149.2,146.0,113.5,111.0,108.4,68.3,48.4,45.6,39.6,33.2,33.0,32.9,26.7,21.0,19.8,16.0.
Embodiment 4
The preparation method of 2-(14-beta-elemene oxygen base carbonyl) phenylformic acid (compound 4)
3mmol 14-β-elemol is dissolved in 10mL anhydrous methylene chloride, adds 0.3mmol DMAP, 0.3mmol EDCI and 3.3mmol Tetra hydro Phthalic anhydride, normal-temperature reaction 10h.Reaction solution is with 10% salt acid elution 3 times, and concentrated dichloromethane layer obtains weak yellow liquid.With sherwood oil: ethyl acetate=8:1 (V:V) column chromatography, obtain colorless liquid product, productive rate is 70%.
1H?NMR(CDCl 3,300MHz)δ:0.93(s,3H),1.33-1.62(m,6H),1.65(s,3H),1.85-1.90(m,1H),2.02-2.07(m,1H),4.62(s,2H),4.65(s,2H),4.85(d,J＝4.5Hz,1H),4.86(s,1H),4.90(s,1H),5.17(s,1H),5.73(dd,J 1＝17.0Hz,J 2＝11.2Hz,1H),7.47-7.56(m,2H),7.63-7.66(m,1H),7.83-7.85(m,1H). 13C?NMR(CDCl 3,300MHz)δ:170.7,166.7,149.0,148.2,144.6,132.2,131.1,129.9,129.3,128.9,127.9,113.3,110.1,107.4,68.8,47.5,44.6,38.7,38.6,32.0,25.6,20.0,15.0.
Embodiment 5
The preparation method of 14-(acetic acid)-β-elemi alcohol ester (compound 5)
3mmol 14-β-elemol is dissolved in 10mL anhydrous methylene chloride, adds 0.3mmol DMAP, 0.3mmol EDCI and 4mmol Glacial acetic acid, normal-temperature reaction 12h.Reaction solution is with 10% salt acid elution 3 times, and concentrated dichloromethane layer obtains weak yellow liquid.With sherwood oil: ethyl acetate=300:1 (V:V) column chromatography, obtain colorless liquid product, productive rate is 78%.
1H?NMR(CDCl 3,300MHz)δ:1.00(s,3H),1.41-1.65(m,6H),1.75(s,3H),1.92-2.04(m,2H),2.08(s,3H),4.48(s,2H),4.72(s,2H),4.89-4.91(m,2H),4.95(s,1H),5.14(s,1H),5.76(dd,J 1＝17.8Hz,J 2＝10.4Hz,1H).
13C?NMR(CDCl 3,300MHz)δ:170.6,150.0,149.3,146.1,113.3,110.9,108.4,68.2,48.4,45.6,39.7,33.0,26.7,21.0,20.9,16.0.
Embodiment 6
The preparation method of 14-(propionic acid)-β-elemi alcohol ester (compound 6)
3mmol 14-β-elemol is dissolved in 10mL anhydrous methylene chloride, adds 0.3mmol DMAP, 0.3mmol EDCI and 4mmol propionic acid, normal-temperature reaction 12h.Reaction solution is with 10% salt acid elution 3 times, and concentrated dichloromethane layer obtains weak yellow liquid.With sherwood oil: ethyl acetate=300:1 (V:V) column chromatography, obtain colorless liquid product, productive rate is 82%.
1H?NMR(CDCl 3,300MHz)δ:0.89(t,J＝7.4Hz,3H),0.93(s,3H),1.34-1.67(m,6H),1.70(s,3H),1.84-1.91(m,1H),1.94-2.00(m,1H),2.25(t,J＝7.4Hz,2H),4.41(s,2H),4.64(s,2H),4.80(s,1H),4.83(d,J＝3.9Hz,1H),4.88(s,1H),5.06(s,1H),5.70(dd,J 1＝17.8Hz,J 2＝10.4Hz,1H).
13C?NMR(CDCl 3,300MHz)δ:174.0,150.0,149.3,146.2,113.1,111.0,108.4,68.0,48.5,45.7,39.7,33.0,27.6,26.7,21.0,16.1,9.1.
Embodiment 7
The preparation method of 14-(butyric acid)-β-elemi alcohol ester (compound 7)
3mmol 14-β-elemol is dissolved in 10mL anhydrous methylene chloride, adds 0.3mmol DMAP, 0.3mmol EDCI and 4mmol butyric acid, normal-temperature reaction 12h.Reaction solution is with 10% salt acid elution 3 times, and concentrated dichloromethane layer obtains weak yellow liquid.With sherwood oil: ethyl acetate=300:1 (V:V) column chromatography, obtain colorless liquid product, productive rate is 60%.
