CN102584763A - 4-methyl-7-hydroxy-8-(1-hydroxyethyl) coumarin as well as preparation method and application thereof - Google Patents
4-methyl-7-hydroxy-8-(1-hydroxyethyl) coumarin as well as preparation method and application thereof Download PDFInfo
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- CN102584763A CN102584763A CN2012100427351A CN201210042735A CN102584763A CN 102584763 A CN102584763 A CN 102584763A CN 2012100427351 A CN2012100427351 A CN 2012100427351A CN 201210042735 A CN201210042735 A CN 201210042735A CN 102584763 A CN102584763 A CN 102584763A
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Abstract
The invention discloses 4-methyl-7-hydroxy-8-(1-hydroxyethyl) coumarin as well as a preparation method and application thereof. The structural formula of the compound provided by the invention is shown as a formula I. The coumarin is obtained by reacting 4-methyl-7-hydroxy-8-acetylcoumarin with NaBH4. The application of the compound comprises the following two aspects: 1, application in preparation of products for preventing and/or treating nerve cell injury; and 2, application in preparation of products for preventing and/or treating nervous system diseases. In vitro pharmacological experiments prove that the compound of the formula I has an obvious protective effect on SH-SY5Y nerve cell injury. Thus, the compound has important significance in the field of nervous system diseases related with oxygen free radicals, such as senile dementia and Parkinson disease, and has a broad prospect in clinical application.
Description
Technical field
The present invention relates to 4-methyl-7-hydroxyl-8-(1-hydroxyethyl) tonka bean camphor and preparation method thereof and application.
Background technology
Alzheimer's disease (Alzheimer ' s disease; AD); Claim senile dementia again; It is a kind of be the senile cranial nerve degeneration of principal feature with memory loss and cognition dysfunction, show as comprehensive obstacle of the acquired Premium Features of pallium, comprise the progressive injury of memory, sensation, motion, linguistic function etc.The pathogenesis of senile dementia it be unclear that; Many scholars have proposed the Different types of etiopathogenises hypothesis from different perspectives; Like gene theory, cholinergic theory, amyloid beta theory, energy metabolism theory, oestrogenic hormon theory, inflammatory lesion, free-radical oxidn damage, genetic flaw and sudden change etc.; Wherein, the oxyradical theory is relevant again with above-mentioned part theory.More and more evidences shows in recent years, and multiple nerve retrograde affection and oxidative stress are closely related, and thinks that oxidative stress plays keying action in taking place, develop at AD.H
2O
2Being a kind of important active oxygen composition, can being transformed into the extremely strong OH of cytotoxicity in vivo, is that a kind of film is prone to passing through property oxygenant, in many neuronal cell culture models, has caused cell injury.It participates in the pathogenesis of many nervous system disorderss, often is used as the inductor of neurocyte oxidative damage.Coumarin kind compound have certain anti-oxidant, suppress platelet aggregation, antibiotic, anti-inflammatory, antiviral, anti-AIDS and extensively biological activity such as antitumor.
Summary of the invention
The purpose of this invention is to provide 4-methyl-7-hydroxyl-8-(1-hydroxyethyl) tonka bean camphor and preparation method thereof.
4-methyl provided by the present invention-7-hydroxyl-8-(1-hydroxyethyl) tonka bean camphor, its structural formula is suc as formula shown in the I:
(formula I)
Its preparation method is following:
Make the 4-methyl shown in the formula II-7-hydroxyl-8-ethanoyl tonka bean camphor and NaBH
4React, obtain the methyl of 4-shown in the formula I-7-hydroxyl-8-(1-hydroxyethyl) tonka bean camphor.
(formula II)
A further object of the present invention provides the application of the methyl of 4-shown in the formula I-7-hydroxyl-8-(1-hydroxyethyl) tonka bean camphor.
Formula I application of compound provided by the present invention comprises following two aspects: 1, prevent and/or treat the application in the product of neural cell injury in preparation; 2, prevent and/or treat the application in the product of nervous system disorders in preparation.
Said neural cell injury specifically can be the neurocyte oxidative damage.
Said nervous system disorders specifically can be the nervous system disorders relevant with oxyradical, comprising: alzheimer's disease, Parkinson's disease etc.
Said product can be medicine and/or healthcare products.
The present invention also protects a kind of product that prevents and/or treats neural cell injury, and its effective constituent is the compound shown in the formula I.
With compound shown in the formula (I) is the medicine that prevents and/or treats nervous system disorders of effective constituent preparation, also belongs to protection scope of the present invention.
Said medicine can import body such as muscle, intracutaneous, subcutaneous, vein, mucosal tissue through the method for injection, injection, collunarium, eye drip, infiltration, absorption, physics or chemistry mediation; Or by other materials mixing or parcel back importing body.
When needing, in said medicine, can also add one or more pharmaceutically acceptable carriers.Said carrier comprises the conventional thinner of pharmaceutical field, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant etc.
