CN106892892B - Fragrant oxygen acid derivative containing piperonyl cyclonene and preparation method thereof - Google Patents
Fragrant oxygen acid derivative containing piperonyl cyclonene and preparation method thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
- C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
The present invention provides a kind of fragrant oxygen acid derivative and preparation method thereof containing piperonyl cyclonene.Fragrant oxygen acid derivative provided by the invention containing piperonyl cyclonene can be applied to the cardiovascular medicament research and development with antiatherosclerosis for the treatment of, with the pharmaceutical active for significantly reducing total cholesterol and triglycerides, and with lesser side effect and there is lesser side effect.The preparation method of fragrant oxygen acid derivative provided by the invention containing piperonyl cyclonene, it is easy to operate, it is easy to implement, it can be completely used for the batch preparation of target compound, and cost is relatively low, is suitable for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical technology fields, it particularly relates to a kind of fragrant oxygen acid derivative containing piperonyl cyclonene.Together
When, the invention further relates to the preparation methods of such compound.
Background technique
Hyperlipidemia is the rich people's disease of modern society.With the improvement of living standards, eat less dynamic is a kind of state more, is caused in vivo
Fatty bulk deposition, heart, blood vessel can't bear the heavy load；And modern life rhythm is accelerated, and works and rests irregular, work, life stress
It increases, also makes the disease incidence of the cardiovascular and cerebrovascular diseases such as hypertension, hyperlipidemia high.Damage feature of the hyperlipemia to body
It is invisible strong, lasting progressive and overall impairment.Its main harm is to accelerate the atherosclerosis of whole body, is caused a variety of
Related disease.Cardiovascular and cerebrovascular disease caused by hyperlipidemia shows the characteristics of " more than four high one "." four is high " refers to that disease incidence is high, multiple
Hair rate is high, disability rate is high, the death rate is high；" more than one " refers to that complication is more, such as heart and brain atherosclerosis, coronary heart disease, high blood
Pressure, diabetes, insomnia, cerebral infarction, headstroke, encephalatrophy, dementia, hemiplegia, hemiplegia, paralysis, gout etc..
Current main lipid lowering agent there are several types of:
Cholic acid integrated agent, the common reducing blood lipid mechanism of this kind of medicine are to prevent cholic acid or cholesterol from intestinal absorption, promote gallbladder
Acid or cholesterol are discharged with excrement, promote the degradation of cholesterol.This kind of medicine has resinae, neomycin class, β-sitosterol and activity
Charcoal etc..Main cholic acid integrated agent has Cholestyramine (ChoIestyramine) also known as cholestyramine；Colestipol
(CoIestipol) also known as Colestid；Divistyramine (Divistyramine), is all resinae.
HMG-CoA reductase inhibitor, it is generally acknowledged that serum total cholesterol effect drops in cholic acid integrated agent, but because of side effect
More, patient is difficult to adhere to taking for a long time.3-hydroxyl-3-methyl glutaryl coenzyme A (HMG-CoA) of discovered in recent years is also
Reductase inhibitor can suppress the biosynthesis of cholesterol.HMG-CoA reductase inhibitor is applied alone, or joins with cholic acid integrated agent
With having more obvious curative effect to hypercholesterolemia.HMG-CoA reductase inhibitor is a kind of novel promising drop blood
Rouge medicine.Statins are mostly methyl hydroxyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor, and existing preparation has Lip river to cut down him
Spit of fland, Pravastatin, holds and cuts down statin and Atorvastatin etc. Simvastatin.
Niacin and its derivative, niacin (Nicotinic Acid also known as Niacin) belong to B family vitamin.When dosage is more than
As vitamin effect dosage when, can play the role of significantly adjusting blood lipid.The curative effect and dosage and clothes of niacin adjusting blood lipid
Blood lipid level before medicine is related, and blood lipid level is extremely more apparent, and medication dose is preferably big, and curative effect also becomes apparent from；Acipimox
(Acipimox) also known as oxygen first pyrrole asks piperazine, olbetam (Olbetam).It is a kind of new artificial synthesized nicotinic acid derivates, it
The scope of application is similar to niacin, but the duration compared with niacin with Anti-lipolytic effect is longer, and it is excellent that efficiency is stronger etc.