1H?NMR(CDCl 3,300MHz)δ:0.86(q,J＝7.5Hz,2H),1.00(s,3H),1.16(t,J＝7.5Hz,3H),1.41-1.65(m,6H),1.74(s,3H),1.91-2.06(m,2H),2.36(q,J＝7.6Hz,2H),4.48(s,2H),4.72(s,2H),4.88(s,1H),4.90(d,J＝3.4Hz,1H),4.95(d,J＝1.4Hz,1H),5.13(s,1H),5.76(dd,J 1＝17.8Hz,J 2＝10.4Hz,1H).
13C?NMR(CDCl 3,300MHz)δ:172.2,149.0,148.3,145.2,112.3,110.0,107.4,66.9,47.4,44.7,38.7,35.3,32.0,25.6,20.0,17.4,15.0,12.7.
Embodiment 8
The preparation method of 14-(Sorbic Acid)-β-elemi alcohol ester (compound 8)
3mmol 14-β-elemol is dissolved in 10mL anhydrous methylene chloride, adds 0.3mmol DMAP, 0.3mmol EDCI and 4mmol Sorbic Acid, normal-temperature reaction 12h.Reaction solution is with 10% salt acid elution 3 times, and concentrated dichloromethane layer obtains weak yellow liquid.With sherwood oil: ethyl acetate=300:1 (V:V) column chromatography, obtain colorless liquid product, productive rate is 89%.
1H?NMR(CDCl 3,300MHz)δ:1.01(s,3H),1.37-1.65(m,6H),1.74(s,3H),1.85(d,J＝5.6Hz,3H),1.89-2.00(m,1H),2.03-2.08(m,1H),4.55(s,2H),4.71(s,2H),4.88(s,1H),4.90(d,J＝3.3Hz,1H),4.95(s,1H),5.15(s,1H),5.73-5.59(m,2H),6.07-6.25(m,2H),7.23-7.31(m,1H).
13C?NMR(CDCl 3,300MHz)δ:166.9,150.0,149.3,145.2,139.4,129.8,127.4,118.9,113.2,110.9,108.4,67.9,48.5,45.7,39.7,33.1,26.7,21.0,18.6,16.1.
Embodiment 9
The preparation method of 14-(phenylformic acid)-β-elemi alcohol ester (compound 9)
3mmol 14-β-elemol is dissolved in 10mL anhydrous methylene chloride, adds 0.3mmol DMAP, 0.3mmol EDCI and 4mmol phenylformic acid, normal-temperature reaction 14h.Reaction solution is with 10% salt acid elution 3 times, and concentrated dichloromethane layer obtains weak yellow liquid.With sherwood oil: ethyl acetate=300:1 (V:V) column chromatography, obtain colorless liquid product, productive rate is 90%.
1H?NMR(CDCl 3,300MHz)δ:1.04(s,3H),1.38-1.71(m,6H),1.75(s,3H),1.94-2.02(m,1H),2.11-2.16(m,1H),4.73(s,4H),4.93(s,1H),4.94(s,1H),4.98(d,J＝3.8Hz,1H),5.25(s,1H),5.82(dd,J 1＝17.0Hz,J 2＝10.5Hz,1H),7.42-7.47(m,2H),7.53-7.58(m,1H),8.05-8.08(m,2H).
13C?NMR(CDCl 3,300MHz)δ:166.2,150.0,149.3,146.2,132.9,130.4,129.6,128.4,113.5,111.1,108.5,68.6,48.7,45.7,39.7,33.1,26.7,21.0,16.2.
Embodiment 10
The preparation method of 14-(4-tolyl acid)-β-elemi alcohol ester (compound 10)
3mmol 14-β-elemol is dissolved in 10mL anhydrous methylene chloride, adds 0.3mmol DMAP, 0.3mmol EDCI and 4mmol 4-tolyl acid, normal-temperature reaction 14h.Reaction solution is with 10% salt acid elution 3 times, and concentrated dichloromethane layer obtains weak yellow liquid.With sherwood oil: ethyl acetate=300:1 (V:V) column chromatography, obtain colorless liquid product, productive rate is 62%.
1H?NMR(CDCl 3,300MHz)δ:1.04(s,3H),1.42-1.69(m,6H),1.75(s,3H),1.93-2.08(m,1H),2.10-2.16(m,1H),2.41(s,3H),4.71(s,4H),4.93(s,2H),4.97(d,J＝4.1Hz,1H),5.24(s,1H),5.81(dd,J 1＝17.7Hz,J 2＝10.5Hz,1H),7.23(d,J＝8.3Hz,2H),7.95(d,J＝8.3Hz,2H).
