CN101966172B - New purpose of caffeic acid and derivatives thereof - Google Patents
New purpose of caffeic acid and derivatives thereof Download PDFInfo
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- CN101966172B CN101966172B CN2009100601322A CN200910060132A CN101966172B CN 101966172 B CN101966172 B CN 101966172B CN 2009100601322 A CN2009100601322 A CN 2009100601322A CN 200910060132 A CN200910060132 A CN 200910060132A CN 101966172 B CN101966172 B CN 101966172B
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Abstract
The invention provides a new purpose of caffeic acid and derivatives thereof in preparing drugs of cranial nerves protective agent, wherein caffeic acid methyl ester, caffeic acid ethyl ester and 3, 4-diacetyl caffeic acid obtained by taking the caffeic acid as a raw material which is subject to structural modification have the obvious protective activity for the cranial nerves; the caffeic acid methyl ester and the 3, 4-diacetyl caffeic acid can penetrate a blood brain barrier and directly reaches to a target organ; and the derivatives are ideal candidate medicines of the cranial nerves protective agent.
Description
Technical field
The present invention relates to the new purposes of caffeic acid and derivant thereof.
Background technology
Apoplexy has another name called apoplexy; Be with unexpected confused servant, hemiplegia, crooked mouth and tongue, speech not smoothgoing puckery or in silence, hemianesthesia is primary symptom; And have onset anxious, change fast characteristics; Good sending out in a kind of disease of person in middle and old age is the common frdquently encountered disease of middle-aged and elderly people, and human existence and health in serious threat.Primary disease is equivalent to ischemic cerebrovascular (the Ischemic Cerebral vascular Disease of western medicine; ICVD); Also claim Ischemic Stroke, have higher case fatality rate and disability rate, human beings'health and life security (Rao Mingli in serious threat; Woods generation and. cerebrovascular disease. People's Health Publisher, 2002.172).As a kind of commonly encountered diseases, frequently-occurring disease, ICVD especially the limitation cerebral infarction with three big diseases that cause death of heart disease, malignant tumor majority state arranged side by side.Epidemiological study finds, China belong to one of this disease hotspot (Chen Jie. the epidemiology of cerebral infarction. practical cardio-cerebral-pulmo angiopathy magazine .2000,8 (3): 179～181).Motherland's medical science thinks, its sick position of apoplexy is at brain, and is closely related with the heart, kidney,liver,spleen, is the card of deficiency in origin and excess in superficiality, and etiology and pathogenesis is complicated, and deficiency in origin is deficiency of the liver and kindey, deficiency of vital energy insufficiency of blood; Mark is real to be liver-wind stirring up internally, and fire and wind stirring up each other is strongly fragrant in burning hot, and phlegm-damp is stopped up and contained, and finally causes the internal resistance of the expectorant stasis of blood, and with the mechanism of qi superinverse, upset empties, and hoodwinks key clearly, becomes excess in the upper and deficiency in the lower, the critical syndrome that negative and positive are not maintained mutually.The symptom of its suddenly confused servant's syncope can be included the category that key closes coma in again.According to statistics, in the syndrome-classification of apoplexy, syndrome of blood stasis is taken the status as the leading factor, account for more than 73% of apoplexy (Tao Genyu, Du Xiaoquan. the status [J] of benefiting QI for activating blood circulation method in the cerebral infarction disease. ShanXi Chinese Medicine Academy journal, 1998,21 (3): 1).Though the pathogenesis of cerebral infarction is complicated, to sum up to get up, principal contradiction is stagnation of blood stasis.Over nearly 10 years, in, doctor trained in Western medicine bound pair stasis cerebral infarction carried out deep clinical and experimentation, the sick curative effect of stasis cerebral infarction obtains certainly basically, its clinical report is also more.
In the treatment of acute ischemic cerebral apoplexy (AIS), the protectant effect of cranial nerve is to alleviate the primary cellular defect behind the ischemia, postpones nerve cell death, asks when striving for and recovers brain perfusion, extended treatment time window.
