CN106831679B - New Radix Codonopsis alkynol compound and preparation method thereof, using and its pharmaceutical composition - Google Patents
New Radix Codonopsis alkynol compound and preparation method thereof, using and its pharmaceutical composition Download PDFInfo
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- CN106831679B CN106831679B CN201710026510.XA CN201710026510A CN106831679B CN 106831679 B CN106831679 B CN 106831679B CN 201710026510 A CN201710026510 A CN 201710026510A CN 106831679 B CN106831679 B CN 106831679B
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- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D309/06—Radicals substituted by oxygen atoms
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- C07—ORGANIC CHEMISTRY
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Abstract
The invention discloses a kind of new Radix Codonopsis alkynol compound 1 extracted from Radix Codonopsis, and preparation method thereof, and the pharmaceutical composition containing new Radix Codonopsis alkynol compound, and the application in nerve protection medicine: especially senile dementia.Pharmacological evaluation shows that the compounds of this invention embodies neuroprotective activity, damages in primary neuronal models and glutamate induction primary neuron toxic model in sodium nitroprussiate and all has good neuroprotective activity.
Description
Technical field
The present invention relates to compounds to extract separation field, in particular to new Radix Codonopsis alkynol and preparation method thereof, application and medicine
Compositions.
Background technique
Radix Codonopsis is China's tradition rare traditional Chinese medicine, is Campanulaceae (Campanulaceae) plant Radix CodonopsisCodonopisis pilosula (Franch) Nannf, codonopsis pilosula var. modestaCodonopsis pilosula Nannf .var .modesta
(Nannf.) L .T .Shen or radix codonpsis tangshenCodonopisis tangshenThe dry root of Oliv, sweet in flavor and neutral in nature are main
Returns spleen lung two passes through, and has the effect of tonifying middle-Jiao and Qi, strengthening spleen and tonifying lung, and it is empty to be clinically usually used in the spleen-lung Qi deficiency, deficiency of qi in middle-jiao, taste
The diseases such as weak, consumption of body fluid caused by febrile disease, main product is in Shanxi, Shaanxi, Gansu and other places.
With the quickening of China's the aging process of the society, elderly population quantity is continuously increased.According to statistics, end to 2020
Year, China's aging level is up to 17.17%, and various disease of old people patient numbers are also in rising trend.It is old in developed country
Dementia has respectively become third and fourth the big death for being only second to cardiovascular disease, cancer as the most common neurodegenerative disease
Killer.And the number of China neurodegenerative disease patient, it has occupied first of countries in the world.There has been no prevention and treatment neurologicals at present
Property disease specific medicament it is available, therefore develop with targeting, Small side effects, can be effectively controlled and reverse disease
Drug is imperative.China's natural resources of Chinese medicinal materials is abundant, and toxic side effect is small, and new type nerve degenerative disease medicine is found from Chinese medicine
Object is one of the important channel of new drug development research.But traditional Chinese medicine ingredients are complicated, effective component is indefinite, and curative effect is unstable, makees
Unclear with mechanism, the use and Chinese medicine seriously affected clinically enters international mainstream market, therefore from conventional medicament
Configuration is found in natural resources, the specific special efficacy neurodegenerative disease therapeutic agent of mechanism is medical scientific research worker phase from now on
When the urgent task in long-time.
Summary of the invention
The effect of Radix Codonopsis water extract tool treatment neurodegenerative disease, isolated 1 new Radix Codonopsis from active component
Alkynol compound, pharmacodynamic evaluation show that it has the function of good neuroprotection.
One of the objects of the present invention is to provide a kind of new Radix Codonopsis alkynol compounds.
The second object of the present invention is the provision of a kind of preparation method of new Radix Codonopsis alkynol compound.
It is refreshing in preparation prevention and/or treatment that the third object of the present invention is the provision of a kind of new Radix Codonopsis alkynol compound
Through the application in degenerative disease drug.
The fourth object of the present invention is to provide a kind of pharmaceutical composition, contains new Radix Codonopsis alkynol compound.