The medicine that prevents and/or treats nervous system disorders with formula I compound can be processed various ways such as injection liquid, tablet, pulvis, granule, capsule, oral liquid, paste, creme.The medicine of above-mentioned various formulations all can be according to the ordinary method preparation of pharmaceutical field.
External effect experiment proves that compound 4-methyl of the present invention-7-hydroxyl-8-(1-hydroxyethyl) tonka bean camphor has the significant protection effect to the SH-SY5Y neural cell injury.Therefore, The compounds of this invention has the nervous system disorders field of certain relation significant in senile dementia, Parkinson's disease etc. with oxyradical, in clinical application, has bright prospects.
Description of drawings
Fig. 1 is the synthetic route chart of 4-methyl-7-hydroxyl-8-(1-hydroxyethyl) tonka bean camphor;
Fig. 2 is the crystalline structure figure of 4-methyl-7-hydroxyl-8-(1-hydroxyethyl) tonka bean camphor;
Fig. 3 is the H of different concns
2O
2To the effect of SH-SY5Y nerve cell damage;
Fig. 4 is that 4-methyl-7-hydroxyl-8-(1-hydroxyethyl) tonka bean camphor is to H
2O
2The provide protection of damage SH-SY5Y cell.
Embodiment
The present invention will be described through specific embodiment below, but the present invention is not limited thereto.
Experimental technique described in the following embodiment like no specified otherwise, is ordinary method; Said reagent and biomaterial like no specified otherwise, all can obtain from commercial sources.
The preparation and the evaluation of embodiment 1, compound 4-methyl-7-hydroxyl-8-(1-hydroxyethyl) tonka bean camphor
The synthetic route of compound is as shown in Figure 1.
One, preparation method
Take by weighing 4-methyl-7-hydroxyl-8-ethanoyl tonka bean camphor 2.18g (10mmol), absolute ethyl alcohol 30mL places the 100mL there-necked flask, under 50 ℃ of conditions, adds 1.5g (20mmol) NaBH
4Behind the reaction 1h, add 1.5g (20mmol) NaBH again
4Continue reaction 2h, reaction is finished.Add proper amount of acetone and water after being cooled to room temperature, regulate pH=5 with 10% hydrochloric acid then, hold over night, suction filtration, the dry bullion that gets, the ethyl alcohol recrystallization with 95% gets the water white transparency styloid, productive rate 80% (1.76g).
Two, identify
The structural information of this compound:
1H?NMR：400MHz?CDCl
3，δ7.72(s，1H)，6.09～6.11(m，1H)，5.14～1.16(m，1H)，2.44(s，3H)，1.43(d，J＝6.4Hz，3H).
LC/MS(ESI)m/z?221[M+H]
+，243[M+Na]
+
Three, crystal structure determination
Choose particle size size and be the monocrystalline of 0.5mm * 0.3mm * 0.3mm, place on the Bruker SMART CCD1000 single crystal diffractometer, adopt monochromatic M
oK
α 
Radiation, under 298 (2) K temperature, with
Mode scans, and in ° scope of 2.37≤θ≤25.01, collects 8405 of point diffractions altogether, 1900 (R of wherein independent point diffraction
Int=0.1147), whole 1900 independent point diffractions are used to structure refinement, adopt direct method to confirm whole non-hydrogen atoms, and by anisotropically refine.All Wasserstoffatoms adopts how much hydrogenation methods to obtain, and adopts rigid model to handle.Structural analysis shows that this crystal belongs to oblique system, P2
1/ c spacer, unit cell parameters: a=0.79609 (9) nm, b=1.7166 (2) nm, c=0.78586 (9) nm, β=91.857 (1) °, V=21.073.3 (2) nm
3, Z=4, D
c=1.363gcm
-3, F (000)=464, uptake factor μ=0.103mm
-1, the residual error factor R
1=0.0419, wR
2=0.1147 [I＞2 σ (I)], S=1.067.Maximum remaining posivtive spike and maximum remaining negative peak are respectively Δ ρ in the final difference electronic cloud
Max=169enm
-3With Δ ρ
Min=-209enm
-3Crystallographic structural analysis and refine adopt SHELXS-97 and SHELXL-97 program to accomplish (reference Sheldrick, G M.Acta Cryst.A.2008,64 (1): 112).