13C?NMR(CDCl 3,300MHz)δ:166.2,150.0,149.3,146.3,143.6,129.6,129.1,113.3,111.0,108.5,68.4,48.6,45.7,39.7,33.1,26.7,21.6,21.1,16.2.
Embodiment 11
The preparation method of 14-(4-methoxybenzoic acid)-β-elemi alcohol ester (compound 11)
3mmol 14-β-elemol is dissolved in 10mL anhydrous methylene chloride, adds 0.3mmol DMAP, 0.3mmol EDCI and 4mmol 4-methoxybenzoic acid, normal-temperature reaction 14h.Reaction solution is with 10% salt acid elution 3 times, and concentrated dichloromethane layer obtains weak yellow liquid.With sherwood oil: ethyl acetate=40:1 (V:V) column chromatography, obtain colorless liquid product, productive rate is 60%.
1H?NMR(CDCl 3,300MHz)δ:0.96(s,3H),1.34-1.63(m,6H),1.67(s,3H),1.85-1.95(m,1H),2.02-2.07(m,1H),3.78(s,3H),4.62(s,3H),4.64(s,1H),4.85(s,2H),4.90(d,J＝3.8Hz,1H),5.16(s,1H),5.74(dd,J 1＝17.7Hz,J 2＝10.5Hz,1H),6.84(d,J＝8.8Hz,2H),7.94(d,J＝8.8Hz,2H).
13C?NMR(CDCl 3,300MHz)δ:162.4,149.0,148.3,145.3,130.6,112.6,112.2,110.0,107.4,67.3,54.4,47.6,44.7,38.7,32.1,25.7,20.0,15.2.
Embodiment 12
The preparation method of 14-(2-chloro-benzoic acid)-β-elemi alcohol ester (compound 12)
3mmol 14-β-elemol is dissolved in 10mL anhydrous methylene chloride, adds 0.3mmol DMAP, 0.3mmol EDCI and 4mmol 2-chloro-benzoic acid, normal-temperature reaction 14h.Reaction solution is with 10% salt acid elution 3 times, and concentrated dichloromethane layer obtains weak yellow liquid.With sherwood oil: ethyl acetate=200:1 (V:V) column chromatography, obtain colorless liquid product, productive rate is 80%.
1H?NMR(CDCl 3,300MHz)δ:1.03(s,3H),1.43-1.69(m,6H),1.75(s,3H),1.93-2.00(m,1H),2.16-2.21(m,1H),4.69-4.80(m,4H),4.93-4.99(m,3H),5.28(s,1H),5.82(dd,J 1＝17.8Hz,J 2＝10.5Hz,1H),7.28-7.34(m,1H),7.38-7.47(m,2H),7.84(dd,J 1＝7.6Hz,J 2＝1.0Hz,1H).
13C?NMR(CDCl 3,300MHz)δ:165.4,150.0,149.3,145.8,132.5,131.5,131.1,126.6,114.5,111.1,108.4,69.6,48.4,45.7,39.8,39.7,33.1,26.7,21.1,16.0.
Embodiment 13
The preparation method of 14-(4-chloro-benzoic acid)-β-elemi alcohol ester (compound 13)
3mmol 14-β-elemol is dissolved in 10mL anhydrous methylene chloride, adds 0.3mmol DMAP, 0.3mmol EDCI and 4mmol 4-chloro-benzoic acid, normal-temperature reaction 14h.Reaction solution is with 10% salt acid elution 3 times, and concentrated dichloromethane layer obtains weak yellow liquid.With sherwood oil: ethyl acetate=200:1 (V:V) column chromatography, obtain colorless liquid product, productive rate is 77%.
1H?NMR(CDCl 3,300MHz)δ:1.04(s,3H),1.32-1.70(m,6H),1.75(s,3H),1.94-2.02(m,1H),2.09-2.14(m,1H),4.72(s,4H),4.94(d,J＝4.4Hz,2H),4.98(d,J＝4.4Hz,1H),5.23(s,1H),5.81(dd,J 1＝17.7Hz,J 2＝10.5Hz,1H),7.41(d,J＝8.4Hz,2H),7.99(d,J＝8.4Hz,2H).
13C?NMR(CDCl 3,300MHz)δ:165.3,150.0,149.2,146.0,139.4,131.0,128.7,113.6,111.1,108.5,68.8,48.7,45.7,39.7,39.6,33.1,26.7,21.0,16.1.