Caffeic acid mainly has antibiotic, antiviral, and central excitation, detoxifcation, Blood clotting, caffeic acid and derivant thereof also have effects such as antioxidation, are not used for the protectant relevant report of cranial nerve but still have caffeic acid and derivant thereof at present.
Summary of the invention
Technical scheme of the present invention has provided the new purposes of caffeic acid and derivant thereof, particularly, is the purposes in the protectant medicine of preparation cranial nerve.
The invention provides and relate to caffeic acid and the purposes of derivant in the protectant medicine of preparation cranial nerve thereof.
Wherein, described medicine is the medicine of treatment cerebral infarction.
Wherein, described caffeic acid derivant is caffeic methyl ester, caffeic acetate, 3,4-diacetyl caffeic acid.
The present invention also provides a kind of cranial nerve protective agent, and it is to be active component by the caffeic acid of effective dose and derivant thereof, adds the medicament that acceptable accessories is prepared from.
Described caffeic acid and derivant thereof are: caffeic methyl ester, caffeic acetate, 3,4-diacetyl caffeic acid.
Wherein, described medicament is ejection preparation or oral formulations.
Caffeic acid is caffeic methyl ester, the caffeic acetate, 3 that raw material mix is modified; 4-diacetyl caffeic acid all has obvious cranial nerve protection active; And caffeic methyl ester and 3; 4-diacetyl caffeic acid all can see through blood brain barrier, directly arrives target organ, is comparatively ideal cranial nerve protective agent drug candidate.
Obviously, according to foregoing of the present invention,,, can also make modification, replacement or the change of other various ways not breaking away under the above-mentioned basic fundamental thought of the present invention prerequisite according to the ordinary skill knowledge and the customary means of this area.
Below, foregoing of the present invention is remake further detailed description through the specific embodiment of embodiment form.But should this be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following instance.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
The specific embodiment
The preparation of embodiment 1 medicine of the present invention
Instrument GC/MS-QP5050A gas chromatograph-mass spectrometer (Tianjin, island company), SOR37 Fourier infrared spectrograph (BRUKER company); The same chapter 2 of NMR; XW-80A vortex mixer (west, Shanghai, Qingpu, Shanghai instrument plant), digital display thermostat water bath (Jin Cheng of Jintan City state wins experimental apparatus factory), R-124 Rotary Evaporators (BUCHI); SHZ-D circulation ability of swimming vacuum pump (Gongyi City gives magnificent instrument plant), YP202N electronic balance (Shanghai Precision Scientific Apparatus Co., Ltd) etc.
Reagent absolute methanol, dehydrated alcohol, phosphoric acid, acetic anhydride, concentrated sulphuric acid, ethyl acetate, calcium carbonate, n-octyl alcohol, sodium bicarbonate etc. (are analytical pure; Chongqing Chuan Dong chemical industry company limited chemical reagent factory); Column chromatography silica gel (100 ~ 200 orders, Haiyang Chemical Plant, Qingdao)
Reagent caffeic acid (Wuhan Basto Fine Chemical Co., Ltd, content is greater than 95%).
