CN107753478A - Application of the nepetalactone trifluoro methyl benzoate in Parkinson's are treated - Google Patents
Application of the nepetalactone trifluoro methyl benzoate in Parkinson's are treated Download PDFInfo
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- CN107753478A CN107753478A CN201711114501.2A CN201711114501A CN107753478A CN 107753478 A CN107753478 A CN 107753478A CN 201711114501 A CN201711114501 A CN 201711114501A CN 107753478 A CN107753478 A CN 107753478A
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- nepetalactone
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- degenerative diseases
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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Abstract
The invention provides application of the nepetalactone trifluoro methyl benzoate in Parkinson's are treated.Cell assay in vitro is found; nepetalactone derivative nepetalactone trifluoro methyl benzoate has the bioactivity of protection neuronal cell; therefore solid orally ingestible can be prepared into by adding auxiliary material, such as granule, tablet, capsule, the prevention and treatment for Parkinson's.
Description
Technical field
The invention belongs to the bioactivity technical field of compound, in particular to nepetalactone trifluoromethylbenzene first
Application of the acid esters in Parkinson's are treated.
Background technology
Parkinson's (Parkinson ' s disease, PD) are most common kinetic system degenerative diseases, mainly
Clinical manifestation is：Static tremor, it is slow in action, astasia and attitudinal reflex obstacle.Parkinsonian's brain it is main
Diseased region is black substance and corpus straitum, and it is to cause to throw that the death of dopaminergic neuron and quantity, which are reduced, wherein in substantia nigra compacta
It is mapped to the immediate cause of Dopamine In Striatum reduction.PD mechanism of causing a disease is also less clearly, but draw with diabetes complicated encephalopathic
The oxidative damage that rises, the disease such as Hippocampal Neuron Cells apoptosis have obvious difference.PD is used as and is only second to Alzheimer's disease
Second largest nerve degenerative diseases, Parkinson's sharply increased with its incidence of disease of the increase at age and illness rate, at 60 years old
Illness rate is up to 1% in above the elderly, and crowd reaches 5%-6% within more than 85 years old, and Parkinsonian's quantity in China exceedes at present
2000000.The PD cause of disease is relevant with aging, environment and inherent cause, and PD pathogenesis is still indefinite at present.But research shows,
The pathomechanisms such as oxidativestress damage, immune inflammation, er stress, apoptosis interact, may cause PD generation and
Development.China has progressed into aging society at present, and with the increase of the aged, the quantity of PD patient will also increase rapidly
Add.PD is not only bringing inconvenience to patient in the action, some patients can spiritedness and disturbance of intelligence, thousands of family is existed
Torment is mentally also enjoyed, therefore, turns into current study hotspot from multipath treatment PD.
At present, the clinical treatment for Parkinson's mainly has chemotherapy and surgical operation therapy, and still locates
Cell therapy and gene therapy in the experimental stage." gold of the chemotherapy using Benserazide preparation as treatment PD
Standard ", but this is the short term efficacy further to injure the functional status of dopaminergic neuron as cost, in control symptom side
Face is better than Chinese medicine, but prolonged application, and toxic side effect is big, and not only curative effect gradually weakens with time lengthening, terminated, and can accelerate
The death rate of the existing dopaminergic neuron of patient, is tantamount to drink poison to quench thirst from long-term effect.