The present invention is achieved by the following technical solutions: new Radix Codonopsis alkynol compound has structure shown in compound 1
1。
The preparation method of new Radix Codonopsis alkynol compound, every 1,5 mg of prepare compound the following steps are included:
A. dry 5 kg of Radix Codonopsis is crushed, and after impregnating 2 h with 40 L of distilled water, heating and refluxing extraction 3 times, 2 is small every time
When；
B. after water extract-alcohol precipitation, volatilization ethyl alcohol is to no alcohol taste, and AB-8 resin adsorption, after being washed with pure water, then with 30 %,
50 %, 70 %, 95 % ethyl alcohol (each 2 times of amount of resin) elution, receive each section of eluent, each medicinal extract are concentrated under reduced pressure to obtain；
C. each extracting solution is concentrated under reduced pressure to obtain 30 %, 50 %, 70 % respectively, 95 % alcohol elution 12 g, 60 g,
100g, 160g；
D. to 50 % alcohol elutions through silica gel (200~300 mesh, 500 g) column chromatographys, CH2Cl2-MeOH
The isolated fraction Fr1-Fr10 of (100:1 → 1:1) gradient elution；
E. 50 are divided by middle compression leg chromatography (methanol elution gradient of 10-90 % 10 hours) to Fr 6 (10g)
A fraction (500 ml are 1 part), obtains a new Radix Codonopsis alkynol compound (5mg) from Fr. 6-12 by preparation liquid phase.
Application of the compound 1 in preparation prevention and/or treatment neurodegenerative disease drug.The nervus retrogression disease
Disease is cerebral apoplexy, dementia, neuroinflamation, heavy metal poisoning, never poison poisoning.It is described dull-witted for alzheimer's disease, vascular
It is dull-witted.
A kind of pharmaceutical composition contains acceptable carrier in 1 compound represented of compound and pharmacodynamics.
Thinking according to the present invention has carried out the relevant pharmacological evaluation of neuroprotection to new Radix Codonopsis alkynol compound.Oxygen
Changing stress be the major reason for causing Neuron Apoptosis to be lost, and be the common feature of neurodegenerative disease.Cause oxidative stress
The reason of there are many kinds of, such as cerebral ischemia, neuroinflamation, excitatory transmitter discharges reuptake mechanism impediment, heavy metal exposure, nerve
Toxic agents exposure etc. shows as intracellular free radicals increase, causes lipid peroxidation, mitochondria dysfunction then activates apoptosis
Access etc..Glutamic acid is all domestic and international many in recent years although the mechanism that sodium nitroprussiate causes Neuron Apoptosis loss is different
The inducing agent for the neure damage model that person advocates.Research thinks that intracerebral excitatory transmitter glutamic acid excessively usually causes nerve
NMDA receptor excessive activation on first film occurs oxidative stress so as to cause neuron and loses, and sodium nitroprussiate is a kind of NO
Donor, NO can transmit oxygen radical through mitochondrial membrane, make mitochondrial function imbalance that apoptosis, mechanism, disease then occur
Managing physiological change and clinical old dementia patients intracerebral performance has similitude.Using glutamic acid, sodium nitroprussiate makes neuron damage
The requirement of wound model condition is low, and technology is easy to grasp, highly reliable, reproducible, therefore in our current research, using glutamic acid mistake
It carries, sodium nitroprussiate (SNP) exposure production neure damage model.
One provided by the invention new Radix Codonopsis alkynol glutamic acid in vitro, the rat cerebral cortex neuron that sodium nitroprussiate induces
Excellent neuroprotection is all shown in dead test.
Positive control medicine is Edaravone (edaravone), and Edaravone is using radicals scavenging as main function machine
The novel anti senile dementia drug of system, brain cell caused by capable of effectively inhibiting because of cerebral ischemia, vascular endothelial cell, nerve cell
Oxidativestress damage.
In the protective effect in vitro study for inducing sodium nitroprussiate rat cerebral cortex Neuron Apoptosis, by the compounds of this invention
With sodium nitroprussiate (350 μM) with after neuronal culture dilutes and rat cerebral cortex neuron temperature incubates 24 hours, MTT method
Cell survival rate is measured, while carrying out Normal group and positive controls test.The experimental results showed that Normal group is added
Absorbance value (OD at 570 nm after sodium nitroprussiate570) be substantially reduced, positive controls and the compounds of this invention OD570It is obvious to return
It rises, suitable with the cell survival rate of Edaravone (edaravone), the cell survival rate of part noval chemical compound compares Edaravone
It is high.
