CN107445821A - Carbene acid derivative - Google Patents
Carbene acid derivative Download PDFInfo
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- CN107445821A CN107445821A CN201710682925.2A CN201710682925A CN107445821A CN 107445821 A CN107445821 A CN 107445821A CN 201710682925 A CN201710682925 A CN 201710682925A CN 107445821 A CN107445821 A CN 107445821A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/18—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon triple bonds as unsaturation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/36—Carboxylic acids; Salts or anhydrides thereof
- A61K8/361—Carboxylic acids having more than seven carbon atoms in an unbroken chain; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/47—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
Abstract
The invention belongs to pharmaceutical technology field, be related to it is a kind of separated from Thesium chinese to carbene acid derivative, and preparation method thereof, and the application in terms of the medicine of oral cavity common disease is prepared.
Description
Technical field
The invention belongs to pharmaceutical technology field, be related to it is a kind of separated from Thesium chinese to carbene acid derivative, and
Its preparation method, and the application in terms of the medicine of oral cavity common disease is prepared
Background technology
Thesium chinese is conventional Chinese herbal medicine, first recorded in Song《Bencao Tujing》, original record in《Chinese Pharmacopoeia》Version one in 1977,
For the drying herb of Santalaceae (Santalaceae) plant Thesium chinese.It is draft or shrub plant, using parasitic or semiparasite as it
Main biological property.The effect of with " clearing heat and detoxicating ", " clear and coherent gaseous pulse ", " regulating the qi flowing in the channels ", it is used for treating acute mastitis, lung
The symptom such as scorching, tonsillitis and lumbago due to the kidney deficiency, seminal emission, its nature and flavor gently, it is slight bitter, puckery, cold, be known as the U.S. of " bouvardin "
Claim.Do not refer to that it treats the activity of oral cavity common disease in document report at present.
Main component in Thesium chinese includes polysaccharide, glycoside, flavones, alkaloid, steroidal, organic acid etc., these chemistry into
Dividing has anti-inflammatory, anti-oxidant, the effect such as analgesia.Currently without Thesium chinense and its treatment oral cavity common disease periodontitis,
The report of dental caries isoreactivity composition.
The content of the invention
The present invention is intended to provide two kinds of new carbene acid derivatives.
Present invention also offers the preparation method of above-mentioned carbene acid derivative.
Another object of the present invention be by this carbene acid derivative be applied to treatment oral cavity common disease periodontitis,
The medicine of dental caries etc..
A kind of carbene acid derivative, there is the structure shown in formula I：
(formula I)
Wherein, R1For hydrogen, C1-C10 saturation or unsaturated alkyl；
R2For hydrogen, C1-C10 saturations or unsaturated alkyl group；Above hydrocarbyl group can be straight or branched.
R1Preferably 1- n-hexylenes base.R2Preferably hydrogen.N is preferably 6 or 7.
Described carbene acid derivative also includes above-mentioned all compounds and its pharmaceutically acceptable acid or alkali institute
The addition salts of formation.
Preferable carbene acid derivative structural formula is as shown in structural formula I, II, III.
Structural formula I
Structural formula II
Structural formula III
The invention provides the method that carbene acid derivative is separated from Thesium chinese, with Santalaceae Thesium Thesium chinese
For plant origin, through isolating and purifying to obtain.
Described plant origin includes Santalaceae (Santalaceae) Thesium (Thesium) plant Thesium chinese
(Thesium chinense Turcz) or congener (Genus Thesium) herb.