Point；Hexanicit (lnositolHexanicotinate) is the ester being combined by 1 molecule inositol and 6 molecule niacin.It should
Medicine slowly metabolism in vivo after intestinal absorption, is gradually hydrolyzed into niacin and inositol, then plays a role.It can mitigate with persistently
Peripheral blood vessel is expanded on ground, improves lipid-metabolism, and have solution fibrin, thrombus and blood coagulation resisting function, reducing blood lipid
Idicatio is identical as niacin.
Fibrates, it mainly passes through inhibition adenyl cyclase, reduces cAMP content in fat cell, inhibits fat
Tissue hydrolysis reduces non-esterified fatty acid levels in blood, causes liver VLDL to synthesize and secrete and reduces.It can make rouge egg simultaneously
The increased activity of white lipase accelerates the catabolism of VLDL and TG.These, make the content of VLDL, TG, LDL-C and TC in blood eventually
It reduces.In addition, it can also make TC in blood by inhibiting liver cell to the synthesis of cholesterol and increasing excretion of the cholesterol from enteron aisle
Content is reduced.In recent years, some derivatives for finding clofibrate, the advantages that being able to maintain its reducing blood lipid, and gall stone occurs etc.
Side effect is aobvious to be reduced.The ability and dosage difference of these derivatives adjusting blood lipid are larger.
Probucol also known as probacol, this medicine have highly lipophilic, can accumulate in adipose tissue, gradually from rouge after drug withdrawal
It is released in fat tissue.Effect can maintain several weeks.All prove that probucol plays the role of dropping TC and LDL-C in animals and human beings body, but
It can make the reduction of Serum HDL-C level simultaneously.On TG without influence.Its mechanism for adjusting blood lipid, fails to illustrate so far.
Fragrant oxygen alkanoic acid class stimulates lipoprotein lipase base by peroxide activator enzyme paraphyte activated receptor-α (PPAR- α)
The expression of cause, enhancing LDL (low-density lipoprotein) activity remove the lipoprotein that TG (triglycerides) is rich in blood plasma, to drop
Low TG and raising HDL-C (high-density lipoprotein) are horizontal, promote the antiport of cholesterol, and make LDL hypotype by small and dense
Grain is widely used in hyperlipidemia patient to convert is dredged greatly.PPAR- α is mainly distributed on the higher tissue of metabolic activity,
Such as liver, kidney, heart, musculature, also have in chrotoplast, smooth muscle cell, mononuclear macrophage and lymphocyte in the blood vessels
Expression.PPAR- α receptor after ligand activation, can increase HDL synthesis, reduce TG, regulation fatty acid peroxidase oxidation and
Mitochondrial oxidation, while being also adjustable the intake and storage of lipid.
Piperine and its derivative show good activity in terms of hypolipidemic activity.It is to cardiovascular work simultaneously
With appearing in the newspapers repeatly, including following effectiveness: myocardial nutrition is acted on, the extract of doses can play the effect of beta-receptor agonist
It answers, can increase coronary flow, improve myocardial metabolism；Improve myocardium resist oxygen lack, anti-sharp property myocardial ischemia, coronary dilatation, anti-arrhythmia；
Antifatigue and protection myocardial cells effect.
Some have preventive and therapeutic effect to atherosclerosis to the monomeric compound of natural drug and its plant origin, and safe
Property it is good, the disadvantage is that mechanism is unknown, work slow.To fibrate with natural constituent extract (such as cyclic piperonyl) progress
Modification, it is higher to synthesize pharmacological activity, thus preparation to angiocarpy have protective effect and study of anti-atherogenic effect and
The lower drug of side effect, this is with very high researching value, but few open reports occur both at home and abroad at present.
Summary of the invention
In view of the above problem of the existing technology, the purpose of the present invention is to provide one kind have good biological activity and
The fragrant oxygen acid derivative containing piperonyl cyclonene of Lipid-regulating effect.
To achieve the goals above, the fragrant oxygen acid derivative provided by the invention containing piperonyl cyclonene, with following general formula
(I) structural formula:
Wherein,
R1 is (- CH=CH -) n, n 0,1,2 or 3；
R2 is the alkyl of H or C1~C4.