Parkinson's belong to motherland medical science " disease of quivering " category, high year prolonged illness, qi and blood be full of less lose it is more, lose then moisten it is foster, tendon and vessel mistake
Flourish and endogenous deficient wind, sends out to tremble.The Chinese medicine disease shows its unique advantage in recent years, can not only improve clinical treatment
Effect, it can also delay the progress of the course of disease.Chinese periodical《Chinese medicine study》, in April, 2000, the 2nd phase of volume 16, the paper published
" flat quiver influence of the soup to Parkinson disease model animal behavior and intracerebral DOPAMINE CONTENT IN RABBIT ", disclose it is a kind of by astragalus root 30g, it is white
Chinese herbaceous peony 30g, yncaria stem with hooks (under rear) 15g, motherwort 30g, rhubarb 30g, the traditional Chinese medicine composition for treating Parkinson of rattletop 10g compositions
Disease, as a result confirm that the flat soup that quivers, without influence, can not increase its striatal dopamine and contain on the rat circling behavior of 6-OHDA modelings
Amount；The flat soup 144g/kg continuous gavage 3d that quiver, have obvious anti-shudder to act on, and prompt the flat soup that quivers not have excited intracerebral dopamine
The effect of function of receptors, can not increase the content of neurotransmitter, but have certain to anti-shudder effect.Chinese periodical《The traditional Chinese medical science
Medicine Leader》, in March, 2010, the 3rd phase of volume 16, the paper published " grind by the clinic of the soup that only quivers joint western medicine Parkinson's
Study carefully ", disclose the decoction of medicinal ingredients thing composition that only quivers：Wind-weed 9g, RADIX PAEONIAE ALBA 30g, yncaria stem with hooks 18g, Radix Astragali 20g, red sage root 20g, rattletop 9g, rheum officinale
9g, 60 patients with Parkinson disease are divided into Chinese medicine Zhi Chan soup treatment group (Chinese medicine group) and Western medicine pergolide (Celance) treatment group
(Western medicine group).Two groups of patient's drug therapies are after 3 months, using the motion inspection in unified Parkinson's disease rating scale (UPDRS)
Scale is scored, and the front and rear scoring decline degree of comparison therapy, assesses its therapeutic effect.As a result：After the treatment of Chinese medicine group under UPDRS scorings
4.55 points of drop, Western medicine group decline 4.49 points, and UPDRS is substantially reduced before relatively treating after two groups of treatments, and difference is statistically significant
(P<0.01), and Chinese medicine group total effective rate is 83.33%, better than 53.33% (P of Western medicine group<0.05).Nothing is obvious not in observation
Good reaction.
Nevertheless, due to Chinese medicinal formulae, existing activity into indefinite drawback, limits it in international market in itself
On application, traditional Chinese medicine monomer so that its toxic side effect is small, curative effect is lasting, the integrally-regulated good and active component advantage such as clearly, into
It is oriented to prevent and treat the research of PD new drugs in recent years.Nepetalactone is by being extracted in Chinese medicine schizonepeta in a kind of isolated monoterpene
Ester, it can be used for preparing anti-cold medicine, anti-inflammation drugs, antibacterials, analgestic etc..By retrieving domestic and foreign literature, at present
Document report in terms of still treating nerve degenerative diseases without nepetalactone or derivatives thereof.
The content of the invention
The present inventor by substantial amounts of cell assay in vitro study and persistent exploration after find, nepetalactone is thin to neuron
Born of the same parents have significant protective effect, so as to confirm that the compound has the bioactivity for the treatment of nerve degenerative diseases.
However, bioactivity of the nepetalactone in terms of neuronal cell is protected be not very good, therefore inventor is more
Structural modification is carried out to the compound according to structure-activity relationship over year, is finally obtained a kind of effect highly significantization nepetalactone
Derivative.
Therefore, the answering in nerve degenerative diseases are treated it is an object of the invention to provide a kind of nepetalactone derivative
With.Specifically, technical scheme can be summarized as follows：Nepetalactone derivative is preparing treatment nerve degenerative diseases
Medicine in apply, nepetalactone derivative therein is nepetalactone trifluoro methyl benzoate, and its structural formula is as follows：
Found in the other experiment of the present invention, nepetalactone and its derivative are particularly suitable for preventing or treat pa gold
Gloomy disease, therefore further preferably nepetalactone derivative should in the medicine for preparing treatment nerve degenerative diseases as described above
With wherein nerve degenerative diseases are Parkinson's.
Still further preferably, nepetalactone derivative as described above is in the medicine for preparing treatment nerve degenerative diseases
It is its raceme, stereoisomer, solvate or after entering body using, nepetalactone trifluoro methyl benzoate therein
It is metabolized as the precursor compound of nepetalactone trifluoro methyl benzoate.