Its specific preparation process is：
(1) using Thesium chinese as raw material, extract solution is obtained using solvent extraction method；Solvent used is preferably water, alcohol or appointed
Meaning compares water-alcohol mixture；Alcohol is C1-C5 saturation or unsaturated monohydric alcohol；Extracting method is preferably heating and refluxing extraction, ultrasound
Extraction, cold soaking are extracted, temperature extraction takes, permeating extraction；
(2) after being extracted with solvent extraction, organic phase is discarded, obtains aqueous phase；Solvent for use is preferably petroleum ether (30-90
DEG C), hexamethylene, n-hexane, chloroform, dichloromethane, ethyl acetate；
Eluted by products therefrom by column chromatography and with solvent, be concentrated under reduced pressure recycling design, obtains total carbene acids class and spreads out
It is raw；Solvent for use is selected from C1-C10 alkyl halide, C1-C10 saturation or unsaturated alcohol, C1-C10 ketone, C1-C10 esters or it is mixed
Compound, wherein alkyl halide have below general formula：CnH2n+1R、CnH2nR2、CnH2n-1R3(n ＜ 10；R=Cl, Br, I), alcohols solvent
With below general formula：CnH2n+1OH or CnH2n-1OH (n ＜ 10), ketones solvent has below general formula：CnH2nO or CnH2n-2O (n ＜
10), esters solvent has below general formula：CnH2nO2Or CnH2n-2O2(n ＜ 10), and above solvent and water, formic acid, times of acetic acid
The mixed solvent of meaning ratio.Column chromatography solvent type of elution includes single or mixed solvent positive, anti-phase or gradient elution；Post
Chromatographic stuffing is the one or more of following kind：Silica gel, diatomite, aluminum oxide, polymeric adsorbent, sephadex or ODS.
Preferred preparation method is：
(1) extract：Using sandalwood plants Thesium chinese as raw material, after crushing, it is heated to reflux with 95% ethanol (4-5 liters/kg)
Extraction 4 hours, extraction 2-6 times is repeated, filters and merges extract solution, ethanol is recovered under reduced pressure, obtained medicinal extract is suspended in water.
(2) it is enriched with：It is closely colourless to petroleum ether layer with (60-90 DEG C) extraction of petroleum ether, discard petroleum ether layer；Water layer is used again
Water saturated ethyl acetate extraction, it is closely colourless to ethyl acetate layer；Ethyl acetate layer is recovered under reduced pressure, obtains ethyl acetate extract.
It is successively (100 with petroleum ether-ethyl acetate system, volume ratio by silica gel column chromatography:1)、(50:1)、(20:1)、(10:
1)、(5:1)、(2:1)、(1:1)、(0:1) elute, collect (5:1) (1 is arrived:1) eluent, solvent is recovered under reduced pressure, obtains medicinal extract.
By ODS reversed phase column chromatographies, eluted respectively with 30%-90% methanol, collect 60%-80% meoh eluates, be recovered under reduced pressure molten
Agent, obtain total carbene acids position.
(3) purify：Above-mentioned total carbene acids position, is separated by gel filtration chromatography, is eluted with methanol, Fractional Collections is thin
Layer chromatography inspects (methylene chloride-methanol system, methylene chloride-methanol 10:1), (254nm), vanillic aldehyde sulphur under ultraviolet lamp
Sour test solution is inspected, and merges the identical cut of spot；Again through the reverse column chromatographies of ODS, 30%-100% methanol elution gradients, Fractional Collections
Cut, thin-layered chromatography inspect (methylene chloride-methanol system, methylene chloride-methanol 10:1), ultraviolet lamp (254nm), vanilla
The colour developing of aldehyde sulfuric acid test solution is inspected, and merges the identical cut of spot, with prepare liquid phase LC3000 (acetonitrile-water, 7:3-9:1；Flow velocity,
3mL/min；Detection wavelength, 254nm；Pressure 3-10bar；Temperature, room temperature), obtain thesine A, thesine C.It is thin with preparing
Layer chromatography (dichloromethane-acetone system, methylene chloride-methanol 10:1) thesine B, is obtained.
Gained carbene acid derivative can be used for treatment oral cavity common disease (such as：Periodontitis, dental caries etc.) medicine,
Pharmaceutical dosage form can be the toothpaste, mouthwash, buccal tablet being administered orally.