Wherein, alkyl of the present invention includes straight chained alkyl and branched alkyl, such as methyl, ethyl or isopropyl
Deng.
In a preferred embodiment of the present invention, for leading to formula (I) compound represented, it is preferred that
R1 is 0,1 or 2；
R2 is H or ethyl.
In especially preferred embodiment of present invention, for leading to formula (I) compound represented, preferably with flowering structure
Formula (II), structure formula (III) and structure formula (IV) compound:
It is another object of the present invention to provide the preparation methods of compound (I) a kind of, and the synthetic route of this method is such as
Under:
Wherein R1 and R2 are as defined above, and X is halogen, reaction step are as follows:
(1) thionyl chloride is added dropwise under ice-water bath in compound (V), after being added dropwise, stirring a moment；Then, it is added dropwise to
Solvent is slowly heated to flow back, and back flow reaction 1-3 hours；
(2) excessive thionyl chloride is steamed, obtains white solid；The white solid is dissolved in tetrahydrofuran, it is spare；
(3) Uteramin is dissolved in NaOH aqueous solution, under ice-water bath, the solution of a dropping step (2) thereto,
Reaction is overnight；
(4) tetrahydrofuran is steamed, filters to obtain solid；The NaOH aqueous solution that concentration is 20% is added in solid, in 40~50
DEG C stirring 30 minutes, until solution clarify；It is acidified after cooling, filters, obtain filtration cakes torrefaction, obtain compound (VI)；
(5) compound (VI) is dissolved in ketone solvent, NaOH is added, in a moment, compound (VII) solution, mistake is added in stirring
Night reaction；
(6) excessive solvent is steamed, dissolves remaining solid with distilled water, acidification filters to obtain compound (I) crude product；
(7) NaOH solution is added dropwise in 50-60 DEG C of water-bath in the crude product of compound (I), until dissolution, is added active carbon,
Temperature is maintained to stir 30-60 minutes, filtering takes filtrate, is acidified, obtains the preliminary purification product of compound (I)；It recrystallizes to change repeatedly
Close object (I) sterling.
Preferably, it is n,N-Dimethylformamide that step (1), which selects solvent,.
Preferably, the solvent in step (5) is acetone.
Another object of the present invention is to provide the synthetic method of compound (I), and the synthesis step of this method is as follows:
(1) in ice-water bath, to the dichloromethane solution that oxalyl chloride is added dropwise in compound (V), after being added dropwise, stirring sheet
It carves；It is to slowly warm up to room temperature, is stirred to react 2-5 hours；
(2) excessive oxalyl chloride is steamed, obtains yellow solid；The yellow solid is dissolved in methylene chloride, it is spare；
(3) triethylamine is added dropwise in the dichloromethane solution of Uteramin, under ice-water bath, a dropping step thereto
(2) solution, reaction is overnight；
(4) 5% NaOH of the dichloromethane solution of step (3), extracts organic phase 3 times, merges aqueous, aqueous acidification
Afterwards, precipitating is filtered to obtain, compound (VI) is obtained；
(5) compound (VI) is dissolved in ketone solvent, K2CO3 and compound (VII) solution is added, is refluxed overnight；
(6) excessive ketone solvent is steamed, remaining solid is dissolved with distilled water, is extracted with ethyl acetate aqueous 3 times, is associated with
Machine layer；Ethyl acetate is evaporated off, solid is by recrystallizing to obtain compound (I).
Preferably, the solvent of step (5) is butanone.
A kind of pharmaceutical composition provided by the invention can connect comprising the above-mentioned fragrant oxygen acid derivative containing piperonyl cyclonene and pharmacy
By carrier.
Fragrant oxygen acid derivative provided by the invention containing piperonyl cyclonene can be used for treating hyperlipidemia related disease, preferably
It is that can be used for treating cardiovascular and antiatherosclerosis.
It is cardiovascular hard with anti-atherogenic that fragrant oxygen acid derivative provided by the invention containing piperonyl cyclonene can be applied to treatment
The medicament research and development of change has the pharmaceutical active for significantly reducing total cholesterol and triglycerides, and has lesser side effect.Separately
The preparation method of the outer fragrant oxygen acid derivative provided by the invention containing piperonyl cyclonene, it is easy to operate, it is easy to implement, it can use completely
It is prepared in the batch of target compound, and cost is relatively low, is suitable for industrialized production.