Embodiment 14
The preparation method of 14-(3-fluorobenzoic acid)-β-elemi alcohol ester (compound 14)
3mmol 14-β-elemol is dissolved in 10mL anhydrous methylene chloride, adds 0.3mmol DMAP, 0.3mmol EDCI and 4mmol 3-fluorobenzoic acid, normal-temperature reaction 14h.Reaction solution is with 10% salt acid elution 3 times, and concentrated dichloromethane layer obtains weak yellow liquid.With sherwood oil: ethyl acetate=200:1 (V:V) column chromatography, obtain colorless liquid product, productive rate is 90%.
1H?NMR(CDCl 3,300MHz)δ:1.04(s,3H),1.43-1.71(m,6H),1.75(s,3H),1.90-2.15(m,2H),4.73(s,4H),4.94-5.00(m,3H),5.24(s,1H),5.81(dd,J 1＝17.8Hz,J 2＝10.4Hz,1H),7.23-7.29(m,1H),7.39-7.46(m,1H),7.71-7.75(m,1H),7.84-7.87(m,1H).
13C?NMR(CDCl 3,300MHz)δ:164.2,150.0,149.2,145.9,130.1,130.0,125.4,125.3,120.1,119.8,116.7,116.3,113.7,111.1,108.5,68.9,48.7,45.7,39.7,39.6,33.1,26.7,21.0,16.1.
Embodiment 15
The preparation method of 14-(4-fluorobenzoic acid)-β-elemi alcohol ester (compound 15)
3mmol 14-β-elemol is dissolved in 10mL anhydrous methylene chloride, adds 0.3mmol DMAP, 0.3mmol EDCI and 4mmol 4-fluorobenzoic acid, normal-temperature reaction 14h.Reaction solution is with 10% salt acid elution 3 times, and concentrated dichloromethane layer obtains weak yellow liquid.With sherwood oil: ethyl acetate=200:1 (V:V) column chromatography, obtain colorless liquid product, productive rate is 70%.
1H?NMR(CDCl 3,300MHz)δ:1.04(s,3H),1.43-1.70(m,6H),1.75(s,3H),1.92-2.17(m,2H),4.72(s,4H),4.94(s,1H),4.95(s,1H),4.98(d,J＝4.1Hz,1H),5.23(s,1H),5.81(dd,J 1＝17.7Hz,J 2＝10.5Hz,1H),7.08-7.14(m,2H),8.05-8.10(m,2H).
13C?NMR(CDCl 3,300MHz)δ:165.2,150.0,149.2,146.2,132.2,132.1,115.7,115.4,113.5,111.1,108.5,68.7,48.7,45.7,39.7,39.6,33.1,26.7,21.0,16.1.
Embodiment 16
The preparation method of 14-(4-nitrobenzoic acid)-β-elemi alcohol ester (compound 16)
3mmol 14-β-elemol is dissolved in 10mL anhydrous methylene chloride, adds 0.3mmol DMAP, 0.3mmol EDCI and 4mmol 4-nitrobenzoic acid, normal-temperature reaction 14h.Reaction solution is with 10% salt acid elution 3 times, and concentrated dichloromethane layer obtains weak yellow liquid.With sherwood oil: ethyl acetate=200:1 (V:V) column chromatography, obtain colorless liquid product, productive rate is 80%.
1H?NMR(CDCl 3,300MHz)δ:1.04(s,3H),1.41-1.71(m,6H),1.75(s,3H),1.94-2.00(m,1H),2.10-2.17(m,1H),4.73(s,2H),4.78(s,2H),4.95(s,1H),4.98(s,1H),4.99(d,J＝4.1Hz,1H),5.25(s,1H),5.81(dd,J 1＝17.7Hz,J 2＝10.5Hz,1H),8.23(d,J＝8.9Hz,2H),8.30(d,J＝8.9Hz,2H).
13C?NMR(CDCl 3,300MHz)δ:164.3,150.6,149.8,149.2,145.6,135.7,130.7,123.6,114.0,111.3,108.6,69.4,48.7,45.7,39.8,39.7,33.1,26.7,21.0,16.1.
Embodiment 17
The preparation method of 14-(styracin)-β-elemi alcohol ester (compound 17)
3mmol 14-β-elemol is dissolved in 10mL anhydrous methylene chloride, adds 0.3mmol DMAP, 0.3mmol EDCI and 4mmol styracin, normal-temperature reaction 14h.Reaction solution is with 10% salt acid elution 3 times, and concentrated dichloromethane layer obtains weak yellow liquid.With sherwood oil: ethyl acetate=200:1 (V:V) column chromatography, obtain colorless liquid product, productive rate is 69%.