The invention has the advantages that: new Radix Codonopsis alkynol compounds 1 can be used for preparing prevention and/or treatment nervus retrogression
The drug of disease.Preferred neurodegenerative disease is in cerebral apoplexy, dementia, neuroinflamation, heavy metal poisoning, never poison
Poison.It is preferred dull-witted selected from alzheimer's disease, vascular dementia.
Detailed description of the invention
The new Radix Codonopsis alkynol compound of Fig. 1 extracts flow chart.
Specific embodiment
The following examples and pharmacological activity experiment further illustrate the present invention, but are not meant to of the invention any
Limitation.
Embodiment 1: dry 5 kg of Radix Codonopsis is crushed, after impregnating 2 h with 40 L of distilled water, heating and refluxing extraction 3 times, often
Secondary 2 hours；After water extract-alcohol precipitation, volatilization ethyl alcohol is to no alcohol taste, and AB-8 resin adsorption, after being washed with pure water, then with 30 %, 50
%, 70 %, 95 % ethyl alcohol (each 2 times of amount of resin) elution, receive each section of eluent, each medicinal extract are concentrated under reduced pressure to obtain；Each extracting solution
30 %, 50 %, 70 %, 95 % alcohol elution 12 g, 60 g, 100g, 160g are concentrated under reduced pressure to obtain respectively；To 50 % ethyl alcohol
Position is eluted through silica gel (200~300 mesh, 500 g) column chromatographys, CH2Cl2- MeOH (100:1 → 1:1) gradient elution point
From obtaining fraction Fr1-Fr10；To Fr 6 (10g), by middle compression leg chromatography, (methanol elution gradient 10 of 10-90 % is small
When) it is divided into 50 fractions (500 ml are 1 part), a new Radix Codonopsis alkynol compound (5 is obtained from Fr. 12 by preparation liquid phase
Mg).
Embodiment 2: application of the compound 1 in preparation prevention and/or treatment neurodegenerative disease drug.The nerve
Degenerative disease is cerebral apoplexy, dementia, neuroinflamation, heavy metal poisoning, never poison poisoning.The dementia is silly for presenile
Slow-witted, vascular dementia.
Physics and chemistry, the spectral data of new Radix Codonopsis alkynol compound are as follows:
Yellow oil, ESI-MSm/z 217 [M + H]+。1H-NMR (500 MHz, CD3OD)δ: 6.23(1H,
dt, J =11.0, 6.0Hz, H-2),6.28(2H, dd, J = 16.0, 5.0Hz, H-9), 5.83(1H, dt, J =
15.5, 2.0Hz, H-8), 5.67(1H, dd, J = 11.0, 1.0Hz, H-3), 4.31(2H, dd, J = 6.5,
1.5Hz, H-1) ; 13C-NMR (125 MHz, CD3OD)δ: 149.1(C-2), 147.5(C-9), 109.5(C-3),
108.9(C-8), 82.1(C-8), 80.0(C-7), 78.4(C-1’), 77.9(C-6), 74.6(C-5), 69.5(C-
5’), 61.3(C-1), 33.0(C-2’), 27.0(C-4’), 24.4(C-3’)。
Pharmacological evaluation
Test material 1, test drug: monomeric compound of the present invention.2, positive control drug: Edaravone, by Chinese food medicine
Research institute's offer is determined in product examine.HPLC detects 98 % of purity >.3, cell: birth same day rat cerebral cortex neuron.4,
Culture medium: DMEM, FBS, the production of Gibco company of the U.S.；ES, the production of Hyclone company of the U.S..5, sodium nitroprussiate is eaten by China
Product drug assay research institute provides, and glutamic acid is provided by Beijing Chemical Plant.
Experimental example 1: it influence of the compounds of this invention to rat cerebral cortex neuronal survival state and is lured in sodium nitroprussiate
Protective effect in the neuronal apoptotic models of hair
In the influence research of compounds on nerve member existing state, by originally culture Cortical Neurons of Rat (DIV-9) point
For control group and administration group (10 μM), n=6；It is ground in the protective effect that compound induces neuronal apoptotic models to sodium nitroprussiate
In studying carefully, originally culture Cortical Neurons of Rat (DIV-7) is divided into control group, sodium nitroprussiate (350 μM) modeling group, sodium nitroprussiate
(350 μM)+Edaravone (100 μM) administration group, sodium nitroprussiate (350 μM)+compound (10 μM) administration group, n=
6.After administration, cell, which is placed in cell incubator, continues culture 24 hours, and MTT method (570 nm) measures cell survival rate.With right
It is standard according to group absorbance, calculates the ratio of each group absorbance and control group.