1 caffeic acetate's is synthetic
1.1 composition principle
Because this experiment is the preparation ester of low-carbon alcohol,, again reactant is carried out the direct esterification method of separation and purification so adopt caffeic acid and excess ethyl alcohol to have next time fluxion hour at concentrated sulfuric acid catalyst.Composition principle is following:
Caffeic acetate's structural formula
1.2 experimental procedure
Take by weighing caffeic acid 5.4g, place the 250mL round-bottomed flask, add dehydrated alcohol 80mL; After waiting to dissolve, add catalyst concentrated sulphuric acid 0.5mL and dehydrant anhydrous sodium sulfate 9g, 80 ℃ of stirring and refluxing 6 hours; Be cooled to room temperature then, add calcium carbonate 1.2g neutralisation of sulphuric acid, reclaim ethanol.Residue is used acetic acid ethyl dissolution, filters, and ethyl acetate layer is abandoned water layer with 2.5% sodium bicarbonate solution washing 3 times, and after the ethyl acetate layer reclaim under reduced pressure, residue is used ethyl alcohol recrystallization, obtains white crystals 3.35g, and recovery rate is 53.67%.M.p.152.8-155 ℃; UV: λ
Max(methanol) 220.8,242.0,326.2nm; IR (KBr) cm
-1: 3435 (ν
OH), 1659 (ν
OH), 1600 (ν conjugation
C=C), 1452 (ν
C=CAr), 1281 (ν
C-H);
1H-NMR (400MHz, DMSO-d
6): 7.47 (1H, d, J=15.9Hz, H-7), 7.04 (1H, d, J=2.0Hz, H-2), 7.00 (1H, dd, J=2.0,8.1Hz, H-6), 6.76 (1H, d, J=8.1Hz, H-5), 6.25 (1H, d, J=15.9Hz, H-8), 4.15 (2H, q, CH
2), 1.24 (3H, t, CH
3); MS m/z:208 [M
+], 163,145,135,134,117,89.Purity detecting: adopt the HPLC method.Condition: C
18Post, 30 ℃ of column temperatures, flow velocity 1mLmin
-1, wavelength 330nm, mobile phase: methanol-0.4% formic acid (1: 1).Record caffeic acetate's content greater than 98% with normalization method.
2 caffeic methyl ester's is synthetic
2.1 composition principle
Adopt caffeic acid and excessive methanol to have next time fluxion hour, again reactant is carried out the direct esterification method of separation and purification at concentrated sulfuric acid catalyst.Composition principle is following:
Caffeic methyl ester's structural formula
2.2 experimental procedure
Take by weighing caffeic acid 5.4g, place the 250mL round-bottomed flask, add absolute methanol 80mL; After waiting to dissolve, add catalyst concentrated sulphuric acid 0.5mL and dehydrant anhydrous sodium sulfate 9g, 80 ℃ of stirring and refluxing 6 hours; Be cooled to room temperature then, add calcium carbonate 1.2g neutralisation of sulphuric acid, reclaim methanol.Residue is used acetic acid ethyl dissolution, filters, and ethyl acetate layer is abandoned water layer with 2.5% sodium bicarbonate solution washing 3 times, and after the ethyl acetate layer reclaim under reduced pressure, residue is used recrystallizing methanol, obtains white crystals 4.77g, and recovery rate is 80.72%.M.p.163.8-166.0 ℃; UV: λ max (methano1) 219.7,242.0,326.2nm; IR (KBr) cm-1:3477 (ν OH), 1674 (ν OH), 1720 (ν C=O), 1607 (ν conjugation C=C), 1445 (ν C=C Ar), 1281 (ν C-H), 1242 (ν C-O-C); 1H-NMR (400MHz, DMSO-d6): 7.48 (1H, d, J=15.9Hz, H-7), 7.05 (1H, d, J=2.0Hz; H-2), 7.00 (1H, dd, J=2.0,8.1Hz, H-6), 6.67 (1H, d, J=8.1Hz; H-5), 6.26 (1H, d, J=15.9Hz, H-8), 3.69 (3H, s, CH3); MS m/z:194 [M+], 163,145,135,134,117,89,77; Purity detecting: adopt the HPLC method.Condition: C18 post, 30 ℃ of column temperatures, flow velocity 1mLmin-1, wavelength 330nm, mobile phase: methanol-0.4% formic acid (1: 1).Record caffeic methyl ester's content greater than 98% with normalization method.