1H?NMR(CDCl 3,300MHz)δ:1.03(s,3H),1.44-1.66(m,6H),1.75(s,3H),1.97-2.13(m,2H),4.62(s,2H),4.73(s,2H),4.92(s,1H),4.94(s,1H),4.98(s,1H),5.21(s,1H),5.81(dd,J 1＝17.8Hz,J 2＝10.4Hz,1H),6.47(d,J＝16.0Hz,1H),7.37-7.39(m,3H),7.52-7.53(m,2H),7.70(d,J＝16.0Hz,1H).
13C?NMR(CDCl 3,300MHz)δ:166.6,150.0,149.3,146.2,144.9,134.5,130.3,128.9,128.1,118.1,113.4,111.0,108.5,68.4,48.5,45.7,39.7,33.1,29.7,26.7,21.1,16.1.
Embodiment 18
The preparation method of 14-(4-fluoro cinnamic acid)-β-elemi alcohol ester (compound 18)
3mmol 14-β-elemol is dissolved in 10mL anhydrous methylene chloride, adds 0.3mmol DMAP, 0.3mmol EDCI and 4mmol 4-fluoro cinnamic acid, normal-temperature reaction 14h.Reaction solution is with 10% salt acid elution 3 times, and concentrated dichloromethane layer obtains weak yellow liquid.With sherwood oil: ethyl acetate=200:1 (V:V) column chromatography, obtain colorless liquid product, productive rate is 65%.
1H?NMR(CDCl 3,300MHz)δ:1.02(s,3H),1.42-1.65(m,6H),1.75(s,3H),1.93-2.03(m,1H),2.07-2.12(m,1H),4.62(s,2H),4.73(s,2H),4.92(s,1H),4.93(s,1H),4.97(d,J＝1.4Hz,1H),5.20(s,1H),5.80(dd,J 1＝17.8Hz,J 2＝10.4Hz,1H),6.40(d,J＝16.0Hz,1H),7.05-7.10(m,2H),7.50-7.54(m,2H),7.66(d,J＝16.0Hz,1H).
13C?NMR(CDCl 3,300MHz)δ:165.6,150.0,149.3,146.2,143.6,130.0,129.9,117.8,116.2,115.9,113.4,111.0,110.0,68.3,48.5,45.7,39.7,33.1,26.7,21.0,16.1.
Embodiment 19
The preparation method of 14-(Whitfield's ointment)-β-elemi alcohol ester (compound 19)
3mmol 14-β-elemol is dissolved in 10mL anhydrous methylene chloride, adds 0.3mmol DMAP, 0.3mmol EDCI and 4mmol Whitfield's ointment, normal-temperature reaction 14h.Reaction solution is with 10% salt acid elution 3 times, and concentrated dichloromethane layer obtains weak yellow liquid.With sherwood oil: ethyl acetate=40:1 (V:V) column chromatography, obtain colorless liquid product, productive rate is 73%.
1H?NMR(CDCl 3,300MHz)δ:1.04(s,3H),1.42-1.67(m,6H),1.75(s,3H),1.94-2.03(m,1H),2.10-2.16(m,1H),4.73(s,2H),4.75(s,2H),4.94-5.00(m,3H),5.25(s,1H),5.85(dd,J 1＝17.7Hz,J 2＝10.6Hz,1H),6.89(t,J＝8.4Hz,1H),6.98(d,J＝8.0Hz,1H),7.43-7.78(m,1H),7.87(dd,J 1＝8.0Hz,J 2＝1.6Hz,1H),10.77(s,1H).
13C?NMR(CDCl 3,300MHz)δ:169.7,161.8,150.0,149.2,145.6,135.7,129.8,119.2,117.6,114.1,112.6,111.2,108.5,68.8,48.6,45.7,39.8,39.7,33.1,26.7,21.0,16.1.
Embodiment 20
The preparation method of 14-(nicotinic acid)-β-elemi alcohol ester (compound 20)
3mmol 14-β-elemol is dissolved in 10mL anhydrous methylene chloride, adds 0.3mmol DMAP, 0.3mmol EDCI and 4mmol nicotinic acid, normal-temperature reaction 20h.Reaction solution is with 10% salt acid elution 3 times, and concentrated dichloromethane layer obtains weak yellow liquid.With sherwood oil: ethyl acetate=40:1 (V:V) column chromatography, obtain colorless liquid product, productive rate is 58%.