Specific embodiment
The preparation of 1 compound of embodiment (II)
The preparation of compound (II):
(1) by 2.0g, 3.4- methylene p-methoxybenzoic acid is under ice-water bath, about 0 DEG C or so, thionyl chloride 6ml is added dropwise, slowly
It is added dropwise, is added dropwise within about 30 minutes, after, stirring a moment；Then, 2 to 3 drop n,N-Dimethylformamide are added as catalysis
Agent is slowly heated to flow back, about 1 hour of whole process, and back flow reaction 2 hours.
(2) excessive thionyl chloride is evaporated off by Rotary Evaporators, obtains white solid.Solid is dissolved in tetrahydrofuran about
It is spare in 30ml.
(3) 1.5g Uteramin is dissolved in 2.3g NaOH aqueous solution 30ml, under ice-water bath, is added dropwise thereto (2)
Solution, whole process had white smoke generation for about 30 minutes, was stirred to react overnight.
(4) tetrahydrofuran is steamed by Rotary Evaporators, remaining aqueous filters to obtain solid.After solid is dry, by itself plus
Enter to 20%NaOH aqueous solution, stirred 30 minutes in 40-50 DEG C, until solution is clarified.It is put into refrigerator freezing to be allowed to cool, with dilute sulphur
Acid acidification has solid precipitation.It filters, obtains filter cake, it is dry, obtain product 2.47g, yield about 71%.
(5) 0.2g step (4) product is dissolved in acetone 30ml, and 0.5g NaOH fine powder (ground with mortar), stirring a moment is added
Afterwards about after ten minutes, chloroform 0.25ml, reaction overnight are slowly dropped into.
(6) excessive chloroform and acetone are steamed with Rotary Evaporators, remaining solid distilled water dissolves remaining solid, dilute
Sulfuric acid acidification, filters to obtain solid 0.162g, yield about 62%.
(7) NaOH is added dropwise in 60 DEG C of water-bath in solid, until dissolution, is added a little active carbon, maintains temperature stirring 30
Minute, filtering takes filtrate, is acidified, obtains the preliminary purification product of compound (II).Sterling 0.14g is recrystallized to obtain repeatedly, and yield is about
55%.
The preparation of 2 compound of embodiment (II)
The preparation of compound (II):
(1), by 1.0g 3.4- methylene p-methoxybenzoic acid, 0.7g Uteramin and 1.5g HAUT, N, N- diformazan are dissolved in
In base formamide 20ml, solution clear is stirred overnight reaction.
(2) reaction solution adds water 60ml, and aqueous is extracted 3 times, each 90ml with chloroform, combining extraction liquid, will with Rotary Evaporators
Extraction liquid layer is rotated to about 80ml, with 5% NaOH aqueous solution extraction organic phase, each 60ml, until organic layer is without color, about 4
It is secondary, merge aqueous, aqueous filters to obtain precipitating after dilute sulfuric acid is acidified, and obtains about 1.44g after product drying, yield is about 84%.
(3) 0.2g step (2) product is dissolved in acetone 30ml, and 0.5g NaOH fine powder (ground with mortar), stirring a moment is added
Afterwards about after ten minutes, chloroform 0.25ml, reaction overnight are slowly dropped into.
(4) excessive chloroform and acetone are steamed with Rotary Evaporators, remaining solid distilled water dissolves remaining solid, dilute
Sulfuric acid acidification, filters to obtain solid 0.162g, yield about 62%.
The preparation of 3 compound of embodiment (III)
The preparation of compound (III):
(1) molten by 1.0g 3- (3.4- methylene phenyl) 2- acrylic acid, 0.7g Uteramin and 1.4g HAUT
In n,N-Dimethylformamide 20ml, reaction solution is gradually become cloudy, and is stirred overnight reaction.