Influence of 1 compound of table to Cortical Neurons of Rat existing state
2 compound of table induces sodium nitroprussiate and glutamic acid the function and effect of Cortical Neurons of Rat apoptosis
Note: the vs of * p < 0.05 mod, * the * vs of p < 0.01 mod, * * * p < 0.001vs mod, ## P < 0.01vs
control.
The results showed that being screened to identified the compounds of this invention into preliminary cell model, of the present inventionization
It closes object and embodies neuroprotective activity, have good neuroprotection living in glutamate induction primary neuron toxic model
Property.Its activity is better than Edaravone.
Embodiment 3: a kind of pharmaceutical composition contains acceptable load in 1 compound represented of compound and pharmacodynamics
Body.
Further aspect of the present invention further relates to the pharmaceutical composition using the compounds of this invention as active ingredient.The pharmaceutical composition
Object can be prepared according to method well known in the art.Can by by the compounds of this invention with it is one or more pharmaceutically acceptable solid
Body or liquid excipient and/or adjuvant combine, and any dosage form used suitable for human or animal is made.The compounds of this invention is in its medicine
Content in compositions is usually 0.1-95 weight %.
The compounds of this invention can be administered in a unit containing its pharmaceutical composition, and administration route can be enteron aisle
Or non-bowel, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin,
Vagina, rectum etc..
Form of administration can be liquid dosage form, solid dosage forms or semisolid dosage form.Liquid dosage form can be solution (including
True solution and colloidal solution), emulsion (including o/w type, w/o type and emulsion), suspension, injection (including liquid drugs injection, powder
Injection and infusion), eye drops, nasal drop, lotion and liniment etc.；Solid dosage forms can be tablet (including ordinary tablet, enteric coatel tablets,
Lozenge, dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet), capsule (including hard capsule, soft capsule, capsulae enterosolubilis),
Granula, powder, pellet, dripping pill, suppository, film, patch, the agent of gas (powder) mist, spray etc.；Semisolid dosage form can be ointment
Agent, gelling agent, paste etc..
It is sustained release preparation, controlled release preparation, targeting preparation and various that the compounds of this invention, which can be made ordinary preparation, also be made,
Particulate delivery system.In order to which tablet is made in the compounds of this invention, various excipient well known in the art can be widely used, wrap
Include diluent, binder, wetting agent, disintegrating agent, lubricant, glidant.Diluent can be starch, dextrin, sucrose, grape
Sugar, lactose, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate etc.；Wetting agent can be
Water, ethyl alcohol, isopropanol etc.；Adhesive can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, I
Primary rubber cement, gelatine size, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic acid tree
Rouge, carbomer, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegrating agent can be dried starch, microcrystalline cellulose, low-substituted hydroxypropyl
Base cellulose, crosslinked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid,
Polyoxyethylene sorbitol aliphatic ester, dodecyl sodium sulfate etc.；Lubricant and glidant can be talcum powder, titanium dioxide
Silicon, stearate, tartaric acid, atoleine, polyethylene glycol etc..
Tablet can also be further made to coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric coated tablets or double
Synusia and multilayer tablet.
In order to which capsule is made in administration unit, effective component the compounds of this invention and diluent, glidant can be mixed
It closes, mixture is placed directly in hard capsule or soft capsule.It can also effective component the compounds of this invention is first and diluent, bonding
Particle or pellet is made in agent, disintegrating agent, then is placed in hard capsule or soft capsule.It is used to prepare each dilute of the compounds of this invention tablet
Release agent, binder, wetting agent, disintegrating agent, glidant kind can also be used for preparing the capsule of the compounds of this invention.
For injection is made in the compounds of this invention, water, ethyl alcohol, isopropanol, propylene glycol or their mixture can be used
Make solvent and appropriate solubilizer commonly used in the art, cosolvent, pH adjustment agent, osmotic pressure regulator is added.Solubilizer or hydrotropy
Agent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin etc.；PH adjust agent can be phosphate, acetate, hydrochloric acid,
Sodium hydroxide etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate etc..Such as prepare freeze-drying
Mannitol, glucose etc. can be also added as proppant in powder-injection.
In addition, if desired, colorant, preservative, fragrance, corrigent or other additions can also be added into pharmaceutical preparation
Agent.