1H?NMR(CDCl 3,300MHz)δ:1.04(s,3H),1.43-1.67(m,6H),1.75(s,3H),1.95-2.03(m,1H),2.11-2.17(m,1H),4.73(s,2H),4.77(s,2H),4.94(s,1H),4.97(s,1H),4.99(d,J＝4.8Hz,1H),5.25(s,1H),5.81(dd,J 1＝17.7Hz,J 2＝10.4Hz,1H),7.40(dd,J 1＝7.9Hz,J 2＝4.9Hz,1H),8.30-8.34(m,1H),8.79(dd,J 1＝4.7Hz,J 2＝1.3Hz,1H),9.26(s,1H).
13C?NMR(CDCl 3,300MHz)δ:164.8,153.4,150.9,149.9,149.2,145.7,137.1,126.2,123.3,113.9,111.2,108.5,69.0,48.6,45.7,39.7,39.6,33.1,26.7,21.0,16.0.
Embodiment 21
The preparation method of 14-(γ-picolinic acid)-β-elemi alcohol ester (compound 21)
3mmol 14-β-elemol is dissolved in 10mL anhydrous methylene chloride, adds 0.3mmol DMAP, 0.3mmol EDCI and 4mmol γ-picolinic acid, normal-temperature reaction 20h.Reaction solution is with 10% salt acid elution 3 times, and concentrated dichloromethane layer obtains weak yellow liquid.With sherwood oil: ethyl acetate=40:1 (V:V) column chromatography, obtain colorless liquid product, productive rate is 85%.
1H?NMR(CDCl 3,300MHz)δ:1.04(s,3H),1.43-1.71(m,6H),1.75(s,3H),1.94-2.03(m,1H),2.10-2.17(m,1H),4.73(s,2H),4.76(s,2H),4.94(s,1H),4.97(s,1H),4.98(d,J＝4.5Hz,1H),5.24(s,1H),5.80(dd,J 1＝17.7Hz,J 2＝10.4Hz,1H),7.86(d,J＝5.6Hz,2H),8.79(d,J＝5.6Hz,2H).
13C?NMR(CDCl 3,300MHz)δ:164.7,150.6,149.9,149.2,145.6,137.5,122.6,114.0,111.2,108.5,69.3,48.7,45.7,39.7,39.6,33.1,26.7,21.0,16.1.
Embodiment 22
The preparation method of 14-(furancarboxylic acid)-β-elemi alcohol ester (compound 22)
3mmol 14-β-elemol is dissolved in 10mL anhydrous methylene chloride, adds 0.3mmol DMAP, 0.3mmol EDCI and 4mmol furancarboxylic acid, normal-temperature reaction 15h.Reaction solution is with 10% salt acid elution 3 times, and concentrated dichloromethane layer obtains weak yellow liquid.With sherwood oil: ethyl acetate=100:1 (V:V) column chromatography, obtain colorless liquid product, productive rate is 83%.
1H?NMR(CDCl 3,300MHz)δ:0.95(s,3H),1.39-1.58(m,6H),1.67(s,3H),1.84-1.94(m,1H),2.01-2.06(m,1H),4.63(s,3H),4.64(s,1H),4.85(s,2H),4.90(d,J＝3.2Hz,1H),5.16(s,1H),5.73(dd,J 1＝17.7Hz,J 2＝10.5Hz,1H),6.44(q,J＝1.7Hz,1H),7.11(dd,J 1＝3.5Hz,J 2＝0.8Hz,1H),7.51(q,J＝0.8Hz,1H).
13C?NMR(CDCl 3,300MHz)δ:157.3,149.0,148.2,145.3,144.8,116.8,112.7,110.8,110.1,107.4,67.3,47.5,44.7,38.7,32.0,25.6,20.0,15.1.
Embodiment 23
The preparation method of succinic acid two (14-β-elemol) ester (compound 23)
6mmol 14-β-elemol is dissolved in 10mL anhydrous methylene chloride, adds 0.3mmol DMAP, 0.6mmol EDCI and 3mmol Succinic anhydried, normal-temperature reaction 8h.Reaction solution is with 10% salt acid elution 3 times, and concentrated dichloromethane layer obtains weak yellow liquid.With sherwood oil: ethyl acetate=100:1 (V:V) column chromatography, obtain colorless liquid product, productive rate is 75%.
1H?NMR(CDCl 3,300MHz)δ:0.92(s,6H),1.33-1.65(m,12H),1.67(s,6H),1.85-1.99(m,4H),2.61(s,4H),4.43(s,4H),4.64(s,4H),4.81(s,2H),4.82(d,J＝3.5Hz,2H),4.87(s,2H),5.06(s,2H),5.68(dd,J 1＝17.8Hz,J 2＝10.5Hz,2H).