It should be noted that nepetalactone derivative should in the medicine for preparing treatment nerve degenerative diseases as described above
Be preferably solid orally ingestible with, medicine therein, including ordinary tablet, dispersible tablet, enteric coatel tablets, oral disintegrating tablet, sustained release tablets, capsule,
Granule.These oral formulations can add available auxiliary material in pharmacy, according to system on the basis of above-mentioned active component
The common process in agent field, those skilled in the art are easy to can in nepetalactone trifluoro methyl benzoate and pharmacy
The auxiliary material of receiving is prepared into conventional oral formulations, such as granule, tablet, capsule.Wherein, acceptable auxiliary material in pharmacy
Including filler, disintegrant, adhesive, flavouring, lubricant etc..Described filler is selected from following one or more：
Pregelatinized starch, lactose, mannitol and microcrystalline cellulose；Described disintegrant is selected from following one or more：Carboxymethyl forms sediment
Powder sodium, PVPP, Ac-Di-Sol and low-substituted hydroxypropyl cellulose；Described adhesive is selected from following
It is one or more：Starch slurry, hydroxypropyl cellulose solution, povidone solution；Described lubricant is selected from following one kind or two
Kind：Magnesium stearate, talcum powder.
Compared with prior art, present invention firstly discovers that nepetalactone and its derivative have the life of protection neuronal cell
Thing activity, the prevention and treatment that medicine is used for nerve degenerative diseases can be prepared into, be especially suitable for treatment Parkinson's.In addition,
Because nepetalactone and its derivative are as active component, it derives from natural plants or its trim, therefore toxic side effect is small,
It is easier to be accepted by patients.
Embodiment
The preparation process of the present invention is further described by following examples and technique effect, embodiment are only used for illustration
Purpose, do not limit the scope of the invention, at the same those of ordinary skill in the art according to the present invention done it is obvious
Change is also contained within the scope of the present invention.
The preparation of the nepetalactone trifluoro methyl benzoate of embodiment 1
Nepetalactone sterling 36.4mg is weighed, will to trifluoromethylbenzoic acid 72.2mg, DMAP 24.5mg
It is placed in round-bottomed flask, and add 6mL dichloromethane is completely dissolved it as reaction dissolvent, stirring, adds N, the hexamethylenes of N'- bis-
Base carbodiimide 78.5mg, fully reacts at 25 DEG C, and TLC examines reaction end.After reaction terminates, methanol, which is added dropwise, makes solution clear
Clearly, the column chromatography silica gel about 600mg of 3 times of amounts are added, stir the lower solvent that is evaporated under reduced pressure to dry.6g silica gel dress post is weighed, with stone
Oily ether:Ethyl acetate=6:1 is eluted as eluant, eluent, and TLC tracking can find target compound nepetalactone trifluoromethyl
Benzoic ether, eluent is now collected, completely after elution, merge eluent, eluent is recovered under reduced pressure, nepetalactone trifluoro can be obtained
Methyl benzoic acid ester white crystalline powder, purity 97.06%, yield 83.9%.
Influence experimental study of the nepetalactone trifluoro methyl benzoate of embodiment 2 to extracorporeal neuron cell
By the good hippocampus neurons in mice cell HT-22 cells of adherent growth, with the trypsin digestion cells of 2mL 0.25%
1-2min, single cell suspension is dispelled into, add a small amount of hyclone FBS (100 μ L).1000rpm centrifuges 5min, removes supernatant, will
Cell precipitation is dispersed in 3mL complete mediums, takes 1mL cell suspensions to be added in 24mL complete mediums, overturns 10 back and forth
Secondary mixing, 0.1mL is taken to be used to count.It is diluted to 8 × 104After cell/mL cell concentrations, 96 orifice plates first add 50 μ L culture mediums, make
Culture medium is thoroughly distributed in orifice plate rims, then by cell seeding in 96 orifice plates.The rotating centrifugal pipe in kind, one half bore of kind are used
Power blows and beats cell, is allowed to uniform, while allows cell suspension to be paved with orifice plate bottom, observes cell point after all finishing under the microscope
Whether uniformly to dissipate, cross, which shakes up, makes cell be uniformly dispersed in orifice plate bottom.Placed 24 hours or so in incubator, cell fusion degree
It is used to test when about 30~40%.