The present invention is on the basis of isolated carbene acid derivative, it was confirmed that this common disease in compounds for treating oral cavity
Disease (such as：Periodontitis, dental caries etc.) activity.
The present invention provides lead compound for exploitation treatment oral cavity common disease, to developing natural products and autonomic drug
New application is significant.
Brief description of the drawings
Fig. 1 is thesine A (1), B (2), C (3) main 2D NMR dependency structure schematic diagrames, and wherein thick line is
COSY；Solid line is related：HMBC.
Fig. 2 is thesine A (1), B (2), C (3) chemical structural formula
Embodiment
Embodiment 1
Thesium chinese herb 6Kg is taken, 95% ethanol heating and refluxing extractions of 30L are added after crushing 5 hours, is repeated 4 times, filters
And merge extract solution, medicinal extract is suspended in water after ethanol is recovered under reduced pressure.
Suspension is repeatedly extracted with petroleum ether (60-90 DEG C), it is closely colourless to petroleum ether layer, discard petroleum ether layer；Water layer is again
Extracted with water saturated ethyl acetate, it is closely colourless to ethyl acetate layer；Ethyl acetate layer is recovered under reduced pressure, obtains ethyl acetate portion
Position.It is successively (100 with petroleum ether-ethyl acetate system, volume ratio by silica gel column chromatography:1)、(50:1)、(20:1)、
(10:1)、(5:1)、(2:1)、(1:1)、(0:1) elute, collect (5:1) (1 is arrived:1) eluent, solvent is recovered under reduced pressure, is soaked
Cream.By ODS reversed phase column chromatographies, with 30%-90% methanol elution gradients (10 hours).60%-80% meoh eluates are collected,
Solvent is recovered under reduced pressure, obtains total carbene acid derivative.
Above-mentioned total carbene acids position, is separated by gel filtration chromatography, is eluted with methanol, Fractional Collections, thin-layered chromatography
Inspect (methylene chloride-methanol system, methylene chloride-methanol 10:1), (254nm), the inspection of vanillin-sulfuric acid test solution under ultraviolet lamp
Depending on merging the identical cut of spot；
Inspected again through the reverse column chromatographies of ODS, 30%-100% methanol elution gradients, Fractional Collections flow point, thin-layered chromatography
(methylene chloride-methanol system, methylene chloride-methanol 10:1), ultraviolet lamp (254nm), the colour developing of vanillin-sulfuric acid test solution are inspected,
Merge the identical cut of spot, with prepare liquid phase LC3000 (acetonitrile-water, 7:3-9:1；Flow velocity, 3mL/min；Detection wavelength,
254nm；Pressure 3-10bar；Temperature, room temperature), obtain thesine A, thesine C.With preparing thin-layer chromatography (dichloromethane-the third
Ketone system, methylene chloride-methanol 10:1) thesine B, is obtained.
By embodiment 1, isolated thesine (carbene acid compounds) A, B and C-structure are for example attached from Thesium chinese
Shown in Fig. 2, wherein 1 is thesine A [(12E)-Heptadec-12-en-8,10-diynoic acid], 2 be thesine B
(Dodec-9,11-diynoic acid), 3 be thesine C (Exocarpic acid), and its spectroscopic data is：
Thesine A [(12E)-Heptadec-12-en-8,10-diynoic acid] is white amorphous powder, high
The accurate mass number that Resolution Mass Spectrometry obtains the compound is 259.1688, and it is C to calculate its molecular formula18H25O2[M-H]-.Infrared spectrum,
υmax 2931,2859,2250,1708,1461,1436,1411,1251,1209,1085,956,728cm-1；Fig. 1 is Thesium chinese
The 2D NMR dependency structure schematic diagrames of plain A (1), wherein thick line are COSY；
Solid line is related：HMBC.