13C?NMR(CDCl 3,300MHz)δ:170.8,149.0,148.3,144.9,112.5110.0,107.5,67.4,47.4,44.6,38.7,32.0,28.2,25.7,20.0,15.0.
Embodiment 24
The preparation method of phthalic acid two (14-β-elemol) ester (compound 24)
6mmol 14-β-elemol is dissolved in 10mL anhydrous methylene chloride, adds 0.3mmol DMAP, 0.6mmol EDCI and 3mmol Tetra hydro Phthalic anhydride, normal-temperature reaction 10h.Reaction solution is with 10% salt acid elution 3 times, and concentrated dichloromethane layer obtains weak yellow liquid.With sherwood oil: ethyl acetate=100:1 (V:V) column chromatography, obtain colorless liquid product, productive rate is 70%.
1H?NMR(CDCl 3,300MHz)δ:0.94(s,6H),1.34-1.56(m,12H),1.67(s,6H),1.80-2.07(m,4H),4.60(s,2H),4.64(s,6H),4.85(s,4H),4.90(s,2H),5.14(s,2H),5.73(dd,J 1＝17.8Hz,J 2＝10.4Hz,2H),7.46-7.48(m,2H),7.65-7.68(m,2H).
13C?NMR(CDCl 3,300MHz)δ:166.1,149.0,148.3,144.8,130.0,127.9,113.0,110.1,107.4,68.4,47.5,44.6,38.7,32.0,25.7,20.0,15.0。

Claims (8)

1. general formula (I) or compound (II) or its pharmacologically acceptable salt pharmaceutically:
R wherein 1represent carboxyl, the C replacing arbitrarily 6-10aryl or C 4-9aromatic heterocyclic, heteroatoms is selected from N, O or S, and described substituting group is selected from halogen, OH, NO 2, CF 3, C 1-3alkyl or C 1-3alkoxyl group;
R 2represent 1 of replacement arbitrarily, 2-benzene two bases, 1,3-benzene two bases, Isosorbide-5-Nitrae-benzene two bases, 1,8-naphthalene two bases or 2,6-naphthalene, two bases, described substituting group is selected from halogen, OH, NO 2, CF 3, C 1-3alkyl, C 1-3alkoxyl group;
R 2expression-(CH also 2) n-, wherein n=0-10 ,-(CH 2) a-CHX-(CH 2) b-, X is selected from C 1-3straight-chain paraffin ,-(CH 2) a-(CH=CH) c-(CH 2) b-,-(CH 2) a-(CCH 3=CH) c-(CH 2) b-,-(CH 2) a-(CH=CCH 3) c-(CH 2) b-or-(CH 2) a-(C ≡ C) c-(CH 2) b-, a=0-10 wherein, b=0-10, c=0-10.
2. the compound of claim 1 or its pharmacy acceptable salt, wherein R 2represent CH 2, CH 2cH 2, CH 2cH 2cH 2, CH 2cH 2cH 2cH 2, CH 2cH 2cH 2cH 2cH 2, CH=CH, CH=CHCH 2, CH=CHCH 2cH 2, CH 2cH=CH, CH 2cH=CHCH 2, CH 2cH 2cH=CH, CH=C (CH 3), CH=C (CH 3) CH 2cH 2or replace arbitrarily 1,2-benzene two bases, 1,3-benzene two bases or Isosorbide-5-Nitrae-benzene two bases, described substituting group is selected from Cl, F, OH, NO 2, CF 3, CH 3or OCH 3.
3. the compound of claim 2 or its pharmacy acceptable salt, wherein R 2represent CH 2, CH 2cH 2, CH=CH, CH 2cH 2cH 2or 1,2-benzene, two bases.
4. the compound of claim 1 or its pharmacy acceptable salt, wherein R 1represent carboxyl, replace arbitrarily phenyl, pyridyl or furyl, described substituting group is selected from Cl, F, OH, NO 2, CF 3, CH 3or OCH 3.
5. the compound of claim 4 or its pharmacy acceptable salt, wherein R 1represent carboxyl, phenyl, 2-chloro-phenyl-, 4-chloro-phenyl-, 3-fluorophenyl, 4-fluorophenyl, 2-nitrophenyl, 4-nitrophenyl, 2-hydroxy phenyl, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, pyridyl or furyl.