(2) reaction solution adds water 60ml, and reaction solution clarification is then extracted 3 times, each 80ml, combining extraction liquid with chloroform, used
Rotary Evaporators are threaded to chloroform residue about 90ml, colourless to organic phase with 5% NaOH extraction organic phase, totally 3 each 80ml,
Merge aqueous to filter to obtain precipitating after the acidification of aqueous dilute sulfuric acid, obtains 1.32g after product drying, yield about 82%.
(3) 0.2g step (2) product is dissolved in butanone 30ml, and 0.5g K2CO3 and ethyl α bromoisobutyrate 0.5ml is added, point
Twice plus first time 0.3ml, it after 8 hours plus second of 0.2ml, is refluxed overnight.
(4) excessive butanone is steamed with Rotary Evaporators, dissolve remaining solid with distilled water 30ml, be extracted with ethyl acetate
Aqueous 3 times, each 40ml, merge organic layer.Ethyl acetate is evaporated off, solid is by recrystallizing to obtain compound (III), dry weighing
0.153g, yield about 56%.
The preparation of 4 compound of embodiment (III)
The preparation of compound (III):
(1) by 1.5g 3- (3.4- methylene phenyl) 2- acrylic acid under ice-water bath, about 0 DEG C or so, it is sub- that dichloro is added dropwise
Sulfone 6ml, is slowly added dropwise, and is added dropwise within about 30 minutes, after, stirring a moment；Then, 2 to 3 drop N, N- dimethyl formyl is added
Amine is slowly heated to flow back as catalyst, about 1 hour of whole process, and back flow reaction 2 hours.
(2) excessive thionyl chloride is steamed with Rotary Evaporators, obtain yellow solid.Solid is dissolved in methylene chloride 20ml
In, it is spare.
(3) triethylamine about 1ml, under ice-water bath, Xiang Qi are added dropwise in the dichloromethane solution 30ml of 1.0g Uteramin
The solution of middle dropwise addition (2), reaction is overnight.There is white smoke generation during being added dropwise.
(4) methylene chloride reaction solution is extracted organic phase 3 times, each 60ml with 5% NaOH, merges aqueous, aqueous dilute sulfuric acid
It after acidification, filters to obtain precipitating, obtains solid 0.757g, yield about 69% after obtaining product drying
(5) 0.2g step (4) product is dissolved in butanone 30ml, and 0.5g K2CO3 and ethyl α bromoisobutyrate 0.5ml is added, point
Twice plus first time 0.3ml, it after 8 hours plus second of 0.2ml, is refluxed overnight.
(6) excessive butanone is steamed with Rotary Evaporators, dissolve remaining solid with distilled water 30ml, be extracted with ethyl acetate
Aqueous 3 times, each 40ml, merge organic layer.Ethyl acetate is evaporated off, solid is by recrystallizing to obtain compound (III), dry weighing
0.158g, yield about 58%.
The preparation of 5 compound of embodiment (IV)
The preparation of compound (IV):
(1) by 1.0g 5- (3.4- methylene phenyl) 2,4- pentadienoic acid, 0.6g Uteramin and 1.4g
HAUT is dissolved in n,N-Dimethylformamide 30ml, and solution clarification is stirred overnight reaction.
(2) reaction solution adds water 60ml, and rear reaction solution is muddy, is then extracted 3 times, each 60ml with chloroform, combining extraction liquid,
Chloroform is evaporated off to about residue 80ml with Rotary Evaporators, is extracted organic phase 3 times, each 60ml with 5% NaOH, organic phase is several
It is colourless, merge aqueous, aqueous filters to obtain precipitating after dilute sulfuric acid is acidified, and obtains the dry weighing 1.36g of product, and yield is about
88%.
(3) 0.2g step (2) product is dissolved in butanone 20ml, and 0.5g K2CO3 and ethyl α bromoisobutyrate 0.5ml is added, point
Twice plus first time 0.3ml, it after 8 hours plus second of 0.2ml, is refluxed overnight.
(4) Rotary Evaporators steam excessive butanone, dissolve remaining solid with distilled water 30ml, water is extracted with ethyl acetate
Liquid 3 times, each 30ml, merge organic layer.Ethyl acetate is evaporated off, solid is by recrystallizing to obtain compound (IV), dry weighing
0.160g, yield are about 60%.