Synthesizing of 3 caffeic acid acetylates
3.1 composition principle
Adopt caffeic acid and excessive acetic acid acid anhydride under the SPA catalytic condition, reacts (notes: the acyl-oxygen key that SPA catalysis makes anhydride is easy fracture more, generation acetyl group, raising productive rate); Again reactant is carried out the direct acidylate method of separation and purification
[60,61]Composition principle is following:
3,4-diacetyl caffeic acid structural formula
3.2 experimental procedure
Take by weighing caffeic acid 3.6g, place the 250mL round-bottomed flask, add acetic anhydride 20mL and catalyst SPA 0.5mL; In 60 ℃ of stirring and refluxing 1 hour, after reaction stops, reactant is poured in the frozen water; With ethyl acetate extraction three times (100mL * 3), ethyl acetate layer is washed with water to neutrality, the reclaim under reduced pressure ethyl acetate; Residue is used ethyl alcohol recrystallization, obtains white crystals 4.30g, and recovery rate is 81.49%.M.p.205.0-208.2 ℃; UV: λ
Max(methanol) 220.8,275.1nm; IR (KBr) cm
-1: 1767 (ν acetyl
C=O), 1690 (ν carboxylic acids
C=O), 1433 (ν
C=C Ar), 1116 (ν aromatic rings
C-O-C);
1H-NMR (400MHz, DMSO-d
6): δ: 7.663 (1H, d, J=1.6Hz, H-2), 7.632 (1H, dd, J=8.4,1.6Hz; H-6), 7.312 (1H, d, J=8.4Hz, H-5), 7.575 (1H, d, J=16.0Hz; H-7), 6.536 (1H, d, J=16.0Hz, H-8), 2.289 (3H, s, H-3-COCH
3), 2.283 (3H, s, H-4-COCH
3); MS m/z:264 [M
+], 222,180,134,77.Purity detecting: adopt the HPLC method.Condition: C
18Post, 30 ℃ of column temperatures, flow velocity 1mLmin
-1, wavelength 260nm, mobile phase: methanol-0.4% formic acid (1: 1).Record caffeic acid acetylate content greater than 98% with normalization method.
Below prove beneficial effect of the present invention through the test of pesticide effectiveness.
Test Example 1 The compounds of this invention cranial nerve protection activity test
Caffeic methyl ester, caffeic acetate, 3,4-diacetyl caffeic acid, scutellarin ethyl ester etc. are self-control.Trypsin, II Collagen Type VI enzyme, hyclone (Gibco company), poly-D-lysine, the DMEM high glucose medium, tetramethyl azo azoles salt (Sigma company), all the other reagent are homemade analytical pure.
SD neonatal rat (birth 1d in) is provided by Chengdu University of Traditional Chinese Medicine's Experimental Animal Center, the quality certification number: SCXK (river) 2004-11.Laboratory observation chamber: Chengdu Medical College pharmacological evaluation chamber.
ELIASA (Multiskan MK3), CO
2Incubator (Thermo), inverted phase contrast microscope (Nikon), Superpure water machine (Sartorius), LDZ5-2 type low speed autobalancing centrifuge (Beijing Medical Centrifugal Machine Factory), LDZX-40BI type automatic electric heating pressure steam sterilizer (Shenan Medical Appliances Factory, Shanghai) etc.
1, experimental procedure
Bed board: get 96 orifice plates, every hole adds 0.1mgmL
-1Poly-D-lysine 50 μ L, vibration is even, and the room temperature hold over night is subsequent use.
Preparation cell suspension: the disconnected neck of neonatal rat is put to death, 75% alcohol-pickled sterilization, aseptic condition separates brain cortical tissue, removes the cerebrovascular film as far as possible, inserts in the ice Hanks liquid rinsing 3 times.Obtaining tissue is cut into the 1mm3 piece of tissue, and the trypsin with 0.25%+37 ℃ of digestion down of 0.05%II Collagen Type VI enzyme adds culture fluid and stops digestion behind the 30min, filter with 75 μ m cell screen clothes.1000rmin will filtrate
-1Centrifugal 8min abandons supernatant.Add complete culture solution (900mLL
-1The DMEM high glucose medium, 100mLL
-1Hyclone, L-glutaminate 0.45gL
-1, NaHCO
33gL
-1, HEPES 4.5gL
-1, penicillin 1 * 10
5UL
-1, streptomycin 1 * 10
5UL
-1), suction pipe piping and druming makes it to be uniformly dispersed and processes single cell suspension.Liquid measure is cultivated in counting and adjustment makes every mL contain 1 * 10
6Individual cell.