Thesine B (Dodec-9,11-diynoic acid) is white amorphous powder, and high resolution mass spectrum obtains the chemical combination
The accurate mass number of thing is 191.1065, and it is C to calculate its molecular formula12H15O2[M-H]-.Infrared spectrum, υmax2929,2856,
2364,2223,1706,1461,1411,1282,1247,1207,1130,1079,941,727cm-1；Fig. 1 is thesine B
(2) 2D NMR dependency structure schematic diagrames, wherein thick line are COSY；Solid line is related：HMBC.
Thesine C (Exocarpic acid) is white amorphous powder, and high resolution mass spectrum obtains the accurate of the compound
Mass number is 273.1843, and it is C to calculate its molecular formula18H25O2[M-H]-.Infrared spectrum, υmax 2931,2857,2235,1708,
1463,1411,1376,1280,1245,1207,1130,1085,954,727cm-1；Fig. 1 is thesine C (3) 2D NMR
Dependency structure schematic diagram, wherein thick line are COSY；Solid line is related：HMBC.
Three above compound1H NMR and13C NMR datas are shown in Table 1.
Table 1. thesine A (1), B (2), C (3)1H NMR (400HZ) and13C NMR (100MHZ) data
Embodiment 2
Detect the gained Thesium chinese ethanol extract (EtOH extract) of embodiment 1, and extraction gained oil ether moiety
(PE fraction), ethyl acetate portion (EtOAc fraction) is to periodontitis pathogenic bacteria Porphyromonas
Gingivalis influence, as a result shows, ethanol extract and ethyl acetate portion have certain suppression periodontitis pathogenic bacteria
Porphyromonas gingivalis activity.
200mg/mL mother liquor is made into DMSO according to the quality of medicine, finds to can dissolve after vibration, no precipitation.From
The μ g/mL of the drug toxicity upper limit 1000 start dilution detection.Start three samples set concentration for 1000 respectively, 500,200,100,
50 μ g/mL, Porphyromonas gingivalis initial concentrations are 10^7/mL, co-culture 48h, visually see that each group bacterium gives birth to
Long situation.It is repeated 2 times.The medicine without bacteriostasis is excluded, remaining medicine successively decreases according to 2 times of dilutions of concentration, detects various medicines
The MIC of thing, the results are shown in Table 2.
The Thesium chinese ethanol extract of table 2, oil ether moiety, the bacteriostasis (MIC of ethyl acetate portion:μg/mL)
Embodiment 3
The three carbene acrylic components of gained of embodiment 1 are detected to periodontosis pathogenic bacteria (Porphyromonas
Gingivalis, Fusobacterium nucleatum) influence, as a result show that carbene acid derivative can suppress periodontal
The growth of sick pathogenic bacteria (Porphyromonas gingivalis, Fusobacterium nucleatum).Simultaneously for hGFs
There is no cytotoxicity.Illustrate that such compound has bacteriostasis and preferable security.
10mM mother liquor is made into DMSO according to the quality of medicine, molecular weight, finds to can dissolve after vibration, without heavy
Form sediment.Doubling dilution detects since 200 μM of the drug toxicity upper limit.It is 200,100,50 μM to start 3 kinds of medicines to set concentration respectively,
Porphyromonas gingivalis initial concentrations are 10^7/mL, and Fusobacterium nucleatum initial concentrations are 10
^5/mL, 48h is co-cultured, visually sees each group bacterial growth situation.It is repeated 2 times.Exclude the medicine without bacteriostasis, remaining medicine
Successively decrease according to 2 times of dilutions of concentration, detect the MIC of various medicines, the results are shown in Table 3.
Embodiment 4
Detect shadow of the three carbene acrylic components of gained of embodiment 1 to dental caries pathogenic bacteria (Streptococcus mutans)
Ring, as a result show that carbene acid derivative can suppress dental caries pathogenic bacteria (Streptococcus mutans) growth.