The preparation of 6 compound of embodiment (IV)
The preparation of compound (IV):
(1) in ice-water bath, about 0 DEG C, drop is slowly added dropwise to 1.0g 5- (3.4- methylene phenyl) 2,4- pentadienoic acid
The dichloromethane solution 20ml (containing oxalyl chloride 0.8ml) for adding oxalyl chloride, after being added dropwise, stirring a moment；Room temperature is to slowly warm up to,
It is stirred to react 4 hours.
(2) excessive oxalyl chloride and methylene chloride are steamed by Rotary Evaporators, obtain yellow solid.Solid is dissolved in two
It is spare in chloromethanes 20ml.
(3) 1.0ml triethylamine is added dropwise in the dichloromethane solution of 0.7g Uteramin to drip thereto under ice-water bath
Add solution (2), is stirred to react overnight.
(4) methylene chloride reaction solution is extracted organic phase 3 times with 5% NaOH, and each 50ml, organic layer is almost colourless later,
Merge aqueous, after aqueous is acidified with dilute sulfuric acid, filter to obtain precipitating, obtains the dry weighing 1.19g of product, yield is about 77%
(5) 0.2g step (4) product is dissolved in butanone 20ml, and 0.5g K2CO3 and ethyl α bromoisobutyrate 0.5ml is added, point
Twice plus first time 0.3ml, it after 8 hours plus second of 0.2ml, is refluxed overnight.
(6) Rotary Evaporators steam excessive butanone, dissolve remaining solid with distilled water 30ml, water is extracted with ethyl acetate
Liquid 3 times, each 30ml, merge organic layer.Ethyl acetate is evaporated off, solid is by recrystallizing to obtain compound (IV), dry weighing
0.169g, yield are about 62%.
The pharmacodynamic evaluation of reducing blood lipid in 7 Mice Body of embodiment
Kun ming white mouse is fed with high lipid food, causes hyperlipidemia.New drug group gives 100mg/kg's respectively daily
The distilled water solution of different compounds (II, III, IV)；Positive drug group gives fenofibrate micronized capsules, dosage 200mg/
Kg is prepared with distilled water；Normal group and model group with hyperlipemia give isometric distilled water.One time a day, continuous gavage
14d.After 14d is administered, 12h is deprived of food but not water before last dose, eyeball takes blood after 1h is administered, 10min is centrifuged with 4200r/min,
Serum is isolated, according to total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-c), low density lipoprotein
Protein cholesterol (LDL-c) RNA isolation kit is loaded respectively at 96 orifice plates, microplate reader measure mice serum TC, TG, HDL-c and
LDL-c is horizontal.It the results are shown in Table 1:
Table 1, new influence of the fragrant oxygen acid derivative to lipid of mice level containing piperonyl cyclonene
Note: " # " indicates P < 0.05, significant difference compared with Normal group；" * " indicates the P < compared with hyperlipidemia model group
0.05, significant difference.
Above embodiments further illustrate the contents of the present invention, but should not be construed as limiting the invention.It is not carrying on the back
In the case where from spirit of that invention and essence, to the modifications or substitutions that the method for the present invention, step or condition are done, this hair is belonged to
Bright scope.
Claims (10)
1. a kind of formula (I) compound represented logical as follows:
Wherein, R1For (- CH=CH -) n, n 0,1,2 or 3；R2For the alkyl of H or C1~C4.
2. logical formula (I) compound according to claim 1, which is characterized in that n 0,1 or 2；R2For H or ethyl.
