CN102584763B - 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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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 again senile dementia, it is a kind of senile cranial nerve degeneration that memory loss and cognition dysfunction be principal feature of take, 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 Different types of etiopathogenises hypothesis from different perspectives, as gene theory, cholinergic theory, amyloid beta theory, energy metabolism theory, oestrogenic hormon theory, inflammatory lesion, Free radicals injury, genetic flaw and sudden change etc., wherein, oxyradical theory is relevant again with above-mentioned part theory.Increasing evidence shows in recent years, and multiple nerve retrograde affection and oxidative stress are closely related, and thinks that oxidative stress plays keying action in occurring, develop at AD.H
2o
2being a kind of important active oxygen composition, can being transformed in vivo the extremely strong OH of cytotoxicity, is the easily saturating property oxygenant of a kind of film, in many neuronal cell culture models, has caused cell injury.It participates in the pathogenesis of many nervous system disorderss, is often used as the inductor of neurocyte oxidative damage.Coumarin kind compound have certain anti-oxidant, suppress platelet aggregation, antibacterial, anti-inflammatory, antiviral, anti-AIDS and the extensively biological activity such as antitumor.
Summary of the invention
The object of this invention is to provide 4-methyl-7-hydroxyl-8-(1-hydroxyethyl) tonka bean camphor and preparation method thereof.
4-methyl-7-hydroxyl-8-provided by the present invention (1-hydroxyethyl) tonka bean camphor, its structural formula is suc as formula shown in I:
(formula I)
Its preparation method is as follows:
Make 4-methyl-7-hydroxyl-8-ethanoyl tonka bean camphor and the NaBH shown in formula II
4react, obtain the methyl-7-of 4-shown in formula I hydroxyl-8-(1-hydroxyethyl) tonka bean camphor.
(formula II)
A further object of the present invention is to provide the application of the methyl-7-of 4-shown in formula I hydroxyl-8-(1-hydroxyethyl) tonka bean camphor.
The application of formula I compound provided by the present invention comprises following two aspects: 1, in preparation, prevent and/or treat the application in the product of neural cell injury; 2, in preparation, prevent and/or treat the application in the product of nervous system disorders.
Described neural cell injury specifically can be neurocyte oxidative damage.
Described nervous system disorders specifically can be the nervous system disorders relevant with oxyradical, comprising: alzheimer's disease, Parkinson's disease etc.
Described 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 formula I.
Take the medicine that prevents and/or treats nervous system disorders that shown in formula (I), compound is prepared as effective constituent, also belong to protection scope of the present invention.
Described medicine can import by the method for injection, injection, collunarium, eye drip, infiltration, absorption, physics or chemistry mediation body as muscle, intracutaneous, subcutaneous, vein, mucosal tissue; Or by other materials, mixed or wrap up after import body.
When needing, in said medicine, can also add one or more pharmaceutically acceptable carriers.Described carrier comprises thinner, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier, lubricant of pharmaceutical field routine etc.
With the medicine that prevents and/or treats nervous system disorders prepared by formula I compound, can make the 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 drug effect experiment showed, that compound 4-methyl-7-hydroxyl-8-of the present invention (1-hydroxyethyl) tonka bean camphor has significant protective effect to 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, has bright prospects in clinical application.
Accompanying drawing explanation
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
2damaging action to SH-SY5Y neurocyte;
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
Below by specific embodiment, the present invention will be described, but the present invention is not limited thereto.
Experimental technique described in following embodiment, if no special instructions, is ordinary method; Described reagent and biomaterial, if no special instructions, all can obtain from commercial channels.
Preparation and the evaluation of embodiment 1, compound 4-methyl-7-hydroxyl-8-(1-hydroxyethyl) tonka bean camphor
Compou nd synthesis route as shown in Figure 1.