6. the compound of claim 1 or its pharmacy acceptable salt are following arbitrary compound or its pharmacy acceptable salt:
4-(14-beta-elemene oxygen base)-4-ketobutyric acid;
5-(14-beta-elemene oxygen base)-4-oxopentanoie acid;
2-(14-beta-elemene oxygen base carbonyl) phenylformic acid;
14-(acetic acid)-β-elemi alcohol ester;
14-(propionic acid)-β-elemi alcohol ester;
14-(butyric acid)-β-elemi alcohol ester;
14-(Sorbic Acid)-β-elemi alcohol ester;
14-(phenylformic acid)-β-elemi alcohol ester;
14-(4-tolyl acid)-β-elemi alcohol ester;
14-(4-methoxybenzoic acid)-β-elemi alcohol ester;
14-(2-chloro-benzoic acid)-β-elemi alcohol ester;
14-(4-chloro-benzoic acid)-β-elemi alcohol ester;
14-(3-fluorobenzoic acid)-β-elemi alcohol ester;
14-(4-fluorobenzoic acid)-β-elemi alcohol ester;
14-(4-nitrobenzoic acid)-β-elemi alcohol ester;
14-(styracin)-β-elemi alcohol ester;
14-(4-fluoro cinnamic acid)-β-elemi alcohol ester;
14-(Whitfield's ointment)-β-elemi alcohol ester;
14-(nicotinic acid)-β-elemi alcohol ester;
14-(γ-picolinic acid)-β-elemi alcohol ester;
14-(furancarboxylic acid)-β-elemi alcohol ester;
Succinic acid two (14-β-elemol) ester;
Phthalic acid two (14-β-elemol) ester.
7. pharmaceutical composition, wherein contains compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of claim 1.
In claim 1 to 6 compound of any one or its pharmacy acceptable salt for the preparation of the purposes of medicine of the atherosclerotic disease for the treatment of.
CN201410377535.0A 2014-08-01 2014-08-01 Beta-elemene 14-site ramification and application of beta-elemene 14-site ramification in treating atherosclerosis Pending CN104119221A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016015480A1 (en) * 2014-08-01 2016-02-04 大连远大医药科技开发有限公司 Β-elemene 14-position derivative and application of same in the treatment of atherosclerosis
CN106928074A (en) * 2017-01-19 2017-07-07 石药集团远大(大连)制药有限公司 Isopropanolamine substituted beta elemene derivatives and its production and use
CN110683932A (en) * 2019-09-29 2020-01-14 杭州师范大学 Beta-elemene halide and preparation method thereof
CN112213400A (en) * 2019-07-09 2021-01-12 成都康弘药业集团股份有限公司 Method for detecting beta-elemene and related substances thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115594646B (en) * 2022-10-12 2024-03-26 石药集团远大(大连)制药有限公司 Beta-elemene hydrogen sulfide donor type derivative, preparation method and medical application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1844084A (en) * 2006-05-10 2006-10-11 沈阳药科大学 Beta-elemene amino acid or carboxylic acid derivatives and preparation process and use thereof
US20100120907A1 (en) * 2007-04-19 2010-05-13 Chandra Ulagaraj Singh Derivatives of amyris alcohols and eudesmol for treating cold sores and herpes

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104119221A (en) * 2014-08-01 2014-10-29 大连远大医药科技开发有限公司 Beta-elemene 14-site ramification and application of beta-elemene 14-site ramification in treating atherosclerosis

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1844084A (en) * 2006-05-10 2006-10-11 沈阳药科大学 Beta-elemene amino acid or carboxylic acid derivatives and preparation process and use thereof
US20100120907A1 (en) * 2007-04-19 2010-05-13 Chandra Ulagaraj Singh Derivatives of amyris alcohols and eudesmol for treating cold sores and herpes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JICHAO CHEN ET AL.: "Design, synthesis and antioxidant activity evaluation of novel β-elemene derivatives", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *

Cited By (6)

* Cited by examiner, † Cited by third party
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WO2016015480A1 (en) * 2014-08-01 2016-02-04 大连远大医药科技开发有限公司 Β-elemene 14-position derivative and application of same in the treatment of atherosclerosis
CN106928074A (en) * 2017-01-19 2017-07-07 石药集团远大(大连)制药有限公司 Isopropanolamine substituted beta elemene derivatives and its production and use
CN106928074B (en) * 2017-01-19 2018-12-18 石药集团远大(大连)制药有限公司 Isopropanolamine replaces beta-elemene derivatives and its preparation method and application
CN112213400A (en) * 2019-07-09 2021-01-12 成都康弘药业集团股份有限公司 Method for detecting beta-elemene and related substances thereof
CN110683932A (en) * 2019-09-29 2020-01-14 杭州师范大学 Beta-elemene halide and preparation method thereof
CN110683932B (en) * 2019-09-29 2022-05-27 杭州师范大学 Beta-elemene halide and preparation method thereof

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