By μ g of nepetalactone 10, μ g of nepetalactone trifluoro methyl benzoate 10,0.02 μm of ol points of watermiscible vitamin E
It is not scattered in 2mL complete mediums, it is standby.Kind of 96 orifice plates of good cell are taken, are divided into Normal group, model control group, dimension
Raw plain E groups, nepetalactone group and nepetalactone trifluoro methyl benzoate group.Every group of 6 multiple holes, it is (normal right that culture medium changes liquid
Liquid is changed using the complete medium for being not added with medicine according to group and model control group), per the μ L of hole 200, before changing liquid every time, piping and druming culture
Base, make dispersion of medicine.Change liquid it is complete 37 DEG C be incubated 1h after add glutamic acid final concentration is reached 3mM (Normal group is not added with
Glutamic acid).37 DEG C of culture 24h are placed on after shaking up, then observe cellular morphology, mtt assay detection cell survival rate, then with 20
μ L 37 DEG C of incubation 2h of MTT (5mg/mL) lucifuge, gently suck liquid, add 200 μ L DMSO, shaking table 5min to shake up per hole.So
Afterwards each light absorption value under 490nm is calculated with multi-function microplate reader.The hole OD values of each group 6 are taken, averages, subtracts blank DMSO OD
Value, then divided by Normal group standardizing average values.
By the test statistics result of table 1 can be seen that nepetalactone trifluoro methyl benzoate group and nepetalactone group,
Vitamin E group is obviously improved compared to the cell survival rate of model control group, and its difference has statistical significance (P ＜ 0.01), and
Nepetalactone group lifts unobvious compared to the cell survival rate of model control group, and its difference is not statistically significant (P ＞ 0.05).
In addition, nepetalactone trifluoro methyl benzoate group significantly rises compared to the cell survival rate of vitamin E group and nepetalactone group
Height, its difference are respectively provided with pole conspicuousness statistical significance (P ＜ 0.01).This explanation nepetalactone trifluoro methyl benzoate for
Neuronal cell has significant protective effect.
The each group cell survival rate of table 1 compares
Compared with model control group,*P ＜ 0.01；With vitamin E group,#P ＜ 0.01；With nepetalactone group,$P ＜ 0.01.
Influence experimental study of the nepetalactone trifluoro methyl benzoate of embodiment 3 to external dopaminergic cell
Take the logarithm the MES23.5 dopaminergic cells in growth period, piping and druming centrifuges after single cell suspension is made, with complete culture
Base is diluted to 2 × 105Individual cell/mL cell suspension, 96 orifice plates are inoculated in per the μ L of hole 200, are placed in 37 DEG C, 5%CO2 incubators
Middle culture.Nepetalactone trifluoro methyl benzoate (the 100 μ g/mL, 10 μ dissolved with DMEM/F12 nutrient solutions are added after adherent
G/mL, 1 μ g/mL) and 6- hydroxyl dopamines (100 μm of ol/L) co-cultivation 24h.Then 5mg/mL 3- (4,5- bis- is added per hole
Methylthiazol -2) 20 μ L of -2,5- diphenyltetrazolium bromide bromides (MTT), cultivate 4h in 37 DEG C of incubators.Abandon after supernatant and added per hole
The μ L of dimethyl sulfoxide (DMSO) 200, automatic elisa reading instrument colorimetric (dominant wavelength 573nm, secondary wavelength 630nm), determine its absorbance, and
Calculate the survival rate of each group MES23.5 dopaminergic cells.Cell survival rate=(experimental group absorbance-blank group absorbance
Value)/(negative control group absorbance-blank group absorbance).
Above-mentioned MTT measurement results prompt (table 2), and when only adding 6-OHDA, the survival rate of cell is decreased obviously, and uses PF
When (1mg/mL) is incubated altogether with 6-OHDA, it can substantially suppress the decline of cell survival rate, compared with 6-OHDA independent role groups
It is statistically significant.Other low concentration groups do not have significant change：0.1mg/mL, 0.01mg/mL, 0.001mg/mLPF be not obvious
Suppress cell survival rate decline effect.The MES23.5 cells that showing 1mg/mL PF can damage to neurotoxin have substantially
Protective effect.