One, preparation method
Take 4-methyl-7-hydroxyl-8-ethanoyl tonka bean camphor 2.18g (10mmol), dehydrated alcohol 30mL is placed in 100mL there-necked flask, under 50 ℃ of conditions, adds 1.5g (20mmol) NaBH
4after reaction 1h, then add 1.5g (20mmol) NaBH
4continue reaction 2h, reaction is finished.After being cooled to room temperature, add proper amount of acetone and water, then with 10% hydrochloric acid, regulate pH=5, standing over night, suction filtration, is dried to obtain crude product, and the ethyl alcohol recrystallization with 95% obtains 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
Choosing a particle size size is the monocrystalline of 0.5mm * 0.3mm * 0.3mm, is placed on Bruker SMART CCD1000 single crystal diffractometer, adopts monochromatic M
ok
α 
radiation, at 298 (2) K temperature, with
mode scans, and collects altogether 8405 of point diffractions, wherein 1900 (R of independent point diffraction within the scope of 2.37≤θ≤25.01 °
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 hydrogen atom adopts how much hydrogenation methods to obtain, and adopts rigid model to process.Structural analysis shows, 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, residual error factor R
1=0.0419, wR
2=0.1147[I > 2 σ (I)], S=1.067.In final difference electronic cloud, maximum remaining posivtive spike and maximum remaining negative peak are respectively Δ ρ
max=169enm
-3with Δ ρ
min=-209enm
-3.Crystallographic structural analysis and refine adopt SHELXS-97 and SHELXL-97 program to complete (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
The provide protection to SH-SY5Y neural cell injury in vitro of 4-methyl-7-hydroxyl-8-(1-hydroxyethyl) tonka bean camphor
The method that adopts cell in vitro to cultivate, sets up SH-SY5Y neurocyte hydrogen peroxide (H
2o
2) damage model.The cell model SH-SY5Y cell that this experiment is selected (American Type Culture Collection, VA, USA) derive from people's neuroblastoma, its form is similar to normal neurons, tapered and there is obvious aixs cylinder, some physiological function also has similarity with normal neurons, is the current good a kind of cell model of Studies On Neuronal function in the world.Experiment is found, the H of 200 μ M
2o
2can produce obvious SH-SY5Y neural cell injury effect (Fig. 3).After research in; apply this concentration as damage concentration; by observation of cell form, measure cell survival rate (MTS method), the provide protection of detection compound 4-methyl-7-hydroxyl-8-(1-hydroxyethyl) tonka bean camphor to SH-SY5Y neural cell injury.That is, SH-SY5Y cell is contained to 5 * 10 by every 1mL
4individual cell is seeded to 96 orifice plates, and when Growth of Cells converges rate and reaches 60%～70%, blank and model group change the DMEM nutrient solution containing 5% foetal calf serum into, and medicine group is changed to containing test compound 0.2,2,20,200 μ molL
-15% foetal calf serum DMEM nutrient solution, each concentration is set 6 parallel holes, continue to cultivate after 24h, adding final concentration is 200 μ molL
-1h
2o
2, to continue to cultivate after 1h, every hole adds MTS 10 μ L, is placed in 37 ℃, 5%CO
2in cell culture incubator, hatch 3h, after vibration, in wavelength 490nm place, measure absorbancy (Absorbance).Application Graphpad Prism 4 statistical processing softwares carry out statistical study, and result represents with " means standard deviation ", adopts variance analysis (ANOVA) and t check to compare, and P < 0.05 thinks to have significant difference.With model group comparison, compound can alleviate H significantly
2o
2the damage of the SH-SY5Y neurocyte causing, obviously improves the survival rate (Fig. 4) of cell.
Result demonstration, 4-methyl-7-hydroxyl-8-(1-hydroxyethyl) tonka bean camphor has significant protective effect to SH-SY5Y neural cell injury.
Claims (4)
1. the compound shown in formula I prevents and/or treats the application in the product of neural cell injury in preparation;
2. application according to claim 1, is characterized in that: described neural cell injury is neurocyte oxidative damage; Described product is medicine and/or healthcare products.
3. compound shown in claim 1 Chinese style I prevents and/or treats the application in the product of nervous system disorders in preparation.
4. application according to claim 3, is characterized in that: described nervous system disorders is the nervous system disorders relevant with oxyradical; Described product is medicine and/or healthcare products.
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| CN102775374B (en) * | 2012-08-03 | 2014-07-02 | 淮海工学院 | Coumarin compound, and 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 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2007134449A1 (en) * | 2006-05-19 | 2007-11-29 | Waratah Pharmaceuticals Inc. | Screening methods for amyloid beta modulators |
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| WO2007134449A1 (en) * | 2006-05-19 | 2007-11-29 | Waratah Pharmaceuticals Inc. | Screening methods for amyloid beta modulators |
Non-Patent Citations (2)
| 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)》.2007,第24卷(第1期),93-98. |
| 简单香豆素天然产物药理作用与化学结构关系研究进展;李锦周 等;《广西师范学院学报(自然科学版)》;20070731;第24卷(第1期);93-98 * |
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