10mM mother liquor is made into DMSO according to the quality of medicine, molecular weight, finds to can dissolve after vibration, without heavy
Form sediment.Doubling dilution detects since 200 μM of the drug toxicity upper limit.It is 200,100,50 μM to start 3 kinds of medicines to set concentration respectively,
Streptococcus mutans initial concentrations are 10^5/mL, co-culture 48h, visually see each group bacterial growth situation.Repeat 2
It is secondary.The medicine without bacteriostasis is excluded, remaining medicine successively decreases according to 2 times of dilutions of concentration, detects that the MIC of various medicines (μM is changed
It is counted as μ g/mL), it the results are shown in Table 3.
The thesine A (1) of table 3, B (2), C (3) bacteriostasis (MIC:μg/mL)
Pg：Porphyromonas gingivalis
Fn：Fusobacterium nucleatum
Sm：Streptococcus mutans
Embodiment 5
Carbene acid compounds xestospongic acid methyl ester beyond detection embodiment 1 cause a disease to periodontosis
The influence of bacterium (Porphyromonas gingivalis, Fusobacterium nucleatum), as a result do not find that it suppresses tooth
The growth of all sick pathogenic bacteria (Porphyromonas gingivalis, Fusobacterium nucleatum).
10mM mother liquor is made into DMSO according to the quality of medicine, molecular weight, finds to can dissolve after vibration, without heavy
Form sediment.Doubling dilution detects since 200 μM of the drug toxicity upper limit.It is 200,100,50 μM to start 3 kinds of medicines to set concentration respectively,
Porphyromonas gingivalis initial concentrations are 10^7/mL, and Fusobacterium nucleatum initial concentrations are 10
^5/mL, 48h is co-cultured, visually sees each group bacterial growth situation.It is repeated 2 times.Exclude the medicine without bacteriostasis, remaining medicine
Successively decrease according to 2 times of dilutions of concentration, detect the MIC of various medicines, the results are shown in Table 4.
Embodiment 6
The carbene acid compounds xestospongic acid methyl ester (4) beyond embodiment 1 are detected to dental caries
The influence of pathogenic bacteria (Streptococcus mutans), as a result do not find that it can suppress dental caries pathogenic bacteria
The growth of (Streptococcus mutans).
10mM mother liquor is made into DMSO according to the quality of medicine, molecular weight, finds to can dissolve after vibration, without heavy
Form sediment.Doubling dilution detects since 200 μM of the drug toxicity upper limit.It is 200,100,50 μM to start 3 kinds of medicines to set concentration respectively,
Streptococcus mutans initial concentrations are 10^5/mL, co-culture 48h, visually see each group bacterial growth situation.Repeat 2
It is secondary.The medicine without bacteriostasis is excluded, remaining medicine successively decreases according to 2 times of dilutions of concentration, detects the MIC of various medicines, as a result
It is shown in Table 4.
Table 4xestospongic acid methyl ester (4) bacteriostasis (MIC:μg/mL)
Embodiment 6
Thesine A mouthwashes
Thesine A 100g sodium chloride for injection 7g
Preparation technology：Take thesine A to cross 100 mesh sieves, add appropriate water for injection to dissolve, add appropriate 3%CMCNa solution,
Sodium chloride for injection is added to isotonic, regulation pH value to 7, filtration, refrigerates 24 hours, injects water to ormal weight, is filtered, is filled
Envelope, sterilizing, is produced.
Thesine B mouthwashes
Thesine B 100g sodium chloride for injection 7g
Preparation technology：Take thesine B to cross 100 mesh sieves, add appropriate water for injection to dissolve, add appropriate 3%CMCNa solution,
Sodium chloride for injection is added to isotonic, regulation pH value to 7, filtration, refrigerates 24 hours, injects water to ormal weight, is filtered, is filled
Envelope, sterilizing, is produced.
Thesine C mouthwashes
Thesine C 100g sodium chloride for injection 7g
Preparation technology：Take thesine C to cross 100 mesh sieves, add appropriate water for injection to dissolve, add appropriate 3%CMCNa solution,
Sodium chloride for injection is added to isotonic, regulation pH value to 7, filtration, refrigerates 24 hours, injects water to ormal weight, is filtered, is filled
Envelope, sterilizing, is produced.