3. logical formula (I) compound according to claim 2, which is characterized in that the structural formula of the compound are as follows:
4. a kind of preparation method of compound described in claim 1 (I), which is characterized in that the synthetic route of this method is as follows:
Wherein X is halogen, reaction step are as follows:
(1) thionyl chloride is added dropwise under ice-water bath in compound (V), after being added dropwise, stirring a moment；Then, it is added dropwise to solvent,
It is slowly heated to flow back, back flow reaction 1-3 hours；
(2) excessive thionyl chloride is steamed, obtains white solid；The white solid is dissolved in tetrahydrofuran, it is spare；
(3) Uteramin is dissolved in NaOH aqueous solution, under ice-water bath, the solution of a dropping step (2), reacts thereto
Overnight；
(4) tetrahydrofuran is steamed, filters to obtain solid；The NaOH aqueous solution that concentration is 20% is added in solid, stirs in 40~50 DEG C
It mixes 30 minutes, until solution is clarified；It is acidified after cooling, filters, obtain filtration cakes torrefaction, obtain compound (VI)；
(5) compound (VI) is dissolved in ketone solvent, NaOH is added, in a moment, compound (VII) solution is added in stirring, anti-overnight
It answers；
(6) excessive solvent is steamed, dissolves remaining solid with distilled water, acidification filters to obtain compound (I) crude product；
(7) NaOH solution is added dropwise in 50-60 DEG C of water-bath in the crude product of compound (I), until dissolution, is added active carbon, maintains
Temperature stirs 30-60 minutes, and filtering takes filtrate, is acidified, obtains the preliminary purification product of compound (I)；Compound is recrystallized to obtain repeatedly
(I) sterling.
5. the preparation method of compound (I) according to claim 4, which is characterized in that it is N, N- that step (1), which selects solvent,
Dimethylformamide.
6. the preparation method of compound (I) according to claim 4, which is characterized in that the solvent in step (5) is third
Ketone.
7. a kind of preparation method of compound described in claim 1 (I), which is characterized in that
The synthetic route of this method is as follows:
Wherein X is halogen, and reaction step is as follows:
(1) in ice-water bath, to the dichloromethane solution that oxalyl chloride is added dropwise in compound (V), after being added dropwise, stirring a moment；
It is to slowly warm up to room temperature, is stirred to react 2-5 hours；
(2) excessive oxalyl chloride is steamed, obtains yellow solid；The yellow solid is dissolved in methylene chloride, it is spare；
(3) triethylamine is added dropwise in the dichloromethane solution of Uteramin, under ice-water bath, a dropping step (2) thereto
Solution, reaction is overnight；
(4) 5% NaOH of the dichloromethane solution of step (3), extracts organic phase 3 times, merges aqueous, after aqueous acidification, mistake
Precipitating is filtered to obtain, compound (VI) is obtained；
(5) compound (VI) is dissolved in ketone solvent, K is added2CO3With compound (VII) solution, it is refluxed overnight；
(6) excessive ketone solvent is steamed, remaining solid is dissolved with distilled water, is extracted with ethyl acetate aqueous 3 times, merge organic
Layer；Ethyl acetate is evaporated off, solid is by recrystallizing to obtain compound (I).
8. the preparation method of compound (I) according to claim 7, which is characterized in that the solvent of step (5) is butanone.
9. a kind of pharmaceutical composition includes compound described in claim any one of 1-3 and pharmaceutically acceptable carrier.
10. compound described in claim any one of 1-3 is in preparation treatment hyperlipidemia and treatment angiocarpy and anti-artery
Application in the drug of atherosis.
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| JPS57171946A (en) * | 1981-04-17 | 1982-10-22 | Kaken Pharmaceut Co Ltd | Novel oxyacetic acid derivative, its preparation, and blood lipid level depressing agent containing said derivative as active component |
| CN1164585C (en) * | 2002-07-24 | 2004-09-01 | 广州市众为生物技术有限公司 | Xanthiphenyl ketamine or its salt and its preparing process |
| CN1166660C (en) * | 2002-07-24 | 2004-09-15 | 广州市众为生物技术有限公司 | Process for preparing N-methyl piperethanamine salt |
| CN100376243C (en) * | 2004-12-03 | 2008-03-26 | 内蒙古大学 | Application of compound of esters of piperic acid in preparing hypolipidemic or health products |
| CN1287785C (en) * | 2004-12-03 | 2006-12-06 | 内蒙古大学 | Use of pepper amide compound in preparation of drug or healthcare product for reducing blood fat |
| WO2011080313A1 (en) * | 2009-12-30 | 2011-07-07 | Universität Wien | Novel piperine derivatives as gaba - a receptors modulators |
| CN103130674B (en) * | 2011-12-03 | 2016-09-07 | 无锡枫华生物科技有限公司 | Prevention and the potential drug gx50 for the treatment of alzheimer's disease, the chemical synthesis process of gx51, gx52, gx180 |
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