10,100 μ g/mL nepetalactone trifluoro methyl benzoate group phases can be seen that by the test statistics result of table 2
Cell survival rate than model control group is obviously improved, and its difference has statistical significance (P ＜ 0.01).10 μ g/mL of this explanation
The MES23.5 cells that the nepetalactone trifluoro methyl benzoate of concentrations above damages to neurotoxin 6- hydroxyl dopamines have
Significant protective effect.
The each group cell survival rate of table 2 compares
Compared with model control group, P ＜ 0.01.
Claims (10)
1. nepetalactone derivative is applied in the medicine for preparing treatment nerve degenerative diseases, described nepetalactone derivative
It is as follows for nepetalactone trifluoro methyl benzoate, its structural formula：
2. nepetalactone derivative is applied in the medicine for preparing treatment nerve degenerative diseases according to claim 1, its
It is characterised by, described nerve degenerative diseases are Parkinson's.
3. nepetalactone derivative is applied in the medicine for preparing treatment nerve degenerative diseases according to claim 1, its
It is characterised by, described nepetalactone trifluoro methyl benzoate is its raceme, stereoisomer, solvate or into machine
The precursor compound of nepetalactone trifluoro methyl benzoate is metabolized as after body.
4. nepetalactone derivative is applied in the medicine for preparing treatment nerve degenerative diseases according to claim 1, its
It is characterised by, described medicine is solid orally ingestible.
5. nepetalactone derivative is applied in the medicine for preparing treatment nerve degenerative diseases according to claim 4, its
It is characterised by, described solid orally ingestible is available auxiliary in pharmacy by being added in nepetalactone trifluoro methyl benzoate
Material is prepared.
6. nepetalactone derivative is applied in the medicine for preparing treatment nerve degenerative diseases according to claim 5, its
It is characterised by, available auxiliary material includes filler, disintegrant, adhesive, flavouring and lubricant in described pharmacy.
7. nepetalactone derivative is applied in the medicine for preparing treatment nerve degenerative diseases according to claim 6, its
It is characterised by, described filler is selected from following one or more：Pregelatinized starch, lactose, mannitol and microcrystalline cellulose.
8. nepetalactone derivative is applied in the medicine for preparing treatment nerve degenerative diseases according to claim 6, its
It is characterised by, described disintegrant is selected from following one or more：Sodium carboxymethyl starch, PVPP, cross-linked carboxymethyl
Sodium cellulosate and low-substituted hydroxypropyl cellulose.
9. nepetalactone derivative is applied in the medicine for preparing treatment nerve degenerative diseases according to claim 6, its
It is characterised by, described adhesive is selected from following one or more：Starch slurry, hydroxypropyl cellulose solution, povidone solution.
10. nepetalactone derivative is applied in the medicine for preparing treatment nerve degenerative diseases according to claim 6, its
It is characterised by, described lubricant is selected from following one or two：Magnesium stearate, talcum powder.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711114501.2A CN107753478A (en) | 2017-11-13 | 2017-11-13 | Application of the nepetalactone trifluoro methyl benzoate in Parkinson's are treated |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201711114501.2A CN107753478A (en) | 2017-11-13 | 2017-11-13 | Application of the nepetalactone trifluoro methyl benzoate in Parkinson's are treated |
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| CN201711114501.2A Withdrawn CN107753478A (en) | 2017-11-13 | 2017-11-13 | Application of the nepetalactone trifluoro methyl benzoate in Parkinson's are treated |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101940588A (en) * | 2010-05-23 | 2011-01-12 | 青岛大学 | Application of benzoylated phaeophyceae polysaccharide for preparing medicines for treating Parkinson disease |
| CN102942544A (en) * | 2012-12-07 | 2013-02-27 | 南京中医药大学 | Nepetalactone trifluoromethyl benzoate as well as preparation process and use of nepetalactone trifluoromethyl benzoate |
-
2017
- 2017-11-13 CN CN201711114501.2A patent/CN107753478A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101940588A (en) * | 2010-05-23 | 2011-01-12 | 青岛大学 | Application of benzoylated phaeophyceae polysaccharide for preparing medicines for treating Parkinson disease |
| CN102942544A (en) * | 2012-12-07 | 2013-02-27 | 南京中医药大学 | Nepetalactone trifluoromethyl benzoate as well as preparation process and use of nepetalactone trifluoromethyl benzoate |
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