Thesine A buccal tablets
Thesine A 10g mannoses 84g
The hydroxypropyl cellulose aqueous solution 50g of citric acid 2g 5%
Magnesium stearate 2g
Preparation technology：Thesine A, lactose cross 100 mesh sieves respectively, are mixed by equal increments method, citric acid is dissolved in into 4% hydroxypropyl
Base cellulose aqueous solution makees adhesive, softwood processed, pelletizes, and dries, and adds magnesium stearate, tabletting, produces.
Thesine B buccal tablets
Thesine B 10g mannoses 84g
The hydroxypropyl cellulose aqueous solution 50g of citric acid 2g 4%
Magnesium stearate 2g
Preparation technology：Take thesine B, mannose to cross 100 mesh sieves respectively, mixed by equal increments method, citric acid is dissolved in 4%
Hydroxypropyl cellulose aqueous solution makees adhesive, softwood processed, pelletizes, and dries, and adds magnesium stearate, tabletting, produces.
Thesine C buccal tablets
Thesine C 10g mannoses 84g
The hydroxypropyl cellulose aqueous solution 50g of citric acid 2g 5%
Magnesium stearate 2g
Preparation technology：Take thesine C, mannose to cross 100 mesh sieves respectively, mixed by equal increments method, citric acid is dissolved in 5%
Hydroxypropyl cellulose aqueous solution makees adhesive, softwood processed, pelletizes, and dries, and adds magnesium stearate, tabletting, produces.
Thesine A toothpaste
Take xylitol 5, FOS 5, thesine A 0.5, glycerine 5, saccharin sodium 0.22, sodium benzoate 0.25, the burnt phosphorus of crystallization
Sour sodium 0.5, flavoring orange essence 0.8, HPMC 1.5, silica 18, laruyl alcohol sodium sulfovinate 1.8, unit (gram),
Appropriate amount of water.
Thesine B toothpaste
Take xylitol 5, FOS 5, thesine B0.5, glycerine 5, saccharin sodium 0.22, sodium benzoate 0.25, crystallization pyrophosphoric acid
Sodium 0.5, flavoring orange essence 0.8, HPMC 1.8, silica 18, laruyl alcohol sodium sulfovinate 1.8, unit (gram), water
In right amount.
Thesine C toothpaste
Take xylitol 5, FOS 5, thesine C0.5, glycerine 5, saccharin sodium 0.22, sodium benzoate 0.25, crystallization pyrophosphoric acid
Sodium 0.5, flavoring orange essence 0.8, HPMC 1.5, silica 18, laruyl alcohol sodium sulfovinate 1.8, unit (gram), water
In right amount.
(1) xylitol, thesine A, FOS and sodium salt are added to the water and are stirred into aqueous phase；
(2) glycerine is added into aqueous phase, stirs 5min~10min, obtain uniform liquid phase；
(3) silica, HPMC are stirred into powder, it is standby；
(4) liquid phase, powder are added into Manufacturing medicine extract machine, vacuum degree control is more than -0.92Mpa, and water-bath temperature control is in 42 DEG C of bars
20min~30min is quickly stirred under part；
(5) add laruyl alcohol sodium sulfovinate, flavoring orange essence, vacuum degree control more than -0.94Mpa quickly stirring 15min~
20min, under vacuum, scraper velocity control stir 8min~10min in 30r/min~50r/min；Vacuum degree control-
More than 0.96Mpa is persistently vacuumized 15 minutes, filling.
The present invention provides lead compound for exploitation treatment oral cavity common disease, to developing natural products and autonomic drug
New application is significant.
Claims (10)
1. a kind of carbene acid derivative, it is characterised in that structural formula is as shown in formula I：
R in formula1For hydrogen, C1-C10 saturation or unsaturated alkyl；R2 is hydrogen, C1-C5 saturations or unsaturated alkyl；N=1-
10；Above-mentioned saturation or unsaturated alkyl are straight or branched.