Inoculated and cultured and medicine adding method: in 96 orifice plates that encapsulate, every hole 100 μ L change liquid after cultivating 24h with cell suspension inoculation, add cytosine arabinoside behind the 72h to suppress non-nerve growth; Later every 2d half amount is changed liquid; 7d changes behind the liquid according to requirement of experiment, and what add various mass concentration gradients respectively respectively receives reagent thing (establishing 5 dose groups, by a certain percentage dilution); Cumulative volume 200 μ L in every hole add culture fluid simultaneously and continue to cultivate as the blank group.
2, the automatic colorimetry of MTT trace
After adding drug effect 1d, every hole adds MTT liquid (tetramethyl azo azoles salt, 5mgmL
-1), after continuing to cultivate 4h, remove supernatant, PBS liquid rinsing 2 times, every hole adds dimethyl sulfoxide (DMSO) 150 μ L, fully vibration, room temperature leaves standstill 10min, measures absorption value with ELIASA in the 492nm wavelength.
3, result
Statistical result from table 1-3 can find out that caffeic acid, caffeic methyl ester, caffeic acetate can promote cerebral cortex neurocyte survival (P＜0.01) in the finite concentration scope.It is active to have cranial nerve protection preferably.
Table 1 caffeic acid to the influence of In vitro culture cerebral cortex neurocyte survival (X, n=6) Tab.4-9 Eeffect of caffeic acid on rat cerebral cortex nerve cells invitro (X, n=6)
Influence (the X of after the esterification of table 2 caffeic acid In vitro culture cerebral cortex neurocyte being survived; N=6) Tab.4-11 Eeffect of caffeoyl methyl ester and caffeoyl ethyl esteron rat cerebral cortex nerve cells in vitro (X, n=6)
The influence of after the acetylation of table 3 caffeic acid In vitro culture cerebral cortex neurocyte being survived (X, n=6)
Tab.4-12?Eeffect?of?3，4-diacetyl?caffeic?acid?on?rat?cerebralcortex?nerve?cells?in?vitro(X，n＝6)
Test Example 2 external blood brain barrier modellings reach passes through blood brain barrier
Because the existence of blood brain barrier, nearly all macromolecular drug and 98% small-molecule drug all can not get into brain and central nervous system, and medicine can cross over blood brain barrier and reach efficacious therapy concentration be vital.For seeking and the effective substance of further analyzing Herba Erigerontis brain targeting neuroprotective this experiment employing brain micro blood vessel endothelium cell of former generation and star spongiocyte co-culture model analog in vitro BBB.Use efficient liquid phase chromatographic analysis, different time points is measured the transmitance of The compounds of this invention in 8h.
1, material and instrument
Day island proper Tianjin LC-10A high performance liquid chromatograph, the SPD-10AV UV-detector; The SCL-10A system controller; The CBL calorstat, N2000 chromatographic data work station.Nitrogen evaporator (KL-512, Beijing Kang Lin science and technology limited Company): high speed centrifuge (centrifuge 5417c, eppendorf company): ultrasonic washing instrument (AS10200, Tianjin Ao Tesaiensi Instr Ltd.)
Methanol, acetonitrile (Fisher company, chromatographically pure), the scutellarin self-control, subsequent use behind the 0.22 μ m membrane filtration with the dissolving of AC culture fluid, process 0.2mgmL
-1Scutellarin.
2, method and result
2.1 sample preparation
Select leak test to test male hole and carry out the permeability experiment, in supplying the pond, add caffeic acid, caffeic methyl ester, caffeic acetate, 3,4-diacetyl caffeic acid (0.2mgmL
-1) receive to add in the pond 600 μ L AC culture fluid.From receive the pond, carefully collected each 100 μ L of filtrating, 50 μ L, 50 μ L, 50 μ L, 50 μ L respectively in-20 ℃ of preservations at the 0th, 1,2,4,8 hour, treat to do sample treatment after all sampling end.Wherein 0 hour is blank, and the medicinal liquid that in supplying the pond, adds is for supplying the initial concentration (referring to Fig. 5-1) in pond.Each sample nitrogen is dried up (37 ℃), respectively to wherein adding methanol, supersound process 20min, it is centrifugal that (5000rmin-1 * 10min), get supernatant makes HPLC and analyzes need testing solution.