To reach medication purpose, enhance therapeutic effect, drug of the invention or pharmaceutical composition well known can be given with any
The administration of prescription method.
The dosage of the compounds of this invention pharmaceutical composition is according to the property and serious journey to be prevented or be treated disease
The individual instances of degree, patient or animal, administration route and dosage form etc. can have large-scale variation.In general, of the present inventionization
The daily Suitable dosage ranges for closing object are 0.001-150 mg/Kg weight, and preferably 0.1-100 mg/Kg weight is more excellent
It is selected as 1-60 mg/Kg weight, most preferably 2-30 mg/Kg weight.Above-mentioned dosage with a dosage unit or can be divided into several
A dosage unit administration, this depends on the clinical experience of doctor and includes the dosage regimen with other treatment means.
The compound of the present invention or composition can individually be taken, or merge use with other treatment drug or symptomatic drugs.
When the compound of the present invention and other therapeutic agents, which exist, to act synergistically, its dosage should be adjusted according to the actual situation.
The above description of the embodiment is only used to help understand the method for the present invention and its core ideas.It should be pointed out that pair
For those skilled in the art, without departing from the principle of the present invention, the present invention can also be carried out
Some improvements and modifications, these improvements and modifications also fall within the scope of protection of the claims of the present invention.
Claims (6)
1. new Radix Codonopsis alkynol compound, it is characterised in that have structure shown in compound 1
1。
2. the preparation method of new Radix Codonopsis alkynol compound 1 as described in claim 1, which is characterized in that every preparation such as right is wanted
Seek the mg of compound 5 shown in 1 the following steps are included:
A. dry 5 kg of Radix Codonopsis is crushed, after impregnating 2 h with 40 L of distilled water, heating and refluxing extraction 3 times, every time 2 hours；
B. after water extract-alcohol precipitation, volatilization ethyl alcohol is to no alcohol taste, and AB-8 resin adsorption, after being washed with pure water, then with 30 %, 50 %,
Each 2 times of amount of resin elution of 70 %, 95 % ethyl alcohol, receives each section of eluent；
C. the % alcohol elution of 30 %, 50 %, 70 %, 95 is concentrated under reduced pressure and obtains 12 g of medicinal extract, 60 g, 100g respectively,
160g；
D. to 50 % alcohol elutions through 500 g, 200~300 mesh silica gel, column chromatography, CH2Cl2-MeOH ,100:1→
The isolated fraction Fr1-Fr10 of 1:1 gradient elution；
E. 50 fractions are obtained by methanol elution gradient 10 hours of middle 10-90 % of compression leg chromatography to 10g Fr 6,
500 mL are 1 part, to the 12nd fraction therein by preparation liquid phase separation, obtain a new Radix Codonopsis alkynol compound 1,
5mg。
3. application of the compound as shown in claim 1 in preparation prevention and/or treatment neurodegenerative disease drug.
4. the compound as shown in claim 1 according to claim 3 is in preparation prevention and/or treatment nervus retrogression disease
Application in medicine, which is characterized in that the neurodegenerative disease is cerebral apoplexy, in dementia, neuroinflamation, heavy metal
Poison, never poison poisoning.
5. the compound according to claim 4 as shown in claim 1 is in preparation prevention and/or treatment nervus retrogression disease
Application in medicine, which is characterized in that described dull-witted for alzheimer's disease, vascular dementia.
6. a kind of pharmaceutical composition, which is characterized in that containing acceptable in compound shown in claim 1 and pharmacodynamics
Carrier.
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| CN110272423A (en) * | 2019-07-12 | 2019-09-24 | 华北理工大学 | Four homocubane class compound of diaza, preparation method and applications |
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| CN110438079B (en) * | 2019-09-12 | 2021-01-19 | 深圳华大基因细胞科技有限责任公司 | Application of codonopsis pilosula glucoside I in-vitro improvement of killing activity of NK (Natural killer) cells |
| CN110438078B (en) * | 2019-09-12 | 2021-01-12 | 美亚宜彬生物科技(北京)有限公司 | Application of codonopsis pilosula alkynol in vitro promotion of NK cell proliferation and enhancement of killing activity of codonopsis pilosula alkynol |
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| CN103169696A (en) * | 2011-12-26 | 2013-06-26 | 中国医学科学院药物研究所 | Use of effective components of Clausena lansium for treating neurodegenerative diseases |
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