2. the carbene acid derivative described in claim 1, it is characterised in that
Structural formula for example structural formula I, II, III it is any shown in,
3. the carbene acid derivative described in claim 1, it is characterised in that be pharmaceutically subjected to including generalformulaⅰcompound
Acid, or alkali formed addition salts.
4. the preparation method of the carbene acid derivative described in claim 1, it is characterised in that with Santalaceae Thesium plant
Thesium chinese is plant origin, through isolating and purifying to obtain.
5. the preparation method of the carbene acid derivative described in claim 4, it is characterised in that described plant origin includes wingceltis
Fragrant section's Thesium plant Thesium chinese or the herb of congener.
6. the preparation method of the carbene acid derivative described in claim 4, it is characterised in that comprise the following steps：
(1) using Chinese herbal medicine Thesium chinese as raw material, using solvent extraction method, extract solution is obtained；Solvent used is water, alcohol or appointed
Meaning compares water-alcohol mixture；Alcohol is C1-C5 saturation or unsaturated monohydric alcohol；Extracting method includes heating and refluxing extraction, ultrasound carries
Take, cold soaking extracts, temperature extraction takes or permeating extraction；
(2) after being extracted with solvent extraction, organic phase is discarded, obtains aqueous phase；Solvent for use be petroleum ether, hexamethylene, n-hexane,
Chloroform, dichloromethane or ethyl acetate；
(3) eluted by products therefrom by column chromatography and with solvent, be concentrated under reduced pressure recycling design, obtains total carbene acids and derives
Thing；Solvent for use is selected from C1-C10 halogenated hydrocarbons, C1-C10 saturation or unsaturated alcohol, C1-C10 ketone, C1-C10 esters or it is mixed
Compound, and above solvent and water, formic acid, acetic acid arbitrary proportion mixed solvent；Wherein halogenated hydrocarbons formula is CnH2n+1R、
CnH2nR2Or CnH2n-1R3, n ＜ 10, R=Cl, Br or I；Alcohols solvent formula is CnH2n+1OH or CnH2n-1OH, n ＜ 10；Ketone is molten
Agent formula is CnH2nO or CnH2n-2O, n ＜ 10；Esters solvent formula is CnH2nO2Or CnH2n-2O2；Column chromatography solvent type of elution
Including single or mixed solvent positive, anti-phase or gradient elution；Column chromatography filler is the one or more of following kind：Silica gel,
Diatomite, aluminum oxide, polymeric adsorbent, sephadex or ODS reverse phase fillers.
7. the preparation method of the carbene acid derivative described in claim 6, it is characterised in that will be total obtained by step (3)
Carbene acid derivative is separated by gel filtration chromatography, is eluted with methanol, and thin-layered chromatography inspects carbene acid derivative,
Being detected with UV detector under 254nm has absorption；With the aobvious blueness of vanillin-sulfuric acid test solution, Fractional Collections；Again by gel point
From position, eluted with the reverse column chromatographies of ODS, thin-layered chromatography is inspected, until obtaining sterling.
8. a kind of pharmaceutical composition, it is active component comprising at least one claim 1 or 2 carbene acid derivative, it is single
Only or combination one or more of pharmaceutically acceptable, inert, nontoxic excipient or carrier.
9. the carbene acid derivative of claim 1 or 2 includes inflammation of upper respiratory tract, oral cavity periodontitis, dental caries in preparation treatment
Purposes in terms of the medicines such as tooth disease.
10. the carbene acid derivative of claim 1 or 2 is preparing the purposes of toothpaste, mouthwash, buccal tablet.
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| CN111024881A (en) * | 2020-01-08 | 2020-04-17 | 河北中医学院 | Rapid double-information thin-layer identification method for thesium Chinese medicinal materials, granules and target decoction dry powder |
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