2.2HPLC analyze
Chromatographic condition: Tianjin, island LC-10A high performance liquid chromatograph; Chromatographic column: be the octadecylsilane chemically bonded silica post, Yi Lite SinoChrom ODS-BP 5 μ m (250 * 4.6mm) posts number: E1817666, flow velocity: 1mLmin
-1Column temperature: room temperature; Mobile phase: acetonitrile: 0.6% formic acid.The detection wavelength is 330nm.
The accurate respectively 20 μ L need testing solutions injection high performance liquid chromatograph of drawing detects.
2.3 transmitance is calculated
Measure the result according to HPLC, get following formula and calculate transmitance.
A wherein
Receive the pondFor receiving the peak area of pond sample, A
Supply the pondFor supplying pond peak area, V
Receive the pondFor receiving cell body to amass V
Supply the pondFor supplying cell body long-pending.Result of calculation is seen table 4.
Table 4 passes through external BBBM composition transmitance
Tab.4?The?permeability?of?compounds?on?the?in?vitro?BBB?model
| Numbering | Chemical compound | Supply the pond peak area | Supply cell body long-pending (μ l) | 8h receives the pond peak area | Receive cell body to amass (μ l) | Transmitance (%) |
| 1 | Caffeic acid | - | 300 | - | 650 | - |
| 2 | The caffeic methyl ester | 89735.9 | 12166.8 | 650 | 29.38 | |
| 3 | The caffeic acetate | 572947 | 300 | - | 650 | - |
| 4 | 3,4-diacetyl caffeic acid | 477783 | 300 | 67289 | 650 | 30.51 |
The result shows that caffeic acid can not see through BBBM.The profit partition coefficient changes discovery before and after the structural modification, and esterification and acidylate afterproduct profit partition coefficient have improved 10
3~ 10
5Doubly, be more conducive to see through blood brain barrier.Caffeic methyl ester, 3 wherein, 4-diacetyl caffeic acid can see through BBBM.The caffeic acetate can not see through BBBM, but external cranial nerve protective effect is obvious, can further carry out structural modification.Caffeic methyl ester, 3,4-diacetyl caffeic acid is the new cranial nerve protection effective ingredient that passes through blood brain barrier.
Claims (3)
1. the purposes of caffeic acid derivant in preparation cranial nerve protectant medicine; Described caffeic acid derivant is caffeic methyl ester, 3,4-diacetyl caffeic acid; Described medicine is the medicine of treatment cerebral infarction.
2. purposes according to claim 1 is characterized in that: described medicine is by the caffeic methyl ester of effective dose or 3, and 4-diacetyl caffeic acid is an active component, adds the medicament that acceptable accessories is prepared from.
3. purposes according to claim 2 is characterized in that: described medicament is ejection preparation or oral formulations.
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| CN104230770B (en) * | 2013-06-17 | 2017-11-21 | 华夏生生药业(北京)有限公司 | The application of styryl sulfone compound, its preparation method as well as neuroprotective agent |
| CN106176701A (en) * | 2016-08-11 | 2016-12-07 | 成都中医药大学 | Caffeic acid and the new application of derivant thereof |
| CN108949743A (en) * | 2018-06-15 | 2018-12-07 | 翁炳焕 | A kind of full-length genome hybridizing clones method |
| CN110746302B (en) * | 2019-10-16 | 2022-04-22 | 山东省分析测试中心 | Method for separating and preparing phenolic acid compounds in echinacea purpurea |
| CN115607557A (en) * | 2021-07-16 | 2023-01-17 | 上海医药工业研究院 | Application of compound as plasma kallikrein inhibitor |
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