The test of pesticide effectiveness of embodiment 2,4-methyl-7-hydroxyl-8-(1-hydroxyethyl) tonka bean camphor
4-methyl-7-hydroxyl-8-(1-hydroxyethyl) tonka bean camphor is in external provide protection to the SH-SY5Y neural cell injury
Adopt the cell in vitro cultured method, set up SH-SY5Y neurocyte hydrogen peroxide (H
2O
2) damage model.The cell model SH-SY5Y cell that this experiment is selected for use (American Type Culture Collection; VA; USA) derive from people's neuroblastoma, its form is similar with normal neurons, and is tapered and have a tangible aixs cylinder; Some physiological function also has similarity with normal neurons, is to study a kind of preferably cell model of neurocyte function in the world at present.Experiment is found, the H of 200 μ M
2O
2Can produce tangible SH-SY5Y neural cell injury effect (Fig. 3).After research in, use this concentration as damage concentration, through the observation of cell form, measure cell survival rate (MTS method), detection compound 4-methyl-7-hydroxyl-8-(1-hydroxyethyl) tonka bean camphor is to the provide protection of SH-SY5Y neural cell injury.That is, the SH-SY5Y cell is contained 5 * 10 by every 1mL
4Individual cell inoculation to 96 orifice plate, the cell growth converges rate and reaches at 60%～70% o'clock, and blank and model group change the DMEM nutrient solution that contains 5% foetal calf serum into, and drug group is changed to and contains test compound 0.2,2,20,200 μ molL
-15% foetal calf serum DMEM nutrient solution, each concentration is set 6 parallel holes, after continuing to cultivate 24h, adding final concentration is 200 μ molL
-1H
2O
2, after continuing to cultivate 1h, every hole adds MTS 10 μ L, places 37 ℃, 5%CO
2Hatch 3h in the cell culture incubator, absorbancy (Absorbance) is measured in the vibration back in wavelength 490nm place.Use Graphpad Prism 4 statistical processing softwares and carry out statistical study, the result adopts variance analysis (ANOVA) and t check to compare with " means standard deviation " expression, and P＜0.05 thinks to have significant difference.With model group relatively, compound can alleviate H significantly
2O
2The SH-SY5Y nerve cell damage that causes obviously improves the survival rate (Fig. 4) of cell.
The result shows that 4-methyl-7-hydroxyl-8-(1-hydroxyethyl) tonka bean camphor has the significant protection effect to the SH-SY5Y neural cell injury.
Claims (10)
1. the compound shown in the formula I:
(formula I).
2. the method for preparing compound shown in the claim 1 Chinese style I comprises the steps: to make the 4-methyl shown in the formula II-7-hydroxyl-8-ethanoyl tonka bean camphor and NaBH4 to react, and obtains compound shown in the formula I;
(formula II).
3. compound shown in the claim 1 Chinese style I prevents and/or treats the application in the product of neural cell injury in preparation.
4. application according to claim 3 is characterized in that: said neural cell injury is the neurocyte oxidative damage; Said product is medicine and/or healthcare products.
5. compound shown in the claim 1 Chinese style I prevents and/or treats the application in the product of nervous system disorders in preparation.
6. application according to claim 5 is characterized in that: said nervous system disorders is the nervous system disorders relevant with oxyradical; Said product is medicine and/or healthcare products.
7. product that prevents and/or treats neural cell injury, its effective constituent is compound shown in the claim 1 Chinese style I.
8. product according to claim 7 is characterized in that: said neural cell injury is the neurocyte oxidative damage; Said product is medicine and/or healthcare products.
9. product that prevents and/or treats nervous system disorders, its effective constituent is compound shown in the claim 1 Chinese style I.
10. product according to claim 9 is characterized in that: said nervous system disorders is the nervous system disorders relevant with oxyradical; Said product is medicine and/or healthcare products.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102775374A (en) * | 2012-08-03 | 2012-11-14 | 淮海工学院 | Coumarin compound, and preparation method and application thereof |
| CN109206392A (en) * | 2017-06-30 | 2019-01-15 | 江苏康缘药业股份有限公司 | A kind of coumarin kind compound and the preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007134449A1 (en) * | 2006-05-19 | 2007-11-29 | Waratah Pharmaceuticals Inc. | Screening methods for amyloid beta modulators |
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2012
- 2012-02-22 CN CN201210042735.1A patent/CN102584763B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007134449A1 (en) * | 2006-05-19 | 2007-11-29 | Waratah Pharmaceuticals Inc. | Screening methods for amyloid beta modulators |
Non-Patent Citations (1)
| Title |
|---|
| 李锦周 等: "简单香豆素天然产物药理作用与化学结构关系研究进展", 《广西师范学院学报(自然科学版)》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102775374A (en) * | 2012-08-03 | 2012-11-14 | 淮海工学院 | Coumarin compound, and preparation method and application thereof |
| CN102775374B (en) * | 2012-08-03 | 2014-07-02 | 淮海工学院 | Coumarin compound, and preparation method and application thereof |
| CN109206392A (en) * | 2017-06-30 | 2019-01-15 | 江苏康缘药业股份有限公司 | A kind of coumarin kind compound and the preparation method and application thereof |
| CN109206392B (en) * | 2017-06-30 | 2022-07-05 | 江苏康缘药业股份有限公司 | Coumarin compound and preparation method and application thereof |
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| Publication number | Publication date |
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| CN102584763B (en) | 2014-03-12 |
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Granted publication date: 20140312 Termination date: 20170222 |